Cimetidine Anti Cancer Drug, Reverses Tumor Immunity

Cimetidine (Tagamet), an H2 Histamine Receptor Blocker,  was FDA approved in 1979  and marketed as antacid drug for treatment of gastritis, and gastric ulcer.  Cimetidine binds to the H2 receptors in parietal cells in the gastric wall, thus inhibiting gastric acid secretion.  In its day, Cimetidine (Tagemet) was the number one top selling drug.  Cimetidine is still available as an over-the counter drug, having been replaced by the newer class of antacids, proton pump inhibitors.    In the 1980’s, clinicians observed remarkable cancer regression in patients on Cimetidine.  For example, in 1987, Dr Strauchen reported two cases of spontaneous regression of gastric lymphoma while on Cimetidine.(1)  A large volume of medical research through the 1980’s and 90’s investigated the various anti-cancer mechanisms of Cimetidine seeming to involve the drug’s ability to reverse immune tumor evasion, block immunosuppressive effects of histamine, and stimulate host immune cell expansion. Above Left Image: Killer T Cells Surround a Cancer Cell Courtesy of Wikimedia Commons.

Cimetidine – Reversing Immunosuppression of Histamine

In 2019 Dr Jafarzadeh reported on the “Immunomodulatory properties of cimetidine: and potential therapeutic potentials for immune-related diseases.(10)  He says:

“Through binding to histamine receptor 2 (H2R). Cimetidine, as an H2R antagonist, reverses the histamine-mediated immunosuppression, as it has powerful stimulatory effects on the effector functions of neutrophils, monocytes, macrophages, DCs, NK cells, NKT cells, Th1-, Th2-, Th17-, and CD8+ cytotoxic T cells…..The therapeutic potentials of cimetidine as an immunomodulatory agent (extends to) a number of human diseases such as cancers, viral warts, allergic disorders, burns, etc.”(10)

Cimetidine Induced IL-18 Production in Monocytes

In 2006, the breakthrough was made by Dr  Takahashi who found that Cimetidine induces IL-18 production  in monocytes.(2)  Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity . (3)   In 2013, Dr Robertson conducted a study in 19 patients using recombinant IL-18 combined with Rituximab for NHL (non-Hodgkeins Lymphoma). (3) Rituximab  is an anti-CD-20 antibody routinely used for B-cell lymphoma. Of 19 patients in the study, there were 2 complete and 3 partial responses.(3)

CAR T Cells Engineered to Secrete IL-18

The use of IL-18 in next generation CAR-T cells highlights its importance in cancer therapy.(4-6) Three studies investigate CAR T Cells Bio-Engineered to secrete IL-18. (Note: CAR T cells are Chimeric Antigen Receptor T Cells)

In 2017, Dr Hu used a melanoma mouse model to study CAR T Cells bio-engineered to secrete IL-18, finding  “augmented anti-tumor immunity”. (6)  Dr Hu said:

“In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. ” (6)

Another melanoma study in mice in 2018 by Dr Kunert, who summarized: (5)

“Transfer of T cells expressing a melanoma specific-TCR (T cell receptor)  and inducible iIL-18 (into mice) was without side effects, enhanced the presence of therapeutic CD8+ T cells within tumors, reduced tumor burden and prolonged survival….treatment with T cells engineered with a TCR and iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response.”(5)

A third study in 2018 by Dr Chmielewski  showed the “release of IL-18 by CAR T cells pro-motes Th1 effector functions and recruitment of innate immune cells resulting in enhanced eradication of solid tumors.“(4)

Immunomodulatory Effects of IL-18

56-Fold Expansion of Anti-Tumor NK Killer Cells

Now that we have your attention, let’s explore cell biology mechanisms of IL-18.  Dr Senju in 2018 studied the effect of IL12 and IL18 on expansion of Human Natural Killer Cells (NK Cells).  These are the immune cells that kill cancer cells in the body. When IL-12, followed by IL-18 was added to the NK cell suspension, by Day 4 NK cells proliferated vigorously, and by Day 10, there was a 56-fold expansion of NK cells. “IL-18 promoted the expansion of NK cells“(7)

IL-12/IL-18 Preactivated Donor NK cells

In 2018 Dr Song  studied IL-12/IL-18 preactivated donor NK cells in a murine model of B cell lymphoma.(8)   Dr Song found:

“IL‐12/18 preactivated NK cells mediated stronger GVL (Graft vs. Lymphoma) effect than control NK cells mainly due to their elevated activation/cytotoxicity and sustained proliferative potential.  The IL‐12/18 preactivated NK cells mitigate aGVHD (Acute Graft vs. Host) despite the severity of the disease. IL‐12/18‐preactivated donor NK cell infusion may be an effective and safe adoptive therapy after allo‐HSCT (Hematopoetic Stem Cell Transplant, a common treatment for hematologic malignancy).(8)

In 2017, Dr Esmailbeig reported on IL-18 cytokine as regulator of cancer and auto-immune disease, most importantly, tumor immunity with the activation of Cytotoxic T Cells (CTLs) and natural Killer (NK) Cells.(9)  Dr Esmailbeig says:

“The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi….IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-γ and, therefore, may contribute to tumor immunity”(9)

2014 Review

In  2014, Dr Pantziarka reviews the Anti-Cancer Effects of Cimetidine with identification of four mechanisms.(11)

1) Anti-Proliferative

Oral cimetidine blocked histamine stimulated growth of colon cancer cells in a mouse model.

2) Immunomodulatory Effects

As discussed above, Dr P says:

“histamine is associated with an immunosuppressive tumour microenvironment (TME),  including increased regulatory T cell (Treg) activity, reduced antigen-presenting activity of dendritic cells (DC), reduced NK-cell activity and increased myeloid-derived suppressor cell (MDSC) activity”. …histamine binding to the H₂ receptor is associated with suppression of IL-12 and stimulation of IL-10 secretion and is implicated with a shift in Th1/Th2 balance toward Th2-dominance of the immune response. This effect was reversed by CIM (Cimetidine) in human PBMC (oeripheral blood monocytes).(11)…MDSCs (myeloid-derived suppressor cell express) H₁–H₃ receptors, and there is in vitro and in vivo evidence that blockade of H₁ (using the H₁RA cetirizine) or H₂ (using CIM), can reverse the immunosuppressive action of these cells…An increase in NK (Natural Killer Cell) activity compared to non-CIM-treated controls has also been noted in cardiopulmonary bypass surgery.

3) Effects on Cell Adhesion

By down-regulating and inhibiting tumor cell adhesion, CIM prevents metastatic spread of tumor cells.

“In a nude mouse model, CIM dose-dependently reduced the incidence of HT-29 liver metastases, suppressing it completely at the highest dose (200 mg/kg/day) [83]. The effect on cell adhesion was mediated by the interaction between tumour sialyl Lewis antigens and E-selectin expressed on the endothelium.”(11)

4) Anti-Angiogenic Action

Production of VEGF which leads to angiogeneisis (new vessels) is mediated by histamine.  The upregulation of VEGF induced by histamine is reversed by Cimetadine. (11) This blocks gowrth of tumor microvascularity needed to support the enlarging tumor mass.

Many of these same points were discussed by Dr Kubecova in her 2011 Review of Cimetidine as an Anti-Cancer Drug .(12)

Cimetidine for Cutaneous Warts (HPV)

Left Image: Plantar Warts in Pediatric Heart Transplant Patient Courtesy of  (Das et al. 2018) (33)

Cimetidine was found effective in restoring immune response and clearing refractory HPV induced cutaneous warts in children who were immuno-suppressed after heart transplant.(33) 7 of 8 patients had complete resolution of their warts after 3-6 months of cimetidine.  The authors state:

“Cimetidine is postulated to act as an immunomodulatory agent at high doses by inhibiting suppressor T-cell function [15]. The paradigm between T helper (Th) 2 cells, and Th1 cells predominance is reflected in the level of cytokines that are released. Cimetidine activates Th1 cells to produce interleukin (IL)-2, IL-12, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and their expression correlates with improvement in cellular immunity and wart remission [16,17]. Patients who received cimetidine were shown to exhibit enhanced cell-mediated immunity, restoration of sensitivity following development of acquired tolerance, and increased response of lymphocytes to mitogen stimulation [18].”(33)

A 2003 study of Cimetidine for viral warts by Mitsuishi in 34) Eur J Dermatol enhances IL-2 and IFN-gamma expression in punch biopsy specimens of the warts after cimetidine treatment. (34)   The authors state:

“cimetidine activates Th1 cells to produce IL-2 and IFN-c and that their expression correlates with wart remission.” (34)

Cimetidine for Painful Bladder Syndrome (IC Intestitial Cystitis)

Interstitial Cystitis/Painful Bladder syndrome in women is a poorly understood medical condition.   The etiology and treatment has not been determined.  One medical hypothesis is the condition is caused by occult infection accompanied by a defect or suppression of the immune system.  If this is true, then up-regulating the immune system with a drug such as Cimetidine might be expected to help.    Indeed, a number of studies suggest Cimetidine provides symptom relief in Women with  Interstitial Cystitis/ Painful Bladder.(42-44)

Adverse Side Effects of Cimetidine

“CIM has low toxicity, with the most common side effects being headache, dizziness, diarrhoea, and rash. Rare side effects include gynaecomastia, reversible impotence (particularly reported in patients receiving very high doses, for example, in the treatment of Zollinger-Ellison Syndrome) and, very rarely, galactorrhoea….. Rarely, CIM has also been associated with reversible leukopenia and thrombocytopenia, effects that may be particularly important to watch for in cancer patients who may be undergoing chemotherapy….CIM is an inhibitor of cytochrome P450, through multiple enzymes (including CYP1A2, CYP2D6, and CYP3A, CYP3A3/A4, CYP”.(11)

Conclusion: Cimetidine as an anti-histamine and immuno-modulotory drug has significant role as anti-cancer agent.  Cimetidine’s ability to reverse tumor induced immunity and restore host cancer killing cellular immunity is remarkable.

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Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792-4663

References:

cimetidine for gastric large cell lymphoma

1) Cancer. 1987 Oct 15;60(8):1872-5. Spontaneous regression of gastric lymphoma. Strauchen JA1, Moran C, Goldsmith M, Greenberg M.

Two cases of spontaneous regression of histologically diagnosed large cell lymphoma of the stomach are reported. Regressions occurred after nonspecific therapy including the H-2 antagonist cimetidine and were documented surgically. Spontaneous regression of intermediate and high-grade non-Hodgkin’s lymphoma is distinctly uncommon. The possible role of cimetidine in these cases is discussed.

2) Takahashi, Hideo Kohka, et al. “Cimetidine induces interleukin-18 production through H2-agonist activity in monocytes.” Molecular pharmacology 70.2 (2006): 450-453.

The present study demonstrates a possible mechanism for the improvement of gastrointestinal cancer patients’ prognosis by the histamine receptor type 2 (H2R) antagonist cimetidine. This agent, but not the H2R antagonists ranitidine and famotidine, induced the production of an antitumor cytokine, interleukin (IL)-18, by human monocytes and dendritic cells (DC). In fact, ranitidine and famotidine antagonized cimetidine-induced IL-18 production. Cimetidine induced the activation of caspase-1, which is reported to modify immature IL-18 to mature/active IL-18, and the elevation of intracellular cAMP, leading to the activation of protein kinase A (PKA). The PKA inhibitor H89 abolished the IL-18 production induced by cimetidine. Moreover, the effects of cimetidine on IL-18 production were reproduced in peripheral blood mononuclear cells from wild-type mice, but not in those from H2R knockout mice. In conclusion, cimetidine, a partial agonist for H2R, has a pharmacological profile different from ranitidine and famotidine, possibly contributing to its antitumor activity on gastrointestinal cancers.

3) Robertson, Michael J., et al. “A dose-escalation study of recombinant human interleukin-18 in combination with rituximab in patients with non-Hodgkin’s lymphoma.” Journal of immunotherapy (Hagerstown, Md.: 1997) 36.6 (2013): 331.

Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical models. Rituximab is a CD20 monoclonal antibody with activity against human B cell lymphomas. A phase I study of recombinant human (rh) IL-18 given with rituximab was performed in patients with CD20+ lymphoma. Cohorts of 3–4 patients were given infusions of rituximab 375 mg/m2 weekly for 4 weeks with escalating doses of rhIL-18 as a 2-hour intravenous infusion weekly for 12 consecutive weeks. Toxicities were graded using standard criteria. Blood samples were obtained for safety, pharmacokinetic, and pharmacodynamic studies. Nineteen patients with CD20+ B cell non-Hodgkin’s lymphoma were given rituximab in combination with rhIL-18 at doses of 1, 3, 10, 20, 30, and 100 μg/kg. Common side effects included chills, fever, headache, and nausea. Common laboratory abnormalities included transient, asymptomatic lymphopenia, hyperglycemia, anemia, hypoalbuminemia, and bilirubin and liver enzyme elevations. No dose-limiting toxicities were observed. Biologic effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes. Increases in serum concentrations of IFN-γ, GM-CSF, and chemokines were observed following dosing. Objective tumor responses were seen in 5 patients, including 2 complete and 3 partial responses. rhIL-18 can be given in biologically active doses by weekly infusions in combination with rituximab to patients with lymphoma. A maximum tolerated dose of rhIL-18 plus rituximab was not determined. Further studies of rhIL-18 and CD20 monoclonal antibodies in B cell malignancies are warranted.

4) Chmielewski, Markus, and Hinrich Abken. “TRUCKs with IL‐18 payload: Toward shaping the immune landscape for a more efficacious CAR T‐cell therapy of solid cancer.” Advances in Cell and Gene Therapy 1.1 (2018): e7.

The present review sum-marizes data showing that the release of IL-18 by CAR T cells pro-motes Th1 effector functions and recruitment of innate immune cells resulting in enhanced eradication of solid tumors.

5) Kunert, Andre, et al. “Intra-tumoral production of IL18, but not IL12, by TCR-engineered T cells is non-toxic and counteracts immune evasion of solid tumors.” Oncoimmunology 7.1 (2018): e1378842.

Adoptive therapy with engineered T cells shows promising results in treating patients with malignant disease, but is challenged by incomplete responses and tumor recurrences. Here, we aimed to direct the tumor microenvironment in favor of a successful immune response by local secretion of interleukin (IL-) 12 and IL-18 by sadministered T cells. To this end, we engineered T cells with a melanoma-specific T cell receptor (TCR) and murine IL-12 and/or IL-18 under the control of a nuclear-factor of activated T-cell (NFAT)-sensitive promoter. These T cells produced IL-12 or IL-18, and consequently enhanced levels of IFNγ, following exposure to antigen-positive but not negative tumor cells. Adoptive transfer of T cells with a TCR and inducible (i)IL-12 to melanoma-bearing mice resulted in severe, edema-like toxicity that was accompanied by enhanced levels of IFNγ and TNFα in blood, and reduced numbers of peripheral TCR transgene-positive T cells. In contrast, transfer of T cells expressing a TCR and iIL-18 was without side effects, enhanced the presence of therapeutic CD8+ T cells within tumors, reduced tumor burden and prolonged survival. Notably, treatment with TCR+iIL-12 but not iIL-18 T cells resulted in enhanced intra-tumoral accumulation of macrophages, which was accompanied by a decreased frequency of therapeutic T cells, in particular of the CD8 subset. In addition, when administered to mice, iIL-18 but not iIL-12 demonstrated a favorable profile of T cell co-stimulatory and inhibitory receptors. In conclusion, we observed that treatment with T cells engineered with a TCR and iIL18 T cells is safe and able to skew the tumor microenvironment in favor of an improved anti-tumor T cell response.

6) Hu, Biliang, et al. “Augmentation of antitumor immunity by human and mouse CAR T cells secreting IL-18.” Cell reports 20.13 (2017): 3025-3033.

The effects of transgenically encoded human and mouse IL-18 on T cell proliferation and its application in boosting chimeric antigen receptor (CAR) T cells are presented. Robust enhancement of proliferation of IL-18-secreting human T cells occurred in a xenograft model, and this was dependent on TCR and IL-18R signaling. IL-18 augmented IFN-γ secretion and proliferation of T cells activated by the endogenous TCR. TCR-deficient, human IL-18-expressing CD19 CAR T cells exhibited enhanced proliferation and antitumor activity in the xenograft model. Antigen-propelled activation of cytokine helper ensemble (APACHE) CAR T cells displayed inducible expression of IL-18 and enhanced antitumor immunity. In an intact mouse tumor model, CD19-IL-18 CAR T cells induced deeper B cell aplasia, significantly enhanced CAR T cell proliferation, and effectively augmented antitumor effects in mice with B16F10 melanoma. These findings point to a strategy to develop universal CAR T cells for patients with solid tumors.

7) Senju, Hiroaki, et al. “Effect of IL-18 on the Expansion and Phenotype of Human Natural Killer Cells: Application to Cancer Immunotherapy.” International journal of biological sciences 14.3 (2018): 331.

When peripheral blood NK cells were stimulated with IL-2, the cells formed clusters beginning on day 5-6 and proliferated thereafter, in which the number of NK cells increased by 10-fold in 10 days. When IL-18 was added, cell clusters were observed as early as on day 4 and NK cells proliferated vigorously. On day 10, the expansion rate was 56-fold on average, showing that IL-18 promoted the expansion of NK cells.

8)  Song, Yuan, et al. “IL‐12/IL‐18‐preactivated donor NK cells enhance GVL effects and mitigate GvHD after allogeneic hematopoietic stem cell transplantation.” European journal of immunology 48.4 (2018): 670-682.

Adoptive transfer of donor NK cells has the potential of mediating graft‐versus‐leukemia (GVL) effect while suppressing acute graft‐versus‐host‐disease (aGVHD) during allogeneic hematopoietic stem cell transplantation (allo‐HSCT). However, these beneficial effects are limited by the transient function of adoptively transferred NK cells. Previous studies demonstrate that cytokine‐induced memory‐like NK cells that are preactivated by IL‐12, IL‐15, and IL‐18 have enhanced effector functions and long life span in vivo. Here, we investigated the effects of IL‐12/18‐preactivated and IL‐12/15/18‐preactivated donor NK cells on GVL and aGVHD in a murine model of allo‐HSCT. We found that both IL‐12/18‐ and IL‐12/15/18‐preactivated NK cells mediated stronger GVL effect than control NK cells mainly due to their elevated activation/cytotoxicity and sustained proliferative potential. Interestingly, we observed that although both IL‐12/18‐ and IL‐12/15/18‐preactivated NK cells significantly inhibited severe aGVHD, only the IL‐12/18‐preactivated NK cells maintained the beneficial effect of donor NK cells on mild aGVHD. The IL‐12/15/18‐preactivated NK cell infusion accelerated aGVHD in the fully‐mismatched mild aGVHD model. Our results demonstrated that IL‐12/18‐preactivated NK cells displayed sustained and enhanced GVL functions, and could mitigate aGVHD despite the severity of the disease. IL‐12/18‐preactivated donor NK cell infusion may be an effective and safe adoptive therapy after allo‐HSCT.

9) Eur Cytokine Netw. 2017 Nov 1;28(4):127-140.
Interleukin-18: a regulator of cancer and autoimmune diseases.
Esmailbeig M1, Ghaderi A2.

Interleukin (IL)-18, structurally similar to IL-1β, is a member of IL-1 superfamily of cytokines. This cytokine, which is expressed by many human lymphoid and nonlymphoid cells, has an important role in inflammatory processes. The main function of IL-18 is mediated through induction of interferon-γ (IFN-γ) secretion from T helper (Th1) cells. This cytokine synergistically with IL-12 contributes to Th1 differentiation and, therefore, is important in host defense mechanisms against intracellular bacteria, viruses, and fungi. Recent evidences showing the involvement of IL-18 in Th2 differentiation and ultimately IgE production from B cells have shed a new insight on the dual effects of IL-18 on Th1 and Th2 inflammatory responses. IL-18 in combination with IL-12 can activate cytotoxic T cells (CTLs), as well as natural killer (NK) cells, to produce IFN-γ and, therefore, may contribute to tumor immunity. The biological activity of IL-18 is not limited to these cells, but it also plays a role in development of Th17 cell responses. IL-18 synergistically with IL-23 can induce IL-17 secretion from Th17 cells. The diverse biological activity of IL-18 on T-cell subsets and other immune cells has made this cytokine a good target for investigating its role in various inflammatory-based diseases. Lately, the discovery of IL-18 binding protein (IL-18BP), a physiological inhibitor of IL-18 and a hallmark of IL-18 biology, made this cytokine an attractive target for studying its pros and cons in the treatment of various diseases. In recent years, the biology, genetics, and pathological role of IL-18 have been studied in a number of diseases.

2019

10) Jafarzadeh, Abdollah, et al. “Immunomodulatory properties of cimetidine: Its therapeutic potentials for treatment of immune-related diseases.” International immunopharmacology 70 (2019): 156-166.

Histamine exerts potent modulatory impacts on the cells of innate- [including neutrophils, monocytes, macrophages, dendritic cells (DCs), natural killer (NK) cells and NKT cells] and adaptive immunity (such as Th1-, Th2-, Th17-, regulatory T-, CD8+ cytotoxic T cells, and B cells) through binding to histamine receptor 2 (H2R). Cimetidine, as an H2R antagonist, reverses the histamine-mediated immunosuppression, as it has powerful stimulatory effects on the effector functions of neutrophils, monocytes, macrophages, DCs, NK cells, NKT cells, Th1-, Th2-, Th17-, and CD8+ cytotoxic T cells. However, cimetidine reduces the regulatory/suppressor T cell-mediated immunosuppression. Experimentally, cimetidine potentiate some immunologic activities in vitro and in vivo. The therapeutic potentials of cimetidine as an immunomodulatory agent were also investigated in a number of human diseases (such as cancers, viral warts, allergic disorders, burn, and bone resorption) and vaccination.

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2014 Review:

11) Pantziarka, Pan, et al. “Repurposing drugs in oncology (ReDO)—cimetidine as an anti-cancer agent.” (2014).

CIM has low toxicity, with the most common side effects being headache, dizziness, diarrhoea, and rash. Rare side effects include gynaecomastia, reversible impotence (particularly reported in patients receiving very high doses, for example, in the treatment of Zollinger-Ellison Syndrome) and, very rarely, galactorrhoea. Rarely, CIM has also been associated with reversible leukopenia and thrombocytopenia, effects that may be particularly important to watch for in cancer patients who may be undergoing chemotherapy [2].

CIM is an inhibitor of cytochrome P450, through multiple enzymes (including CYP1A2, CYP2D6, and CYP3A, CYP3A3/A4, CYP2C9, and CYP2C18), which may have a significant impact on the metabolism of a wide range of drugs

Early interest in the potential anti-cancer action of CIM was aroused by investigations into the relationship between histamine levels and cancer, particularly by the finding that histamine levels were increased in distant non-cancer tissues in tumour-bearing mice [13, 14] and decreased in plasma, a result confirmed in humans [15]. An early investigation suggested that a histamine H₂ receptor agonist stimulated cellular proliferation in dimethylhydrazine-induced colonic carcinoma in rats, an effect reversed by CIM and another H₂RA (metiamide), and that an H₁ receptor antagonist had no effect

perioperative CIM in patients undergoing surgical resection of colorectal cancer. CIM helped reduce post-operative immunosuppression following resection .  median follow-up at 30 months, the calculated 3-year survival was 93% for CIM-treated patients and 59% for controls[35, 36].

The earliest clinical evidence of an effect of the CIM on melanoma was in a series of three cases of recurrent malignant melanoma being treated with coumarin (at a dose of 100 mg per day). Oral CIM was started at a dose of 1000 mg per day when these patients were no longer responding to coumarin treatment. In these cases there was rapid regression of multiple lesions and a corresponding and long-lasting improvement in physical condition. [42].[43].[44].

The anti-tumour action of CIM has been shown to be due to four distinct mechanisms:

Anti-proliferative action on cancer cells

A direct effect on cancer cell proliferation has been shown in two xenograft experiments in which exogenous histamine increased tumour growth in C170 and LIM2412 human colorectal cell lines implanted in Balb/c nu/nu mice, an effect that was reversed by oral CIM but not by the H₁RA diphenhydramine [27].

Immunomodulatory effects

histamine is associated with an immunosuppressive tumour microenvironment, including an increase in CD4+CD25+ regulatory T cell (Treg) activity, reduced antigen-presenting activity of dendritic cells (DC), reduced NK-cell activity and increased myeloid-derived suppressor cell (MDSC) activity [75–77].

histamine binding to the H₂ receptor is associated with suppression of IL-12 and stimulation of IL-10 secretion and is implicated with a shift in Th1/Th2 balance toward Th2-dominance of the immune response. This effect was reversed by CIM in human PBMC [78].

MDSCs myeloid-derived suppressor cell express H₁–H₃ receptors, and there is in vitro and in vivo evidence that blockade of H₁ (using the H₁RA cetirizine) or H₂ (using CIM), can reverse the immunosuppressive action of these cells [77].

An increase in NK activity compared to non-CIM-treated controls has also been noted in cardiopulmonary bypass surgery [82].

Effects on cell adhesion

In a nude mouse model, CIM dose-dependently reduced the incidence of HT-29 liver metastases, suppressing it completely at the highest dose (200 mg/kg/day) [83]. The effect on cell adhesion was mediated by the interaction between tumour sialyl Lewis antigens and E-selectin expressed on the endothelium.

Anti-angiogenic action

Ghosh et al investigated the role of histamine in the production of vascular endothelial growth factor (VEGF) in carrageenin-induced granulation tissue in rats, and found that it was mediated by the H₂ receptor, and that the upregulation of VEGF induced by histamine was reversed by CIM [87].

Additionally, there is also evidence that the anti-angiogenic effect of CIM administration may also be related to a reduced expression of platelet-derived endothelial growth factor (PDECGF), as well as VEGF, in mouse and rat models of bladder cancer [89].

CIM may be more efficacious in patients with lower tumour burden and higher immune function, and in cancers with a greater antigenic potential. there is still considerable scope for clinical investigation of CIM as an immunostimulant, with a possible anti-metastatic action, in a range of cancer types.

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Excellent Review 2011

12) Kubecova, Martina, et al. “Cimetidine: An anticancer drug?.” European Journal of Pharmaceutical Sciences 42.5 (2011): 439-444. Cimetidine anticancer drug Kubecova Martina Europ J Pharm 2011

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13) Second Opinions is the website of Barry Groves PhD, Is Cimetidine (Tagamet) a Better Cure for Cancer?

Cimetidine is probably the easiest drug to obtain and is suggested as the drug of first choice when cancer is suspected. The recommended dose is 1,000 mg per day.

References

1. Armitage J O, Sidner R D. Antitumour effect of cimetidine? Lancet 1979; i: 882-3.
2. Osband M E, et al. Successful tumour immunotherapy with cimetidine in mice. Lancet 1981; i: 636-38.
3. Gifford R R M, Fergusson R M, Voss B V. Cimetidine reduction of tumour formation in mice. Lancet 1981; i: 638-40.
4. Thornes R D, Lynch G, Sheehan M V. Cimetidine and coumarin therapy of melanoma. Lancet 1982; ii: 328.
5. Borgström S, et al. Human leukocyte interferon and cimetidine for metastatic melanoma. N Eng J Med 1982; 307: 1080-81.
6. Thornes R D, Lynch G. Combination of cimetidine with other drugs for treatment of cancer. N Eng J Med 1983; 308: 591.
7. Burtin C, et al. Combination of cimetidine with other drugs for treatment of cancer. N Eng J Med 1983; 308: 591-2.
8. Strauchen J A, Moran C, Goldsmith M, Greenberg M. Spontaneous regression of gastric lymphoma. Cancer . 1987; 60: 1872-5
9. Tonnesen H, et al. Effect of cimetidine on survival after gastric cancer. Lancet 1988; 2: 990-2.
10. Adams W, Morris D L. Short-course cimetidine and survival with colorectal cancer. Lancet 1994; 344: 1768-9.
11. Matsumoto S. Cimetidine and survival with colorectal cancer. Lancet 1995; 346: 115.
12. Adams W J, Morris D L. Pilot study cimetidine enhances lymphocyte infiltration of human colorectal carcinoma: results of a small randomized control trial. Cancer 1997; 80: 15-21.
13. Lawson J A, Adams W, Morris D L. Ranitidine and cimetidine differ in their in vitro and in vivo effects on human colonic cancer growth. Br J Cancer. 1996; 73: 872-6.
14. Hahm K B, et al. Comparison of antiproliferative effects of 1-histamine-2 receptor antagonists, cimetidine, ranitidine, and famotidine, in gastric cancer cells. Int J Immunopharmacol . 1996; 18: 393-9

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Excellent review

14) Lefranc, Florence, et al. “Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma.” International journal of oncology 28.5 (2006): 1021-1030.Cimetidine unexpected anti-tumor agent Lefranc Int j oncology 2006

The mechanisms proposed for the cell-mediated immuno-modulation of CIM (Fig.
1) include the inhibition of suppressorT lymphocyte activity (26),
2) stimulation of natural killer (NK) cell activity (27),
3) an increase in interleukin-2 (IL-2) production in helper T lymphocytes (28),

Note: Ibrutinib is an ITk inhibitor which Inhibits production of  IL2 (see below)  IL-2 main function is induction of T-Reg Immune suppressor cells.- immune suppressive in the TME tumor micro-envionment

4) an increase in tumor inhibitory cytokines (35)
5) and the enhancement of the host’s anti-tumorcell-mediated immunity by improving the suppressed dendritic cell function in advanced cancer patients (44).

combining CIM with temozolomide improved survivalwhen compared to temozolomide alone in human glioblastomaorthotopic xenograft-bearing nude mice.

Surgery. 1987 Aug;102(2):242-7. Histamine type-2 receptor antagonist immune modulation. II.   Cimetidine and ranitidine increase interleukin-2 production.  Gifford RR, Tilberg AF.

The effect of cimetidine and ranitidine (histamine type-2 receptor antagonists) on the production of interleukin-2 (IL-2) by mitogen-activated, normal murine spleen cells was studied in vitro. Cimetidine (10(-4) mol/L to 10(-6) mol/L) increased IL-2 production to a maximal 8.8 +/- 1.6 U (IL-2 activity), as compared with media controls of 1 U. Ranitidine (10(-4) mol/L to 10(-6) mol/L) also increased IL-2 production to a maximal 5.6 +/- 1.2 U, as compared with media controls of 1 U. The increases for both drugs were statistically significant- (p at least less than 0.03 for all doses tested). These data suggest that our previously demonstrated immunofacilitation of proliferative and cytotoxic lymphocyte responses by cimetidine was probably mediated by the presence of increased IL-2. These data further suggest that histamine type-2 receptor antagonists may have immunorestorative potential in clinical immunotherapy of IL-2 deficient states.

Cutaneous Warts- Cimetidne

Das, Bibhuti, et al. “Cimetidine: a safe treatment option for cutaneous warts in pediatric heart transplant recipients.” Medical Sciences 6.2 (2018): 30.

Background and Objectives: Immunosuppressed individuals are at particularly increased risk for human papilloma virus-related infections. The primary objective of our study is to determine if there are any adverse effects associated with high-dose cimetidine treatment. A secondary objective is to report our experience with cimetidine in the treatment of cutaneous warts in pediatric heart transplant recipients. Methods and Results: This was a retrospective observational study. A total of 8 pediatric heart transplant recipients diagnosed with multiple recalcitrant warts were the subject of the study. All patients were treated with cimetidine (30–40 mg/kg/day) in two divided doses for 3 to 6 month durations. All patients had complete resolution of their lesions except 1 patient who had no clinical improvement. Of these 8 patients, one had recurrence of warts at one year follow-up, which resolved with restarting cimetidine therapy. One patient who had only 3 months of cimetidine therapy had immediate relapse after cimetidine was stopped. None of them had significant change in their tacrolimus trough, serum creatinine, and alanine transaminase levels. No adverse events were reported except one patient experienced mild gynecomastia. Conclusion: Cimetidine can be a safe and alternative treatment option for multiple warts in pediatric heart transplant recipients.

Cimetidine is postulated to act as an immunomodulatory agent at high doses by inhibiting suppressor T-cell function [15]. The paradigm between T helper (Th) 2 cells, and Th1 cells predominance is reflected in the level of cytokines that are released. Cimetidine activates Th1 cells to produce interleukin (IL)-2, IL-12, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and their expression correlates with improvement in cellular immunity and wart remission [16,17].  Patients who received cimetidine were shown to exhibit enhanced cell-mediated immunity, restoration of sensitivity following development of acquired tolerance, and increased response of lymphocytes to mitogen stimulation [18].

Eur J Dermatol. 2003 Sep-Oct;13(5):445-8.
Cimetidine treatment for viral warts enhances IL-2 and IFN-gamma expression but not IL-18 expression in lesional skin.Mitsuishi T1, Iida K, Kawana S.

Cimetidine has been shown to improve various types of human neoplasms and more recently it has been shown to be effective in treating recalcitrant or multiple viral warts in some reports. However, it is not well understood why cimetidine is effective on those kinds of viral warts. We investigated 55 patients with multiple viral warts treated only with oral cimetidine for up to 4 months to examine the efficacy of treatment. The patients were divided into two groups: group A received oral cimetidine (<20 mg/kg/day) and group B received the drug (30 to 40 mg/kg/day). In addition, using real time PCR, we measured mRNA levels of the cytokines interleukin-2 (IL-2), IL-18, and interferon (IFN)-gamma taken from selected punch biopsy specimens before and during treatment. As a result, 34.5% (19/55) of the patients had a dramatic clinical improvement or complete remission (CR) of their viral warts and 23.6% (13/55) of the patients had partial responses (PR) within 4 months of cimetidine therapy. IL-2 and IFN-gamma mRNA levels were significantly increased and IL-18 mRNA levels were decreased in tissues of effectively treated viral warts. Our results show that the higher dose of oral cimetidine was more effective in treating multiple viral warts, that cimetidine activates Th1 cells to produce IL-2 and IFN-c and that their expression correlates with wart remission. These results suggest that cimetidine is an effective treatment for viral warts. In addition, based on the decrease in IL-18 mRNA elicited by the drug, IL-18 might be expressed by keratinocytes infected with HPV.

free pdf
Ballesteros-Tato, André, and Troy D. Randall. “THE BIOLOGY OF THE INTERLEUKIN-2 (IL-2)-BASED IMMUNOTHERAPIES IN CANCER AND AUTOIMMUNE DISEASE.” International Journal of Cancer Research and Prevention 7.3/4 (2014): 213.

Interleukin-2 (IL-2) is an important T cell growth factor with the capacity to promote T cell expansion. Consistent with this idea, IL-2 is used clinically to enhance T cell responses to viral and tumor antigens in both preclinical models and patients. However, the role of IL-2 in immune responses is far more complex than initially expected. In addition to its ability to promote immune responses, IL-2 signaling is essential for the differentiation of regulatory T cells (Tregs), which suppress immune responses. Thus, IL-2 signaling can both promote and inhibit immune responses depending on the context, the dose, and the nature of the IL-2/IL-2 receptor interactions. As a result, IL-2 therapies that selectively target Tregs may be useful for treating autoimmune diseases, whereas IL-2 therapies that selectively target effector T cells may improve cancer immunotherapy. In this chapter we summarize our current understanding of the biology of IL-2-based immunotherapies for cancer and autoimmune disease.

Sachivko, N. V., et al. “Interleukin-2 (Ronkoleykin) in the first-line chemotherapy for B-cell non-Hodgkin lymphoma.” Voprosy onkologii 59.2 (2013): 52-58.

de Menezes, Daniel E. Lopes, et al. “Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma.” Journal of Immunotherapy 30.1 (2007): 64-74.

Hooijberg, Erik, et al. “Eradication of large human B cell tumors in nude mice with unconjugated CD20 monoclonal antibodies and interleukin 2.” Cancer research 55.12 (1995): 2627-2634.

Golay, Josée, et al. “Rituximab-mediated antibody-dependent cellular cytotoxicity against neoplastic B cells is stimulated strongly by interleukin-2.” Haematologica 88.9 (2003): 1002-1012.

Khan, Khuda D., et al. “A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin’s lymphoma.” Clinical Cancer Research 12.23 (2006): 7046-7053.
The addition of human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) may enhance rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) because rIL-2 promotes natural killer (NK) cell expansion (9–11) and enhances intrinsic NK cell cytotoxicity

Eisenbeis, Charles F., et al. “Combination immunotherapy of B-cell non-Hodgkin’s lymphoma with rituximab and interleukin-2: a preclinical and phase I study.” Clinical Cancer Research 10.18 (2004): 6101-6110.

use of low-dose interleukin (IL)-2 to expand and activate human NK cells, and we have studied this in both animal models and cancer patients

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Ibrutinib irreversibly inhibits ITK  interleukin-2–inducible kinase (ITK)

In vitro cellular assays confirm that (ITK inhibitor) PRN694
prevents T-cell receptor- and Fc receptor-induced cellular and molecular activation, inhibits T-cell receptor-induced T-cell proliferation,
and blocks proinflammatory cytokine release as well as activation of Th17 cells.

T cell growth factor called interleukin 2 (IL-2) which acts upon itself in an autocrine fashion. Activated T cells also produce the alpha sub-unit of the IL-2 receptor (CD25 or IL-2R), enabling a fully functional receptor that can bind with IL-2, which in turn activates the T cell’s proliferation pathways.

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http://www.bloodjournal.org/content/122/15/2539.long
Dubovsky, Jason A., et al.   “Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes.” Blood 122.15 (2013): 2539-2549.

A common mechanism of immune subversion is the aberrant recruitment of a Th2-dominant response that promotes B-cell antibody production and interferes with direct effector cell cytotoxicity. In contrast, a Th1-dominant response evokes cytotoxic effects with the production of interferon γ (IFN-γ) and interleukin 2 (IL-2), which contribute to effector-cell–based immune surveillance.

Clinically applicable ITK inhibitors are sought by the medical community given their potential to inhibit a number of Th2-dominant autoimmune, inflammatory, and infectious diseases ranging from cancer immunosuppression and atopic dermatitis to inflammatory bowel disease

In CLL, an increasingly defective immune synapse enables malignant B cells to evade immune detection by inducing T-cell anergy as well as improper Th2 polarization.24,25 In addition to being incapable of responding to environmental pathogens, these improperly polarized T cells contribute both cytokine and direct signaling support to malignant B cells

Our molecular analysis confirms that ibrutinib irreversibly binds ITK and inhibits activation of Th2 cells after TCR stimulation. This inhibition is specific to Th2-polarized CD4 T cells, because RLK remains functional, thus providing a compensatory platform for activation of Th1 and CD8 T cells. These data demonstrate that CD4 T-cell populations isolated from CLL patients are skewed toward a Th1 profile after exposure to ibrutinib.

Ibrutinib selectively limits Th2 activation, thereby initiating a Th1-selective pressure in a mixed population of CD4 T cells in vitro, in vivo, and in human CLL patients receiving ibrutinib

clinical treatment of CLL with ibrutinib results in a dramatic decrease of infectious complications between the first 6 months of treatment and thereafter.

tumors develop a prosurvival niche enhanced by Th2-polarized CD4 T cells.1,2 In leukemia, these cells provide constitutive IL-4, IL-6, and CD40L stimulation, driving the expansion of disease

In solid tumors, subversion of Th1 in lieu of Th2 promotes tumor immune evasion.45 In such settings, a specific advantage given to Th1 cells may allow the effective generation of antitumor immunity. The combination of ibrutinib with T-cell–based immunotherapy may prove synergistic.

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Cholangiocarcinoma

2017 CIM suppression of the protein kinase B signaling pathway.
Suppression of Akt phosphorylation, caspase-3, −8 and −9 activation,

15) Dana, Paweena, et al. “Repurposing cimetidine for cholangiocarcinoma: Antitumor effects in vitro and in vivo.” Oncology letters 13.3 (2017): 1432-1436.

Cimetidine is a histamine type-2 (H2) receptor antagonist that has been demonstrated to have antitumor effects on various types of malignancy. However, its effect on cholangiocarcinoma (CCA), a chemotherapy-resistant bile duct tumor, has yet to be investigated. In the present study, the antitumor activity of cimetidine in vitro and in vivo was evaluated. A methylthiotetrazole assay revealed that the proliferation of certain CCA cell lines was inhibited by cimetidine, which induced the caspase-dependent apoptosis of CCA cells via suppression of the protein kinase B signaling pathway. Suppression of Akt phosphorylation, caspase-3, −8 and −9 activation, phosphotidylserine exposure determined by Annexin V binding assay and the presence of a sub-G1 population were demonstrated by western blotting and flow cytometry analysis. In a CCA xenograft mouse model cimetidine inhibited the growth of CCA cells without observable adverse effects.

anticancer activities of cimetidine have been revealed, including the inhibition of cell proliferation by blocking the cell growth-promoting effect of histamine (14), the inhibition of tumor angiogenesis (15), the stimulation host immune responses (16) and the suppression of cell adhesion (17).

cimetidine effectively inhibited cell proliferation in a dose- and time-dependent manner.

it was hypothesized that cimetidine induces apoptosis in CCA cell lines via the inhibition of Akt phosphorylation (25).  This study is the first to demonstrate that cimetidine induces caspase-dependent apoptosis via the suppression of the Akt signaling pathway.

16) Zheng, Yisheng, et al. “Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells.” Molecular immunology 54.1 (2013): 74-83.

Cimetidine, a histamine type-2 receptor antagonist, is known to inhibit the growth of several tumors in human and animals, however the mechanism of action underlying this effect remains largely unknown. Here, in the mice model of 3LL lung tumor, cimetidine showed significant inhibition of tumor growth. However, an in vitro study demonstrated that cimetidine showed no effect on proliferation, survival, migration and invasion of 3LL cells. We found that cimetidine reduced CD11b(+)Gr-1(+) myeloid derived-suppressive cell (MDSC) accumulation in spleen, blood and tumor tissue of tumor-bearing mice. In vitro coculture assay showed that cimetidine reversed MDSC-mediated T-cell suppression, and improved IFN-γ production. Further investigation demonstrated that the NO production and arginase I expression of MDSCs were reduced, and MDSCs prone to apoptosis by cimetidine treatment. However, MDSC differentiation was not affect by cimetidine. Importantly, although histamine H2 receptor was expressed in MDSC surface, histamine could not reverse the proapoptosis of cimetidine. Moreover, famotidine also did not have this capacity. We found that cimetidine could induce Fas and FasL expression in MDSC surface, and sequentially regulate caspase-dependent apoptosis pathway. Thus, these findings revealed a novel mechanism for cimetidine to inhibit tumor via modulation of MDSC apoptosis.\

17) Kobayashi, Ken-ichi, et al. “Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression.” Cancer research 60.14 (2000): 3978-3984.

18) Kikonyogo, Alexandra, and Regina Pietruszko. “Cimetidine and other H2-receptor antagonists as inhibitors of human E3 aldehyde dehydrogenase.” Molecular pharmacology 52.2 (1997): 267-271.

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19) Cimetidine For Cancer Treatment

Life Extension – July 2002 By Michele Morrow, Board Certified Family Physician & Life Extension Medical Tonnesen H, Knigge U, Bulow S, Damm P, Fischerman K, Hesselfeldt P, Hjortrup A, Pedersen IK, Pedersen VM, Siemssen OJ. Effect of cimetidine on survival after gastric cancer. Lancet 1988 Oct 29;2(8618):990-2.
Adams WJ, Morris DL. Short-course cimetidine and survival with colorectal cancer. Lancet. 1994 Dec 24-31;344(8939-8940):1768-9.
Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. Brit J Can 2002 (86) 161-167.
Kobayashi K, Matsumoto S, Morishima T, Kawabe T, Okamoto T. Cimetidine inhibits cancer cell adhesion to endothelial cells and prevents metastasis by blocking E-selectin expression. Cancer Res. 2000 Jul 15;60(14):3978-84.
Adams WJ, Lawson JA, Morris DL. Cimetidine inhibits in vivo growth of human colon cancer and reverses histamine stimulated in vitro and in vivo growth. Gut 1994 Nov;35(11):1632-6.
Siegers CP, Hiltl DM, Stich R. Cimetidine hemmt das Tumorzellwachstum. Therapie-woche. 1995 (36) 2110-2114.
Melmon KL, Bourne HR, Weinstein Y, Sela MD. Receptors for histamine can be detected on the surface of selected leukocytes. Science 1972 (177) 707.
Rocklin RE, Greineder DK, Melmon KL. Histamine induced suppressor factor (HSF) Further studies on the nature of the stimulus and the cell which produces it. Cell Immunol 1979 (44) 404-415.
Hansbrough J, Zapata-Sirvent R, Bender E. Prevention of alterations in postoperative lymphocyte subpopulations by cimetidine and ibuprofen. Am. J surg 1986 151, 249-255.
Adams W. Cimetidine preserves immune function after colonic resection of cancer. Aust. NZ J. Surg 1994 64, 847-852.
Adams WJ, Lawson JA, Nicholson SE, Cook TA, Morris DL. The growth of carcinogen-induced colon cancer in rats is inhibited by cimetidine. Eur J Surg Oncol 1993 Aug;19 (4):332-5.
Harrison JC, Dean PJ, El-Zeky F, Vander Zwaag R. From Dukes through Jass: Pathological prognostic indicators in rectal cancer. Hum. Path. 1994 (25) 495-498.
Morris DL, Adams WJ. Cimetidine and colorectal cancer-old drug, new use? Nat Med. 1995 Dec;1(12):1243-4.
Uchida A. Biological significance of autologous tumour killing activity and its induction therapy. Cancer Immun. Immunother 1993 (37) 75-83.
American Cancer Society website – Statistics section.

20) Dorr, Robert T., and David S. Alberts. “Cimetidine enhancement of cyclophosphamide antitumour activity.” British journal of cancer 45.1 (1982): 35.
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21) TL-118 is a novel drug combination produced by Tiltan Pharma Ltd, Israel. Designed as a multi-targeted anti-angiogenic agent, the four drugs that make up the combination are: CIM, low-dose cyclophosphamide, diclofenac, and sulfasalazine

22) Bekhti, A., and J. Pirotte. “Cimetidine increases serum mebendazole concentrations. Implications for treatment of hepatic hydatid cysts.” British journal of clinical pharmacology 24.3 (1987): 390-392.
In eight patients (five with peptic ulcer disease and three with hydatid cysts), the [14C]-aminopyrine breath test (ABT) and maximum serum concentration of mebendazole following a dose of 1.5 g of mebendazole three times daily were determined before and after treatment with cimetidine (400 mg three times daily for 30 days). Serum mebendazole concentrations were measured in blood samples taken 2 h after each drug intake. Cimetidine lowered the 14CO2 specific activity (SA) at 1 h (P less than 0.01) and increased the maximum serum concentration of mebendazole (P less than 0.01). A significant correlation was found between SA at 1 h and the highest concentration of mebendazole before (r = -0.71, P less than 0.05) and after (r = -0.82, P less than 0.05) cimetidine ingestion. Combined administration of cimetidine and mebendazole resulted in the complete resolution of previously unresponsive hydatid cysts.

23) Messaritakis, J., et al. “High mebendazole doses in pulmonary and hepatic hydatid disease.” Archives of disease in childhood 66.4 (1991): 532-533.
Thirty nine children with 71 hydatid cysts were given mebendazole orally in a dose of 100-200 mg/kg/day for 12 weeks and were followed up for a mean (SD) of 63 (24) months. Twenty children (three of them after a second course) were cured and another two avoided at least one operation. No serious side effects of the drug were observed.

100 x 70 kg = 7000 mg = 7 grams
400 mg caps x 2 = 800 mg tid = 2.4 grams

24) Med Parazitol (Mosk). 1993 Jul-Sep;(4):15-7.
[The efficacy of the mebendazole treatment of patients with hydatid disease].
[Article in Russian]  Shcherbakov AM, Panteleeva EIa, Firsova RA.

Chemotherapy was administered to 53 patients with hydatid disease; to 27 of them it was administered to prevent recurrences. Mebendazole was prescribed by courses lasting for 14 to 30 days with intervals between the courses of 1 to 3 months,

in a daily dose of 50 mg/kg to be taken 4 times.
50 x 60 kg = 3000 mg per day
800 mg QID = 3200 mg

The treatment efficacy was assessed in accordance with the criteria suggested by the WHO experts. On the whole our results did not evidence any essential differences in mebendazole therapy efficacy in our patients and in those represented in a WHO report. No recurrences occurred over the period of observation, that lasted for 6 months to 6 years, in the 27 patients who were administered the drug to prevent the disease recurrences. The treatment was fairly effective in 27% of the patients, good effect was attained in 42%, no desirable results were attained in 19%, and lethal outcomes were recorded in 12% of patients.

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Cimetidine Tagamet is rapidly eliminated, with an elimination half-life of 123 minutes, or about 2 hours.[5] It has been said to have a duration of action of 4 to 8 hours.[1]

Histamine H2 receptor antagonism

The mechanism of action of cimetidine as an antacid is as a histamine H2 receptor antagonist.[33] It has been found to bind to the H2 receptor with a Kd of 42 nM.[34]

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25) Blaya, Bruno, et al. “Histamine and histamine receptor antagonists in cancer biology.” Inflammation & Allergy-Drug Targets (Formerly Current Drug Targets-Inflammation & Allergy) 9.3 (2010): 146-157.  Histamine receptor antagonists in cancer Blaya Bruno Inflam Allergy 2010

H2 antagonist ranitidine and the
H1 antagonist terfenadine
30 Fexofenadine HCl Tablet, 180MG
Fexofenadine, sold under the trade name Allegra & FX 24 among others[1] is an antihistamine pharmaceutical drug used in the treatment of allergy symptoms, such as hay fever and urticaria.[4] Therapeutically, fexofenadine is a selective peripheral H1-blocker. \

26)  Indian Dermatol Online J. 2010 Jul-Dec; 1(1): 45–46.
Fexofenadine in higher doses in chronic spontaneous urticaria
Kiran V. Godse, Nitin J. Nadkarni, Gaurang Jani, and Sunil Ghate

Recommended dose range of fexofenadine is 120-180 mg daily.[6]

All patients were started with fexofenadine 180 mg tablet in the morning after breakfast.

famotidine
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mantle cell lymphoma cyproheptadine (Periactin) antagonist of the H1 receptor.

cyproheptadine as an inhibitor of D-cyclin expression.

27) Paoluzzi, L.; Scotto, L.; Marchi, E.; Seshan, V.E.; O ´Connor, O.A. The Anti-histamine cyproheptadine synergizes the antineoplastic activity of bortezomib in mantle cell lymphoma through its effects as a histone deacetylase inhibitor. Br. J. Haematol., 2009, 146, 656.

Cyproheptadine is a very potent antihistamine or antagonist of the H1 receptor. At higher concentrations, it also has anticholinergic, antiserotonergic, and antidopaminergic activities. Of the serotonin receptors, it is an especially potent antagonist of the 5-HT2 receptors, and this underlies its effectiveness in t he treatment of serotonin syndrome.

Cyproheptadine is a known inhibitor of H1 histamine and 5-HT serotonin receptors, leading to its use for the treatment of migraines, anorexia and atopic dermatitis (Rao et al, 2000; Kardinal et al, 1990; Klein & Galant, 1980). Recently, using a chemical biology approach, Mao et al (2007, 2008) identified cyproheptadine as an inhibitor of D-cyclin expression. They demonstrated that cyproheptadine decreased D-cyclin expression, and induced apoptosis in models of myeloma and leukaemia in vitro and in vivo (Mao et al, 2007, 2008). Mantle cell lymphoma (MCL) represents a distinct subtype of aggressive lymphoma, characterized by dysregulated cyclin D1 gene (CCND1) expression secondary to the t(11;14) translocation. This reciprocal translocation places CCND1 under the control of the IGH promoter, leading to constitutive expression (Williams & Swerdlow, 1994). The proteasome inhibitor bortezomib was approved for the treatment of relapsed or refractory MCL based on five phase 2 studies, and has been shown to complement the activity of a host of other drugs, including BH3-only mimetics (O’Connor et al, 2005, 2006; Paoluzzi & O’Connor, 2006; Fisher et al, 2006; Goy et al, 2008). Based on the cyclin-D1 rationale noted above, we investigated the cytotoxicity of cyproheptadine alone and in combination with the proteasome inhibitor bortezomib in models of MCL. \

cyproheptadine suppresses the PI3K/AKT signaling pathway,

28) Eur J Haematol. 2013 Dec;91(6):514-21. Cyproheptadine-induced myeloma cell apoptosis is associated with inhibition of the PI3K/AKT signaling.
Li J1, Cao B, Zhou S, Zhu J, Zhang Z, Hou T, Mao X.

Recent studies revealed that the anti-allergic cyproheptadine displays anti-blood cancer activity. However, its mechanism is still elusive. In this study, cyproheptadine was found to decrease the expression of anti-apoptotic proteins, including Bcl-2, Mcl-1, and XIAP. More importantly, cyproheptadine-induced apoptosis was accompanied by suppressing AKT activation in myeloma cells. In the subsequent study, cyproheptadine was found to inhibit insulin-like growth factor 1-triggered AKT activation in a time- and concentration-dependent manner. Specifically, cyproheptadine blocked AKT translocation from nuclei for phosphorylation. This inhibition led to suppressed activation of p70S6K and 4EBP1, two key downstream signaling proteins in the PI3K/AKT pathway. However, cyproheptadine did not display inhibition on activation of IGF-1R or STAT3, possible upstream signals of AKT activation. These results further demonstrated that cyproheptadine suppresses the PI3K/AKT signaling pathway, which is probably critical for cyproheptadine-induced MM cell apoptosis.

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free pdf
Pantziarka, Pan, et al. “Repurposing drugs in your medicine cabinet: untapped opportunities for cancer therapy?.” Future Oncol 11.2 (2015): 182.

Examples of the drugs that the ReDO project has identified as high-potential agents includes
mebendazole (anthelminthic) [6] cimetidine (H2-receptor antagonist) [7], nitroglycerin (vasodilator), diclofenac (NSAID), itraconazole (antifungal) and clarithromycin (antibiotic).

30) Blood. 2005 Jan 1;105(1):178-85. Epub 2004 Sep 14.
Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.
Palumbo JS1, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, Jirousková M, Degen JL.

To test the hypothesis that platelet activation contributes to tumor dissemination, we studied metastasis in mice lacking Galphaq, a G protein critical for platelet activation. Loss of platelet activation resulted in a profound diminution in both experimental and spontaneous metastases. Analyses of the distribution of radiolabeled tumor cells demonstrated that platelet function, like fibrinogen, significantly improved the survival of circulating tumor cells in the pulmonary vasculature. More detailed studies showed that the increase in metastatic success conferred by either platelets or fibrinogen was linked to natural killer cell function. Specifically, the pronounced reduction in tumor cell survival observed in fibrinogen- and Galphaq-deficient mice relative to control animals was eliminated by the immunologic or genetic depletion of natural killer cells. These studies establish an important link between hemostatic factors and innate immunity and indicate that one mechanism by which the platelet-fibrin(ogen) axis contributes to metastatic potential is by impeding natural killer cell elimination of tumor cells.

31) Elaskalani, Omar, et al. “Targeting Platelets for the Treatment of Cancer.” Cancers 9.7 (2017): 94.
The majority of cancer-associated mortality results from the ability of tumour cells to metastasise leading to multifunctional organ failure and death. Disseminated tumour cells in the blood circulation are faced with major challenges such as rheological shear stresses and cell-mediated cytotoxicity mediated by natural killer cells. Nevertheless, circulating tumour cells with metastatic ability appear equipped to exploit host cells to aid their survival. Despite the long interest in targeting tumour-associated host cells such as platelets for cancer treatment, the clinical benefit of this strategy is still under question. In this review, we provide a summary of the latest mechanistic and clinical evidence to evaluate the validity of targeting platelets in cancer.

32) Scand J Gastroenterol. 1995 Mar;30(3):265-71.
Comparison of immunomodulative effects of the histamine-2 receptor antagonists cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells in gastric cancer patients.
Hahm KB1, Kim WH, Lee SI, Kang JK, Park IS.

Histamine-2 receptor antagonist (H2-RA) have been shown to improve the function of various parts of the immune system. The proposed mechanism of the immunomodulative effects of H2-RA has been considered to be the inhibition of suppressor T-lymphocyte activity, an increase in interleukin-2 production, and an enhancement of natural killer cell activity. Most of these studies were done with cimetidine. Comparative data with other H2-RA are limited and conflict on immunomodulative effects. Comparison of the actions of H2-RA on the immune system is required.
METHODS:

We compared the immunodulative effect of the H2-RAs cimetidine, ranitidine, and famotidine on peripheral blood mononuclear cells (PBMC) in normal controls and patients with gastric cancer. DNA synthesis, cytotoxicity against K562 cells, and the levels of soluble interleukin-2 receptor (sIL-2R) in supernatant were measured after addition of the various H2-RA to PBMC cultures.
RESULTS:

Subjects with gastric cancer showed significantly higher levels of suppressor lymphocyte activity than normal controls. These levels were restored to levels of normal controls by the addition of cimetidine. Statistically significant lymphoblastogenesis and cytotoxicity against K562 cells were observed only in cimetidine-treated PBMC (p < 0.05); such effects were not observed in ranitidine- or famotidine-treated PBMC. Significantly increased levels of sIL-2R were found in supernatants obtained from culture flasks treated with cimetidine and phytohemagglutinin or ranitidine and phytohemagglutinin (p < 0.01).
CONCLUSIONS:

Of the three H2-RAs tested, cimetidine had the strongest and famotidine the weakest immunomodulating effect. Only cimetidine augmented the cytotoxicity and proliferative response of lymphocyte to mitogen; neither ranitidine nor famotidine had such an effect. These results might be due to their structural differences. In addition, the immunologic effects of H2-RA are unlikely to be mediated via specific interaction at the H2 receptor.

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Cutaneous Warts

Cimetidine activates Th1 cells to produce interleukin (IL)-2,

33) Das, Bibhuti, et al. “Cimetidine: a safe treatment option for cutaneous warts in pediatric heart transplant recipients.” Medical Sciences 6.2 (2018): 30.

Background and Objectives: Immunosuppressed individuals are at particularly increased risk for human papilloma virus-related infections. The primary objective of our study is to determine if there are any adverse effects associated with high-dose cimetidine treatment. A secondary objective is to report our experience with cimetidine in the treatment of cutaneous warts in pediatric heart transplant recipients. Methods and Results: This was a retrospective observational study. A total of 8 pediatric heart transplant recipients diagnosed with multiple recalcitrant warts were the subject of the study. All patients were treated with cimetidine (30–40 mg/kg/day) in two divided doses for 3 to 6 month durations. All patients had complete resolution of their lesions except 1 patient who had no clinical improvement. Of these 8 patients, one had recurrence of warts at one year follow-up, which resolved with restarting cimetidine therapy. One patient who had only 3 months of cimetidine therapy had immediate relapse after cimetidine was stopped. None of them had significant change in their tacrolimus trough, serum creatinine, and alanine transaminase levels. No adverse events were reported except one patient experienced mild gynecomastia. Conclusion: Cimetidine can be a safe and alternative treatment option for multiple warts in pediatric heart transplant recipients.

Cimetidine is postulated to act as an immunomodulatory agent at high doses by inhibiting suppressor T-cell function [15]. The paradigm between T helper (Th) 2 cells, and Th1 cells predominance is reflected in the level of cytokines that are released. Cimetidine activates Th1 cells to produce interleukin (IL)-2, IL-12, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ and their expression correlates with improvement in cellular immunity and wart remission [16,17]. Patients who received cimetidine were shown to exhibit enhanced cell-mediated immunity, restoration of sensitivity following development of acquired tolerance, and increased response of lymphocytes to mitogen stimulation [18].

34) Eur J Dermatol. 2003 Sep-Oct;13(5):445-8.
Cimetidine treatment for viral warts enhances IL-2 and IFN-gamma expression but not IL-18 expression in lesional skin.Mitsuishi T1, Iida K, Kawana S.

Cimetidine has been shown to improve various types of human neoplasms and more recently it has been shown to be effective in treating recalcitrant or multiple viral warts in some reports. However, it is not well understood why cimetidine is effective on those kinds of viral warts. We investigated 55 patients with multiple viral warts treated only with oral cimetidine for up to 4 months to examine the efficacy of treatment. The patients were divided into two groups: group A received oral cimetidine (<20 mg/kg/day) and group B received the drug (30 to 40 mg/kg/day). In addition, using real time PCR, we measured mRNA levels of the cytokines interleukin-2 (IL-2), IL-18, and interferon (IFN)-gamma taken from selected punch biopsy specimens before and during treatment. As a result, 34.5% (19/55) of the patients had a dramatic clinical improvement or complete remission (CR) of their viral warts and 23.6% (13/55) of the patients had partial responses (PR) within 4 months of cimetidine therapy. IL-2 and IFN-gamma mRNA levels were significantly increased and IL-18 mRNA levels were decreased in tissues of effectively treated viral warts. Our results show that the higher dose of oral cimetidine was more effective in treating multiple viral warts, that cimetidine activates Th1 cells to produce IL-2 and IFN-c and that their expression correlates with wart remission. These results suggest that cimetidine is an effective treatment for viral warts. In addition, based on the decrease in IL-18 mRNA elicited by the drug, IL-18 might be expressed by keratinocytes infected with HPV.

35) https://www.podiatrytoday.com/how-treat-recalcitrant-plantar-warts
How To Treat Recalcitrant Plantar Warts June 25, 2013n Volume 26 – Issue 7 – July 2013 Pages:68 -73 Christina A. Weber, DPM, FACFAS, and Kristine M. Hoffman, DPM

36) Ballesteros-Tato, André, and Troy D. Randall. “THE BIOLOGY OF THE INTERLEUKIN-2 (IL-2)-BASED IMMUNOTHERAPIES IN CANCER AND AUTOIMMUNE DISEASE.” International Journal of Cancer Research and Prevention 7.3/4 (2014): 213.

Interleukin-2 (IL-2) is an important T cell growth factor with the capacity to promote T cell expansion. Consistent with this idea, IL-2 is used clinically to enhance T cell responses to viral and tumor antigens in both preclinical models and patients. However, the role of IL-2 in immune responses is far more complex than initially expected. In addition to its ability to promote immune responses, IL-2 signaling is essential for the differentiation of regulatory T cells (Tregs), which suppress immune responses. Thus, IL-2 signaling can both promote and inhibit immune responses depending on the context, the dose, and the nature of the IL-2/IL-2 receptor interactions. As a result, IL-2 therapies that selectively target Tregs may be useful for treating autoimmune diseases, whereas IL-2 therapies that selectively target effector T cells may improve cancer immunotherapy. In this chapter we summarize our current understanding of the biology of IL-2-based immunotherapies for cancer and autoimmune disease.

37) Sachivko, N. V., et al. “Interleukin-2 (Ronkoleykin) in the first-line chemotherapy for B-cell non-Hodgkin lymphoma.” Voprosy onkologii 59.2 (2013): 52-58.

de Menezes, Daniel E. Lopes, et al. “Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma.” Journal of Immunotherapy 30.1 (2007): 64-74.

38) Hooijberg, Erik, et al. “Eradication of large human B cell tumors in nude mice with unconjugated CD20 monoclonal antibodies and interleukin 2.” Cancer research 55.12 (1995): 2627-2634.

39) Golay, Josée, et al. “Rituximab-mediated antibody-dependent cellular cytotoxicity against neoplastic B cells is stimulated strongly by interleukin-2.” Haematologica 88.9 (2003): 1002-1012.

40)  Khan, Khuda D., et al. “A phase 2 study of rituximab in combination with recombinant interleukin-2 for rituximab-refractory indolent non-Hodgkin’s lymphoma.” Clinical Cancer Research 12.23 (2006): 7046-7053.
The addition of human recombinant interleukin-2 (rIL-2; aldesleukin, Proleukin) may enhance rituximab-mediated antibody-dependent cellular cytotoxicity (ADCC) because rIL-2 promotes natural killer (NK) cell expansion (9–11) and enhances intrinsic NK cell cytotoxicity

41)  Eisenbeis, Charles F., et al. “Combination immunotherapy of B-cell non-Hodgkin’s lymphoma with rituximab and interleukin-2: a preclinical and phase I study.” Clinical Cancer Research 10.18 (2004): 6101-6110.\

42)  Thilagarajah, R., R. O’N. Witherow, and M. M. Walker. “Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, double‐blind placebo‐controlled trial.” BJU international 87.3 (2001): 207-212.

OBJECTIVE: To evaluate the efficacy of oral cimetidine as a treatment for painful bladder disease (PBD, variously described as a ‘symptom complex’ of suprapubic pain, frequency, dysuria and nocturia in the absence of overt urine infection) by assessing symptom relief and histological changes in the bladder wall tissue components, compared with placebo.
PATIENTS AND METHODS:  The study comprised 36 patients with PBD enrolled into a double-blind clinical study with two treatment arms, i.e. oral cimetidine or placebo, for a 3-month trial. Patients were asked to complete a symptom questionnaire (maximum score 35), and underwent cystoscopy and bladder biopsy before treatment allocation. On completing treatment the patients were re-evaluated by the questionnaire and biopsy. The symptom scores and bladder mucosal histology were compared before and after treatment, and the results analysed statistically to assess the efficacy of cimetidine.
RESULTS: Of the 36 patients recruited, 34 (94%) completed the study. Those receiving cimetidine had a significant improvement in symptoms, with median symptom scores decreasing from 19 to 11 (P < 0.001). Suprapubic pain and nocturia decreased markedly (P = 0.009 and 0.006, respectively). However, histologically the bladder mucosa showed no qualitative change in the glycosaminoglycan layer or basement membrane, or in muscle collagen deposition, in either group. The T cell infiltrate was marginally decreased in the cimetidine group (median 203 before and 193 after) and increased in the placebo group (median 243 and 250, P > 0.3 and > 0.2, respectively). Angiogenesis remained relatively unchanged. The incidence of mast cells and B cells was sporadic in both groups.
CONCLUSIONS:

Oral cimetidine is very effective in relieving symptoms in patients with PBD but there is no apparent histological change in the bladder mucosa after treatment; the mechanism of symptom relief remains to be elucidated.

43) Seshadri, Pieter, Laurel Emerson, and Alvaro Morales. “Cimetidine in the treatment of interstitial cystitis.” Urology 44.4 (1994): 614-616.
OBJECTIVES:

To assess the effect of the H2-antagonist cimetidine in the treatment of patients with interstitial cystitis (IC) refractory to other conservative therapies.
METHODS:  A group of 9 patients previously treated conservatively for IC without success were entered in the study. They were thoroughly investigated and treated with cimetidine at the dose of 300 mg orally twice a day for 1 month.
RESULTS:  Six of the 9 patients (66%) experienced various degrees of symptomatic relief while on the drug. Of these, 4 (44%) have noted a complete and sustained response to the medication.
CONCLUSIONS:  The encouraging results observed in this pilot study together with the simplicity and tolerance of the treatment makes it an alternative when other options have been exhausted. Its use as a first-line monotherapy remains speculative.

44) Dasgupta, P., et al. “Cimetidine in painful bladder syndrome: a histopathological study.” BJU international 88.3 (2001): 183-186.

45) Patel, Shabnum, et al. “Beyond CAR T Cells: Other Cell-Based Immunotherapeutic Strategies Against Cancer.” Frontiers in oncology 9 (2019).

46) Adverse side effects on Libido, Sperm, Testosterone see wikipedia https://en.wikipedia.org/wiki/Cimetidine

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Cimetidine for Herpes

47)  Kapińska-Mrowiecka, M., and G. Turowski. “Efficacy of cimetidine in treatment of Herpes zoster in the first 5 days from the moment of disease manifestation.” Polski tygodnik lekarski (Warsaw, Poland: 1960) 51.23-26 (1996): 338-339.

Cimetidine (CIM) reduces regulatory T cell (Treg) levels1

48) Zhang, Yizhi, et al. “Cimetidine down-regulates stability of Foxp3 protein via Stub1 in Treg cells.” Human vaccines & immunotherapeutics 12.10 (2016): 2512-2518.

Cimetidine (CIM) modulates immunity, at least in part, by reducing regulatory T cell (Treg) levels1

Foxp3-expressing Treg cells have been well documented to provide immune regulation by promoting immune tolerance and suppressing immune over-reaction. Cimetidine (CIM), used to inhibit stomach acid secretion, has been reported to promote immune responses and suppress Treg cell function in several studies. However, the underlying mechanism is unknown. To investigate CIM effects on the suppressive function of Treg and Foxp3, here we used CIM to stimulate human CD4+CD25+ Treg cells and Jurkat T cells and evaluated changes of Foxp3 expression and stability. Our data showed that CIM leads to a reduction of Foxp3 via E3 ligase Stub1-mediated proteosomal degradation, which is dependent on an activated PI3K-AKT-mTOR pathway. Thus, CIM affects the suppressive function of Treg cells by destabilizing their Foxp3 expression.

49) Xie, Xiaoping, et al. “Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8+ T cell.” Human vaccines & immunotherapeutics 10.6 (2014): 1688-1699.

Cimetidine synergizes with Praziquantel to enhance the immune response of HBV DNA vaccine via activating cytotoxic CD8(+) T cell.
Xie X1, Geng S2, Liu H1, Li C2, Yang Y3, Wang B4.
Previously, we have reported that either CIM or PZQ, 2 clinical drugs, could be used to develop as adjuvants on HBV DNA vaccine to elicit both humoral and cellular immune responses. Here, we demonstrate that combinations of CIM and PZQ as adjuvants for a HBV DNA vaccine, could induce much stronger antigen specific CD4(+) and CD8(+) T cell responses compared either with CIM or PZQ alone. The synergistic effects of CIM plus PZQ to HBV DNA vaccine were observed on a higher IgG2a/IgG1 ratio, an increase of HBsAg-specific CD4(+) T cells capable of producing IFN-γ or IL-17A and a robust IFN-γ-, IL-17A-, or TNF-α-producing CD8(+) T cells to HBsAg. Most importantly, the antigen-specific CTL response was also elevated significantly, which is critical for the eradication of hepatitis B virus (HBV) infected cells. Using an HBsAg transgenic mouse model, the expression of HBsAg in the hepatic cells was also significantly reduced after immunized with pCD-S 2 in the presence of 0.5% CIM and 0.25% PZQ. Further investigations demonstrated that the synergistic effects of combination of CIM and PZQ were dependent on enhanced cytotoxic CD8(+) T cells, which was correlated with impaired activities of regulatory T cells. Therefore, combinations of CIM and PZQ have great potential to be used as effective adjuvants on DNA-based vaccinations for the treatment of chronic hepatitis B.

Cimetidine Adverse Effects

https://www.ncbi.nlm.nih.gov/books/NBK544255/

50) Pino, Maria A., and Samy A. Azer. “Cimetidine.” StatPearls [Internet]. StatPearls Publishing, 2019.

High doses of cimetidine (over 5 g/day) can cause reversible impotence or gynecomastia.[20] This effect appears to be the result of the antiandrogenic potential of cimetidine, which depends on an increase in prolactin levels secondary to histamine H2 receptor blockade. Also, cimetidine has non-specific actions that stimulate prolactin secretion, causing galactorrhea in men in a dose-related pattern.[21][22] The effects could also be related to a blockade of the 2-hydroxylation of estradiol. However, gynecomastia in men is not an adverse effect with the other H2 receptor blockers (ranitidine, famotidine, and nizatidine).

Patients receiving treatment with drugs metabolized through the cytochrome P450 enzymatic pathway may experience enhanced drug effects resulting from pharmacokinetic interaction when treated concomitantly with cimetidine, as it is a well-known enzyme inhibitor of several CYP isoforms including 1A2, 2C9, 2D6, 3A4 P450 isoforms. Clinically relevant is inhibition of cytochrome 3A4 and 1A2.[20][23]. Inhibition of these enzymes can lead to increased plasma levels of certain drugs including warfarin, tricyclic antidepressants, lidocaine, calcium channel blockers, quinidine, oral sulfonylureas, phenytoin, theophylline, benzodiazepines, and beta-blockers (metoprolol and propranolol).

51)

Drug Repurposing for Colorectal Cancer: Redesigning a House Into a Bookstore

Drug Repurposing for Colorectal Cancer: Redesigning a House Into a Bookstore

Tumours have defensive mechanisms (the Empire’s TIE fighters, or in this case myeloid-derived suppressor cells and regulatory T cells) to stop immune cells from attacking it. This allows the tumour to continue to grow without surveillance.

Several studies have shown that cimetidine targets and shuts down the suppressor cells (Empire TIE fighters) [2,3]. By shutting down suppressor cells, the immune cells are free to attack the tumour with the ultimate goal of destroying that Death Star.

To̸nnesen H, Bulow S, Fischerman K, Hjortrup A, Pedersen V.M,

Svendsen L, et al. Effect of cimetidine on survival after gastric cancer.
The Lancet. 1988;332(8618):990-992.

Zheng Y, Xu M, Li X, Jia J, Fan K, Lai G. Cimetidine suppresses lung tumor growth in mice through proapoptosis of myeloid-derived suppressor cells. Molecular Immunology. 2013;54(1):74-83.

Matsumoto S, Imaeda Y, Umemoto S, Kobayashi K, Suzuki H, Okamoto T. Cimetidine increases survival of colorectal cancer patients with high levels of sialyl Lewis-X and sialyl Lewis-A epitope expression on tumour cells. British Journal of Cancer. 2002;86(2):161-167.

Deva S, Jameson M. Histamine type 2 receptor antagonists as adjuvant treatment for resected colorectal cancer. [Internet]. 2012 [cited 8 February 2017]. Available from: http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD007814.pub2/full

Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme V.P. Repurposing drugs in oncology (ReDO)—Cimetidine as an anti-cancer agent. ecancermedicalscience. 2014;8.

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T-Reg Cell re-programming

free pdf
Moreno Ayala, Mariela A., Zehui Li, and Michel DuPage. “Treg programming and therapeutic reprogramming in cancer.” Immunology 157.3 (2019): 198-209.

Overcoming the immunosuppressive tumour microenvironment is the major challenge impeding cancer immunotherapy today. Regulatory T-cells (Tregs) are prevalent in nearly all cancers and, as immunosuppressive regulators of immune responses, they are the principal opponents of cancer immunotherapy. However, disabling Tregs systemically causes severe autoimmune toxicity, hastening the need for more selective methods to target intratumoural Tregs. In this review, we discuss a burgeoning new modality to specifically target tumour-infiltrating Tregs (TI-Tregs) by reprogramming their functionality from immunosuppressive to immune stimulatory within tumours. As the basis for therapeutic selectivity of TI-Tregs, we will focus on the defining features of Tregs within cancer: their highly activated state controlled by the engagement of key surface receptors, their distinct metabolic programme, and their unique transcriptional programme. By identifying proteins and pathways that distinguish TI-Tregs from other Tregs in the body, as well as from the beneficial antitumour effector T-cells within tumours, we highlight mechanisms to selectively reprogramme TI-Tregs for the treatment of cancer.

the selective reprogramming of Tregs within cancers represents a singular methodology to overcome the last barriers that impede the broad suc-cess of cancer immunotherapy in patients by both over-coming immunosuppression in the TME and limiting autoimmune toxicity.

Munn, David H., Madhav D. Sharma, and Theodore S. Johnson. “Treg destabilization and reprogramming: implications for cancer immunotherapy.” Cancer research 78.18 (2018): 5191-5199.
Regulatory T cells (Tregs) are an important contributor to the immunosuppressive tumor microenvironment. To date, however, they have been difficult to target for therapy. One emerging new aspect of Treg biology is their apparent functional instability in the face of certain acute proinflammatory signals such as IL6 and IFNγ. Under the right conditions, these signals can cause a rapid loss of suppressor activity and reprogramming of the Tregs into a proinflammatory phenotype. In this review, we propose the hypothesis that this phenotypic modulation does not reflect infidelity to the Treg lineage, but rather represents a natural, physiologic response of Tregs during beneficial inflammation. In tumors, however, this inflammation-induced Treg destabilization is actively opposed by dominant stabilizing factors such as indoleamine 2,3-dioxygenase and the PTEN phosphatase pathway in Tregs. Under such conditions, tumor-associated Tregs remain highly suppressive and inhibit cross-presentation of tumor antigens released by dying tumor cells. Interrupting these Treg stabilizing pathways can render tumor-associated Tregs sensitive to rapid destabilization during immunotherapy, or during the wave of cell death following chemotherapy or radiation, thus enhancing antitumor immune responses. Understanding the emerging pathways of Treg stabilization and destabilization may reveal new molecular targets for therapy. Cancer Res; 78(18); 5191–9

Aldinucci, Donatella, Cinzia Borghese, and Naike Casagrande. “Formation of the immunosuppressive microenvironment of classic Hodgkin lymphoma and therapeutic approaches to counter it.” International journal of molecular sciences 20.10 (2019): 2416.

Classic Hodgkin lymphoma (cHL) is characterized by a few tumor cells surrounded by a protective, immunosuppressive tumor microenvironment composed of normal cells that are an active part of the disease. Hodgkin and Reed–Sternberg (HRS) cells evade the immune system through a variety of different mechanisms. They evade antitumor effector T cells and natural killer cells and promote T cell exhaustion. Using cytokines and extracellular vesicles, they recruit normal cells, induce their proliferation and “educate” (i.e. reprogram) them to become immunosuppressive and protumorigenic. Therefore, alternative treatment strategies are being developed to target not only tumor cells but also the tumor microenvironment. Here we summarize current knowledge on the ability of HRS cells to build their microenvironment and to educate normal cells to become immunosuppressive. We also describe therapeutic strategies to counteract formation of the tumor microenvironment and related processes leading to T cell exhaustion and repolarization of immunosuppressive tumor-associated macrophages.

Checkpoint Inhibitors and Adjuvants: Nivolumab, Pembrolizumab, and Indoximod

Nivolumab and pembrolizumab are human IgG4 (S228P) monoclonal antibodies that target PD-1, which is expressed on activated T cells, B cells, and myeloid cells. Both nivolumab and pembrolizumab bind and block engagement of PD-1, thereby activating T cells and cell-mediated immune responses.

Despite a great inflammatory infiltrate, patients with cHL have an impaired cellular immune response [107,142]. This is mediated by several factors including the high expression of PD-L1 and PD-L2 ligands by HRS cells, since PD-1 engagement by PD-L1 leads to T cell exhaustion, that is reduced T cell activation and proliferation

Idelalisib is the first PI3K-δ inhibitor to be approved for follicular lymphoma [163] and chronic lymphocytic leukemia [164]. Recently, it has been demonstrated that the selective targeting of the ϒ isoform of PI3K in TAMs modulates the immunosuppressive TME, resulting in tumor regression [165]. Hyperactivation of the PI3K/AKT pathway is involved in the pathogenesis of cHL

 

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