Dr Lisanti’s Group reported in 2015 Oncotarget that common antibiotics such as erythromycin (clarithromycin) and doxycycline can be re-purposed as very effective anti-cancer agents which “eradicate cancer stem cells “. (4) They point out that these two antibiotics work by inhibiting ribosomal protein production in bacteria. Similarly, they also inhibit mitochondrial ribosomal protein production in cancer cells which have mitochondria which look remarkably similar to bacteria. Doxycycline targets the small ribosome and clarithromycin targets the larger ribosome. See above image showing similarity of ribosomes for mitochondria and bacteria Courtesy of Lamb, Lisanti 2015 (4).
Indeed, this similarity between bacteria and mitochondria was the basis of the endosymbiotic theory of Lynn Margulis, a biologist who revolutionized evolutionary theory by suggesting that mitochondria “evolved” from free living bacteria.(13)
Lisanti’s group also showed that cancer stem cells depend on “mitochondrial biogenesis”. Cancer stem cells have increased mitochondrial mass, and rely on mitochondrial oxidative phospharylation for energy requirements. Left Image Courtesy of Lamb, Lisanti 2015 (4).
Cancer Stem Cell Plasticity
Dr. Michael Lisanti’s more recent paper in Oncotarget 2017 was the subject of my article (1): Doxycycline Vitamin C Anti-Cancer Synergy Eradicates Cancer Stem Cells
In this report, Dr Lisanti explores the “metabolic plasticity of cancer stem cells“, meaning that cancer cells develop resistance to antibiotic treatment by switching from an “oxidative phenotype” to a “glycolytic phenotype“. The cancer stem cells adapt by switching away from mitochondrial energy production, and instead use the less efficient aerobic glycolysis pathway in the cytosol. These glycolytic cancer stem cells are now sensitive to treatment with a glycolysis inhibitor, providing “synthetic lethal synergy“.(1) Among others, high dose IV vitamin V (ascorbate) may serve as such a glycolysis inhibitor. Left Image Courtesy of Lamb, Lisanti 2015 (4).
Combined use of Doxycycline (tetracycline) and Clarithromycin (erythromycin), targeting both large and small ribosomes, provides more profound inhibition of mitochondrial protein production in cancer stem cells than either agent alone.
Dual Inhibition Targets Cancer Stem Cells
In 2016 in Breast cancer research, Dr Lisanti’s group studied Breast cancer stem cells suggesting that dual blockade of glycolysis and mitochondrial respiration “may represent a better way to eradicate Cancer Stem Cell (CSC) heterogeneity than focusing exclusively on glycolysis inhibition or suppression of mitochondrial respiration.” (16)They also pointed out features of the tumor micro-environment:
“inflammatory cytokines generated by the tumour microenvironment (such as IL-6 and IL-8) with activation of NF-κB induce glycolysis with activation of PI3K and AKT and stimulate CSC self-renewal, which then may promote tumour growth and metastasis”(16)
Clarithromycin as Repurposed Anti-Cancer Drug,
In addition ribosomal inhibition, Clarithromycin (CAM) has other anti-cancer effects such as “prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis”(3). “At clinically relevant concentrations (6 to 50 μg/mL) CAM inhibits lysosomal function (after fusion of the autophagosomes with the lysosomes)”(3)
In-vitro, animal xenograft studies and human studies have been done. Use of CAM in multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer seems to have the highest level of evidence, so far.(3)
CAM for Pharyngitis in Lymphoma Patients
Dr. Carella et al reported in 2012 improved clinical outcome of CML (Chronic Leukemia) patients with CAM in combination with a tyrosine kinase inhibitor (TKI), (either dasatinib or nilotinib). Dr Carella observed in a patient responding poorly to Tyrosine Kinase Inhibitor (dasatinib) , a dramatic change with complete response after treatment with CAM for pharyngitis.(6)
“the remarkable responses obtained in these seven patients support the hypothesis that (CAM) inhibition of autophagy may make CML cells sensitive to killing by TKIs (Tyrosine Kinase Inhibitors).”(6)
CAM downregulation of Bcl-xL, Inhibits Lysosomal function(7), Increases Natural killer Cell Activity(3)
“Semino-Mora et al,(14) reported that β-catenin levels were decreased in the cytoplasm, the cell nuclei, and the mucin-associated cells while β-catenin levels within membranes increased in pseudomyxoma peritonei patients after H pylori eradication treatment containing CAM, providing potential protection against cell detachment, cellular invasion, and metastasis.”(14)
CAM is an Anti-inflammatory Drug
CAM temporarily suppresses the production of the pro-inflammatory cytokines IL-1α, IL-1β, interleukin-1 receptor antagonist (IL-1RA), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), IL-6, IL-8 and TNF-α in human monocytes, eosinophils, monocytic leukemia cell lines, and bronchial epithelial cells [104–108]. A decrease in IL-6 was confirmed in serum of lung cancer patients . CAM inhibits NF-κB activation.(3)
CAM for MALT Lymphoma-Human Study
MALT lymphoma is a B-cell lymphoma originating in the “mucosa-associated lymphoid tissue (MALT)”, frequently involving stomach or other parts of the GI tract. Dr Andres Ferreri analyzed 55 cases of MALT lymphoma treated with CAM mono-therapy.(4) Three year survival was 96% with no patient dying of lymphoma. Four year progression free survival was 60%. Dr Ferreri reported in 2017 Brit j heme, saying that CAM should be re-purposed drug against MALT lymphoma, and a long term daily dose of one gram a day is safe and effective.(4) Dr Ferreri suggested the combination of CAM and lenalidamide might by synergistic and more effective.
CAM for B Cell Lymphoma – In-Vitro study
Dr Ohara reported in 2004 Anticancer research that CAM directly induces apoptosis in B cell lymphoma cells derived from mice in this in-vitro study.(5) They identified down-regulation of BCL-2 in the CAM treated cell cultures. BCL2 is the anti-apoptotic protein frequently upregulated in lymphoma which “immortalizes ” the cancer cells by preventing programmed cell death. (5)
CAM CASE Reports in Lymphoma
Dr Masashi Ohe from Korea reported success in a number of case reports using CAM for various lymphoma cell types.(8-11) CAM dosage was 400 mg twice a day, given long-term.(11)
Another case report of diffuse large B-cell lymphoma of the oral cavity underwent “spontaneous remission” 20 days after biopsy. In fact, the patient had been treated with azithromycin post biopsy to prevent infection. The patient was followed for 2.5 years with no recurrence.(27)
Clarithromycin Used for Multiple Myeloms
New York Weil Cornell Dr Tomer Mark
Dr Tomer Mark is enthusiastic about excellent results in Multiple Myeloma by adding in Clarithromycin to the standard regimen of Revlimid and Dexamethazone.(28-34) Dr Tomer Mark found longer remissions and ability to overcome resistant cell types when adding in the clarithromycin.
Conclusion: The evidence for Clarithromycin as an anti-cancer agent is now overwhelming, one wonders why it is not routinely used on the oncology wards for all lymphoma patients.
Articles with Related Interest:
Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Fl 33314
Links and References
CAM inhibits IL-6 secretion-Repurposed as Anticancer Drug
1) De Francesco, E. M., Michael Lisanti et al. “Vitamin C and Doxycycline: a synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).” Oncotarget (2017). Vitamin C and Doxycycline: A synthetic lethal combination therapy targeting metabolic flexibility in cancer stem cells (CSCs).
CAM inhibits NF-κB activation
Repurposed for Lymphoma
2) Ferreri, Andrés JM, et al. “Clarithromycin as a “repurposing drug” against MALT lymphoma.” British Journal of Haematology (2017).
Clarithromycin is an exemplary model of a repurposing drug for lymphoma patients; a long-lasting treatment with a daily dose of 1 g is safe, active and cost-effective; an important issue at a time when the sustainability of oncology drugs is a major concern.
CAM downregulation of Bcl-xL, Inhibits Lysosomal function, Increases Natural killer Cell Activity
3) Van Nuffel, An MT, et al. “Repurposing Drugs in Oncology (ReDO)—clarithromycin as an anti-cancer agent.” ecancermedicalscience 9 (2015).
Clarithromycin (CAM) is a well-known macrolide antibiotic available as a generic drug. CAM is traditionally used for many types of bacterial infections, treatment of Lyme disease and eradication of gastric infection with Helicobacter pylori. Extensive preclinical and clinical data demonstrate a potential role for CAM to treat various tumours in combination with conventional treatment. The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis. Here, we present an overview of the current preclinical (in vitro and in vivo) and clinical evidence supporting the role of CAM in cancer. Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence. Finally, a series of proposals are being made to further investigate the use of CAM in clinical trials which offer the greatest prospect of clinical benefit to patients.
Long-term (from 3 to 12 months) administration of CAM at the dose of 500 mg daily has been shown to be safe and effective in patients with chronic pulmonary disease or chronic sinusitis [3, 4]. Treatment for four years with 200 mg/day has been trialed in ten patients with diffuse panbronchiolitis with no adverse events except for transient mild diarrhoea which spontaneously resolved after a few days in one patient
CAM inhibits cytochrome P450 3A4 (CYP3A4) which is involved in the hepatic metabolism of many drugs. It belongs to the intermediate CYP3A4 inhibition group of antibiotic macrolides
CAM administered seven days or more after vindesine or cisplatin significantly enhanced the effect of chemotherapy by increasing natural killer cell activity and CD8 T cell cytotoxicity, by inducing the well-balanced expansion of helper T cell subsets recovering from immunosuppression caused by the chemotherapy. Intriguingly, this effect was not seen when CAM was administered immediately after chemotherapy
There is evidence that CAM is a potent and continuous inhibitor of autophagy in both myeloma and chronic myeloid leukaemia cells. At clinically relevant concentrations (6 to 50 μg/mL) CAM inhibits lysosomal function (after fusion of the autophagosomes with the lysosomes)
At least in activated lymphocytes, the downregulation of Bcl-xL has been reported as the mechanism by which CAM induces apoptosis
Semino-Mora et al reported that β-catenin levels were decreased in the cytoplasm, the cell nuclei, and the mucin-associated cells while β-catenin levels within membranes increased in pseudomyxoma peritonei patients after H pylori eradication treatment containing CAM, providing potential protection against cell detachment, cellular invasion, and metastasis
In MM cells, CAM contributed to the anti-tumour effect by halting the autophagy process at clinically relevant concentrations of 6–50 μg/mL
It is possible that a very short course of CAM just at the time of chemo or radiation therapy might increase cell kill by inhibition of autophagy. However, allowing autophagy to take place may be critical for antigen presentation by dendritic cells , which occurs a few days after chemotherapy-induced cell kill. Thus CAM administration may be best avoided for a week or two following cell kill. On the other hand, autophagy blockade aids NK cell lysis, so that late institution of CAM treatment would serve this purpose . The paper by Hamada et al emphasises the fact that CAM treatment was beneficial only when started one week post chemotherapy  and CAM treatment was instituted by Mikasa et al about a month after chemo and radiation therapy was over .
The mechanisms of action underlying the anti-tumour activity of CAM are multiple and include prolonged reduction of pro-inflammatory cytokines, autophagy inhibition, and anti-angiogenesis.
Overall these findings justify further research with CAM in many tumour types, with multiple myeloma, lymphoma, chronic myeloid leukaemia (CML), and lung cancer having the highest level of evidence.
The antibacterial effect of macrolides is related to their capacity to inhibit protein synthesis in bacteria. They do so by binding to subunit 50S of the bacterial ribosome.
Treatment with CAM alone was able to significantly delay the growth of Lewis lung carcinoma and reduce the number of tumour nodules in C57BL/6 mice, with a dose of 10 mg/kg/day being most effective in inducing antitumor effects
CAM can inhibit tumour-induced angiogenesis in mice
CAM is a potent and continuous inhibitor of autophagy in both myeloma and chronic myeloid leukaemia cells.
At clinically relevant concentrations (6 to 50 μg/mL) CAM inhibits lysosomal function (after fusion of the autophagosomes with the lysosomes)
The first report of the use of CAM in MM patients dates back to 1997. Durie et al reported at that time a greater than 50% response rate when 500 mg CAM was administered twice per day
Carella et al reported in 2012 that CAM could also improve clinical outcome of CML patients in combination with a tyrosine kinase inhibitor (TKI), either dasatinib or nilotinib.
They serendipitously observed in one patient whose disease was not controlled with dasatinib that after treatment with CAM for otitis/pharyngitis the patient had a complete cytogenetic response
Eradication of H pylori results in durable tumour regression in the majority of patients with low-grade gastric MALT lymphoma [50, 51]. In patients with high-grade gastric MALT lymphoma or primary gastric diffuse large B-cell lymphoma (DLBCL) durable complete remissions have been described in response to a combination of antibiotics which includes CAM
case report of a patient with Hodgkin’s disease of the nodular sclerotic type who benefited from antibiotic treatment. CAM combined with another antibiotic, ciprofloxacin, resulted in an almost complete disappearance of the pulmonary lesions. The antibiotics were continued for another five months and more than two years later a complete remission was documented
CAM inhibits IL-6 secretion
CAM temporarily suppresses the production of the pro-inflammatory cytokines IL-1α, IL-1β, interleukin-1 receptor antagonist (IL-1RA), granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage colony stimulating factor (GM-CSF), IL-6, IL-8 and TNF-α in human monocytes, eosinophils, monocytic leukemia cell lines, and bronchial epithelial cells [104–108]. A decrease in IL-6 was confirmed in serum of lung cancer patients 
Antibiotics eradicate cancer stem cells…Lisanti
4) Oncotarget. 2015 Mar 10; 6(7): 4569–4584.
Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease Rebecca Lamb,#1,2 Bela Ozsvari,#1,2 Camilla L. Lisanti,3,** Herbert B. Tanowitz,4 Anthony Howell,1,2 Ubaldo E. Martinez-Outschoorn,5 Federica Sotgia,1,2 and Michael P. Lisanti1,2
Here, we propose a new strategy for the treatment of early cancerous lesions and advanced metastatic disease, via the selective targeting of cancer stem cells (CSCs), a.k.a., tumor-initiating cells (TICs). We searched for a global phenotypic characteristic that was highly conserved among cancer stem cells, across multiple tumor types, to provide a mutation-independent approach to cancer therapy. This would allow us to target cancer stem cells, effectively treating cancer as a single disease of “stemness”, independently of the tumor tissue type. Using this approach, we identified a conserved phenotypic weak point – a strict dependence on mitochondrial biogenesis for the clonal expansion and survival of cancer stem cells. Interestingly, several classes of FDA-approved antibiotics inhibit mitochondrial biogenesis as a known “side-effect”, which could be harnessed instead as a “therapeutic effect”. Based on this analysis, we now show that 4-to-5 different classes of FDA-approved drugs can be used to eradicate cancer stem cells, in 12 different cancer cell lines, across 8 different tumor types (breast, DCIS, ovarian, prostate, lung, pancreatic, melanoma, and glioblastoma (brain)). These five classes of mitochondrially-targeted antibiotics include: the erythromycins, the tetracyclines, the glycylcyclines, an anti-parasitic drug, and chloramphenicol. Functional data are presented for one antibiotic in each drug class: azithromycin, doxycycline, tigecycline, pyrvinium pamoate, as well as chloramphenicol, as proof-of-concept. Importantly, many of these drugs are non-toxic for normal cells, likely reducing the side effects of anti-cancer therapy. Thus, we now propose to treat cancer like an infectious disease, by repurposing FDA-approved antibiotics for anti-cancer therapy, across multiple tumor types. These drug classes should also be considered for prevention studies, specifically focused on the prevention of tumor recurrence and distant metastasis. Finally, recent clinical trials with doxycycline and azithromycin (intended to target cancer-associated infections, but not cancer cells) have already shown positive therapeutic effects in cancer patients, although their ability to eradicate cancer stem cells was not yet appreciated.
5) Ohara, Tadashi, et al. “Antibiotics directly induce apoptosis in B cell lymphoma cells derived from BALB/c mice.” Anticancer research 24.6 (2004): 3723-3730.
BACKGROUND: The effects of bacterial eradication therapy cannot be fully explained simply by elimination of the target bacteria, if one considers the effects of eradication therapy in H. pylori-negative cases of low-grade malignancy MALTomas of the rectum. The present study was undertaken to examine the possibility and mechanism of direct induction of apoptosis of the tumor cells by the antibiotics used for bacterial eradication therapy.
MATERIALS AND METHODS: A B cell lymphoma cell line (300-19) derived from BALB/c mice was co-cultured with amoxicillin or clarithromycin, and amoxicillin and clarithromycin at concentrations equal to or 1/10 x MIC of either drug. Cells co-cultured with 1/100 x MIC of the standard anti-tumor agents, adriamycin, vincristine and cyclophosphamide, served as positive controls. Cells cultured without any antibiotic or anti-tumor agent served as controls. In each group, the following analyses were performed: (i) the time-course of changes in the cellular morphology, (ii) the time-course of occurrence of DNA fragmentation, (iii) the appearance of apoptotic changes as evaluated by trypan blue staining, (iv) Bcl-2 expression as examined by immunoblotting; and (v) the expression of TNFR1, Fas, FasL and caspase-3, -8 and -9, as evaluated by immunoblotting.
RESULTS: Cells treated with amoxicillin and clarithromycin showed the formation of apoptotic bodies, and degeneration and detachment of the cells in a dose-dependent manner. DNA fragmentation was induced in these cells to a degree similar to that seen in cells treated with the anti-tumor agents. Trypan blue staining also demonstrated apoptosis of the cells and loss of cell viability. Bcl-2 expression was seen only in the control group and FasL was never seen, while the expression of TNFR1, Fas and caspase-3, -8 and -9 was seen in the amoxicillin-treated group, clarithromycin-treated group, amoxicillin and clarithromycin-treated group and the positive control group.
CONCLUSION: Antibiotics used for the eradication of H. pylori can also directly induce apoptosis in mouse B cell lymphoma cells, an action which involves the TNF system.
CAM (Clarithyromycin) directly induces apoptosis in a murine B cell lymphoma cell line, via the TNF system.
Clarith Potentiates Tyrosine Kinase Inhibitor
6) Clarithromycin potentiates tyrosine kinase inhibitor treatment in patients with resistant chronic myeloid leukemia.
Carella AM, Beltrami G, Pica G, Carella A, Catania G.
Comment in A new purpose for an old drug: inhibiting autophagy with clarithromycin. [Leuk Lymphoma. 2012]
In conclusion, the remarkable responses obtained in these seven patients support the hypothesis that inhibition of autophagy may make CML cells sensitive to killing by TKIs.1, 2 These results cannot be explained by the inhibition of CYP3A3 alone, but probably the main underlying mechanism was reversal of the effects of autophagy. We checked the patients weekly, and we can conclude that this combination did not result in liver, renal or cardiac toxicity. Although prolonged response in advanced cases is unlikely, there is great potential for a combination of this type to increase the potential to cure CML if given early in the disease.
7) Blood Cancer Journal (2016) 6, e423; Macrolide antibiotics (Z-Pack) exert antileukemic effects by modulating the autophagic flux through inhibition of hERG1 potassium channels
8) Korean J Hematol. 2011 Sep; 46(3): 203–206.
A case of follicular B-cell lymphoma treated using clarithromycin
Masashi Ohe, corresponding author1 and Satoshi Hashino, 2
We report a case of follicular B-cell lymphoma (FL) treated successfully using clarithromycin (CAM). A 44-year-old man who presented with lymphadenopathy was diagnosed with FL after a histological examination of his biopsy specimens. He was administered chemotherapy with R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, and prednisolone) following which stable disease was achieved. However, the subsequent clinical course showed partial remission of FL and stable disease with tumor regrowth, each of which was treated with chemotherapeutic regimens. Since the patient was diagnosed with leukocytopenia, he could not undergo chemotherapy for the third regrowth; hence, he was administered CAM. His lymphadenopathy regressed and the levels of soluble interleukin 2-receptor decreased. This case shows that treatment using CAM may be effective in some cases of FL.
9) Korean J Hematol. 2012 Dec;47(4):293-297. English.
Successful treatment of diffuse large B-cell lymphoma with clarithromycin and prednisolone Masashi Ohe,1 Satoshi Hashino,3 and Atsuo Hattori2
1Department of General Medicine, Hokkaido Social Insurance Hospital, Sapporo, Japan.
We report a case of diffuse large B-cell lymphoma (DLBCL) treated successfully with clarithromycin (CAM) and prednisolone (PSL). A 71-year-old woman presented with fever and cervical pain. DLBCL was diagnosed based on histological results from lymph node biopsy. Cervical pain was thought to be caused by the invasion of lymphoma cells into the cervical vertebrae. She initially received radiotherapy for the cervical lesion. She did not receive conventional chemotherapy because of the risk of recurrent non-tuberculous mycobacteria infection; therefore, she was treated with 20 mg/day PSL and 800 mg/day CAM to induce apoptosis in lymphoma cells. Complete remission was achieved after 6 months. The present findings suggest that CAM and PSL may be effective in some cases of DLBCL.
Complete remission (CR) was achieved after 6 months, with improvements in lymphadenopathy and lesions of the bone and bone marrow apparent on both CT (Fig. 1B) and FDG-PET (Fig. 3B). The sIL-2R levels decreased to 215 U/mL. Slightly reduced taste sensation was reported, and was considered a side effect of long-term CAM use. She remains in CR 7 months after initiation of treatment.
10) Blood Res 2016; 51(2): 139-142 Successful treatment of angioimmunoblastic T-cell lymphoma with clarithromycin Masashi Ohe1*, and Satoshi Hashino21Department of General Medicine, JCHO Hokkaido Hospital, Sapporo, Japan.
Based on these data, the effectiveness of CAM treatment in the present case may have been partly associated with the inhibitory effects of CAM on VEGF production.
11) Ohe, Masashi, and Satoshi Hashino. “Successful treatment of recurrent follicular B-cell lymphoma with clarithromycin, prednisolone, and cyclophosphamide.” The Korean journal of internal medicine 28.3 (2013): 377.
We previously reported a case of bcl-2-positive diffuse large B-cell lymphoma (DLBCL) that was treated successfully with CamP . Because CAM is known to induce down-regulation of bcl-2 protein in lymphoid cells  and glucocorticoids are known to induce apoptosis of lymphoid cells, we suggest that the CamP treatment had induced apoptosis of lymphoma cells in our previous case. Because no superficial lymph nodes, other than the para-aortic lymph nodes, were palpable and the platelet count was 52 × 109/L in this recurrence, we did not rebiopsy the lymph nodes.
Regarding specific details of the regimens, the CAM dosage was 400 mg, twice daily, for the long-term.
13) Lynn Margulis and the Question of How Cells Evolved
(excerpts from the book “Doing Biology” by Joel Hagen et al)
14) Semino-Mora, Cristina, et al. “Antibiotic treatment decreases microbial burden associated with pseudomyxoma peritonei and affects β-catenin distribution.” Clinical Cancer Research 19.14 (2013): 3966-3976.
Neurotoxicity Long term
15) J Clin Neurosci. 2011 Mar;18(3):313-8. Clarithromycin-induced neurotoxicity in adults. Bandettini di Poggio M1, Anfosso S, Audenino D, Primavera A.
Clarithromycin is a relatively new antibiotic of the macrolide family heralded for an improved side effect profile, dosing schedule, and microbiological activity relative to its parent compound, erythromycin. We review the literature on clarithromycin-induced neurotoxicity in adults and present an illustrative case. A total of 38 patients with clarithromycin-induced neurotoxicity have been reported. The average age of patients was 51.3 years (range: 19-87 years) with females comprising 52.6% of patients. Psychiatric illness was the most common comorbidity, while only two patients had renal failure. Clarithromycin had been prescribed for respiratory infections in most patients, and only two patients were receiving more than 1000 mg/day of antibiotic. The symptoms started 1 day to 10 days after starting clarithromycin (mean: 5 days). A total of 71% of patients were under treatment with concomitant medication, and eight patients were undergoing treatment with psychoactive drugs. Patients had a very good outcome after clarithromycin was discontinued, but medication with neuroleptics or benzodiazepine was required for 58% of patients in the acute phase. Only four patients underwent an electroencephalogram (EEG). Our illustrative patient was a 74-year-old woman with clarithromycin-induced delirium due to non-convulsive status epilepticus (NCSE). Her clinical symptoms and electroencephalogram (EEG) readings dramatically improved after discontinuation of clarithromycin. The mechanism underlying the central nervous system side effects remains unclear. We suggest including an EEG in the diagnostic procedures of patients under treatment with clarithromycin who develop features of neurotoxicity because an EEG can help to differentiate patients with psychiatric illness from those with encephalopathy or epilepsy. Because of the widespread use of clarithromycin, clinicians should be aware of its neurotoxicity. Early detection of clarithromycin-induced neurotoxicity and discontinuation of the drug may result in full recovery.
cancer stem cells Antibiotics Michael P. Lisanti
16) Peiris-Pagès, Maria, et al. “Cancer stem cell metabolism.” Breast Cancer Research: BCR 18 (2016). Maria Peiris-Pagès, Ubaldo E. Martinez-Outschoorn, Richard G. Pestell, Federica Sotgia,corresponding author and Michael P. Lisanti
Given that CSCs are considered to be the source from which cancer cells arise, are therapy resistant and are responsible for metastatic dissemination, eliminating them could potentially achieve a permanent cure for the patient.if conventional therapy fails to kill CSCs, acting only against differentiated cancer cells, the tumour can eventually relapse . The specific elimination of CSCs may thus represent one of the most important challenges of current cancer research
a glycolytic phenotype seems to be a shared feature of normal stem cells and differentiated cancer cells in culture.
CSCs treated with a mitochondrial ROS inducer such as menadione do not become resistant, suggesting that increasing mitochondrial ROS levels to non-viable levels might be a better approach to eliminate CSCs .
the dual blockade of glycolysis and mitochondrial respiration may represent a better way to eradicate CSC heterogeneity than focusing exclusively on glycolysis inhibition or suppression of mitochondrial respiration.
Conversely, inflammatory cytokines generated by the tumour microenvironment (such as IL-6 and IL-8) with activation of NF-κB induce glycolysis with activation of PI3K and AKT and stimulate CSC self-renewal, which then may promote tumour growth and metastasis
17) Cheong, Jae-Ho, et al. “Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models.” Molecular cancer therapeutics 10.12 (2011): 2350-2362.
However, 2DG and metformin led to significant cell death associated with decrease in cellular ATP, prolonged activation of AMPK, and sustained autophagy.
18) Cell Metab. 2015 Oct 6;22(4):590-605. doi: 10.1016/j.cmet.2015.08.015. Epub 2015 Sep 10.
MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.
Sancho P1, Burgos-Ramos E2, Tavera A2, Bou Kheir T3, Jagust P3, Schoenhals M3, Barneda D3, Sellers K4, Campos-Olivas R5, Graña O6, Viera CR2, Yuneva M4, Sainz B Jr2, Heeschen C7.
The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.
Similar to K2(menadione), Alpha lipoic acid and carnitine both increase ROS in mitrochondria.
19) Lamb, Rebecca, et al. “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: treating cancer like an infectious disease.” Oncotarget 6.7 (2015): 4569.
20) Antibiotics target mitochondria eradicate cancer stem cells Treating cancer like infectious disease Bošković Bogdan Acta Medica Academica 2015 Bošković, Bogdan. “Antibiotics that target mitochondria effectively eradicate cancer stem cells, across multiple tumor types: Treating cancer like an infectious disease.” Acta Medica Academica 44.1 (2015): 85.
21) De Luca, Arianna, et al. “Mitochondrial biogenesis is required for the anchorage-independent survival and propagation of stem-like cancer cells.” Oncotarget 6.17 (2015): 14777.
22) Lamb, Rebecca, et al. “Mitochondrial mass, a new metabolic biomarker for stem-like cancer cells: Understanding WNT/FGF-driven anabolic signaling.” Oncotarget 6.31 (2015): 30453.
23) Chiarugi, Paola, and Persio Dello Sbarba. “Cancer stemness and progression: mitochondria on the stage.” Oncotarget 6.35 (2015): 36924.
the papers recently published by Lisanti’s group together with current literature point to the existence, among cancer cell subsets, of a phenotype in which several features (as shown in the Figure) are intimately associated:
i) addiction to mitochondrial functions,
ii) activation of anabolic pathways,
iii) achievement of stem-like traits,
iv) resistance to stress and therapy,
v) ability to undergo epithelial/mesenchymal transition.
Interestingly, this complex phenotype is deeply influenced by microenvironmental factors, including cancer-associated “supporting” cells such as fibroblasts or macrophages (1), cytokines  and oxygen/glucose shortage
24) Korotchkina, Lioubov G., Sukhdeep Sidhu, and Mulchand S. Patel. “R-lipoic acid inhibits mammalian pyruvate dehydrogenase kinase.” Free radical research 38.10 (2004): 1083-1092.
An inhibitory effect of lipoic acid on PDKs would result in less phosphorylation of E1 and hence increased PDC activity.
pyruvate dehydrogenase complex (PDC)
25) Zhang, Wen, et al. “Targeting tumor metabolism for cancer treatment: is pyruvate dehydrogenase kinases (PDKs) a viable anticancer target?.” International journal of biological sciences 11.12 (2015): 1390.
inhibition of PDKs could upregulate the activity of PDC and rectify the balance between the demand and supply of oxygen, which could lead to cancer cell death. Thus, inhibitors targeting PDKs represent a promising strategy for cancer treatment by acting on glycolytic tumors while showing minimal side effects on the oxidative healthy organs. This review considers the role of PDKs as regulator of PDC that catalyzes the oxidative decarboxylation of pyruvate in mitochondrion. It is concluded that PDKs are solid therapeutic targets. Inhibition of PDKs could be an attractive therapeutic approach for the development of anti-cancer drugs.
26) Katoh, Masaru. “Canonical and non-canonical WNT signaling in cancer stem cells and their niches: Cellular heterogeneity, omics reprogramming, targeted therapy and tumor plasticity.” International Journal of Oncology 51.5 (2017): 1357-1369.
27) Kaibuchi, Nobuyuki, et al. “A case of spontaneous regression of lymphoma in the mandibular gingiva after biopsy.” Oral and Maxillofacial Surgery Cases 1.3 (2015): 33-37. (After Zithromycin)
We report a case of lymphoma that developed on the mandibular gingiva and spontaneously regressed after biopsy was performed. The patient was an 87-year-old man who visited our hospital with a complaint of gingival swelling in the left mandibular molar region. We observed an elastic, soft, well-demarcated, granuloma-like mass measuring 30 × 25 mm in size and comprising partially white pseudomembranous areas. We conducted a biopsy, which confirmed a pathologic diagnosis of a diffuse large B-cell lymphoma. After biopsy, azithromycin was administered to prevent infection. Because of age constraints, the patient was monitored without being administered aggressive therapy, and the mass disappeared 20 days after biopsy. We then performed a follow-up biopsy, which revealed the absence of tumor cells. There was no recurrence of lymphoma during the 2.5-year follow-up period.
Clarithromycin used for multiple myeloma
28) Using Antibiotics in Myeloma Combos To Kill Myeloma Cells by Reducing Inflammation with Dr. Tomer Mark, MD, Weill Cornell Medical Center by Jenny A on November 16, 2015 Myeloma Crowd
Dr. Tomer Mark, MD of the Weill Cornell Medical Center shares his use of Biaxin (clarithromycin) in a combination called “BIRD” – Biaxin, Revlimid and Dexamethasone. He notes that the use of the antibiotic with lenalidomide and dexamethasone can get equally good responses as VRD (Velcade-Rev-Dex) or CyborD (cyclophosphamide-bortezomib-dex). He likes the antibiotic combination option because it can spare patients some up-front chemo toxicity and allows doctors to reserve some active myeloma treatments for later, when patients relapse.
29) Shaulov, Adir, et al. “Progressive refractory light chain amyloidosis and multiple myeloma patients are responsive to the addition of clarithromycin to Imid based therapy.” American journal of hematology 92.2 (2017): 131-135.
Multiple myeloma (MM) and primary systemic light chain amyloidosis (AL) are both chronic plasma cell dyscrasias with different clinical expression but limited treatment options for relapsed refractory disease. We report the effect of the addition of clarithromycin on 31 MM and 17 AL with relapsed or refractory disease who had an insufficient response or disease progression while on an IMiD based therapy. In this high risk population, hematological response was reported in 48% of MM patients and 94% of AL patients. Responses were reported early in both groups (median 35 days) and were more sustained in AL patients. Adverse events were common and included mostly grade 1-2 fatigue, infections and abdominal discomfort. Cytopenias were common and cardiac complications were rare in both MM and AL patients. Clarithromycin-IMiD combination therapy appears to be both effective and safe in progressive MM and primarily in AL patients, although a prospective clinical trial is warranted to validate these results. Am. J. Hematol. 92:131-135, 2017.
30) Ghosh, Nilanjan, et al. “Clarithromycin overcomes resistance to lenalidomide and dexamethasone in multiple myeloma.” American journal of hematology 89.8 (2014).
The combination of clarithromycin, lenalidomide and dexamethasone (BiRd) has led to highly durable responses in newly diagnosed myeloma. However, the ability of clarithromycin to overcome resistance to lenalidomide and dexamethasone (Rd) is not known. To study this, we performed a retrospective analysis of 24 patients with myeloma for which clarithromycin was added to Rd at the time of progression on Rd. The median number of prior therapies was 3 (range 1–8). The best response was complete response (CR) in one (4.2%), very good partial response (VGPR) in one (4.2%) and partial response in eight (33.3%) patients. Ten patients, 41.7% (95% CI: 22.1, 63.4), achieved ≥PR. The median time to response was 4.4 months (range 1–13.6 months) and the median duration of response was 6.9 months (range 3–52.2 months). The clinical benefit rate (CR + VGPR + PR + MR) was 45.8% (95% CI 25.6, 67.2). The median progression-free survival was 4 months. Median overall survival was 25 months with a median follow-up of 27.5 months. The regimen was well tolerated and only 2 patients needed a clarithromycin dose reduction. Addition of clarithromycin to Rd can overcome resistance to Rd in a subset of patients and lead to durable clinical responses.
31) Rossi, Adriana, et al. “BiRd (clarithromycin, lenalidomide, dexamethasone): an update on long-term lenalidomide therapy in previously untreated patients with multiple myeloma.” Blood 121.11 (2013): 1982-1985.
The combination of clarithromycin, lenalidomide, and dexamethasone (BiRd) was evaluated as therapy for treatment-naive symptomatic multiple myeloma (MM), with overall response at 2 years of 90%. We reviewed the long-term follow-up of initial BiRd therapy. Seventy-two patients were given dexamethasone 40 mg weekly, clarithromycin 500 mg twice daily, and lenalidomide 25 mg daily on days 1 to 21 of a 28-day cycle. After a median follow-up of 6.6 years, overall response rates were 93%, with a very good partial response or better of 68%. Median progression-free survival was 49 months. Evaluation for the development of second primary malignancies (SPMs) was conducted, and no increase in incidence was noted in our cohort of patients who received frontline immunomodulatory therapy. BiRd remains a highly potent and safe regimen for frontline therapy in patients with MM without apparent increase in risk of SPMs. This trial was registered at www.clinicaltrials.gov as #NCT00151203.
32) Gay, Francesca, et al. “Clarithromycin (Biaxin)-lenalidomide-low-dose dexamethasone (BiRd) versus lenalidomide-low-dose dexamethasone (Rd) for newly diagnosed myeloma.” American journal of hematology 85.9 (2010): 664.
Francesca Gay, MD,1 S. Vincent Rajkumar, MD,1 Morton Coleman, MD,2 Shaji Kumar, MD,1 Tomer Mark, MD,2 Angela Dispenzieri, MD,1 Roger Pearse, MD,2 Morie A. Gertz, MD,1 John Leonard, MD,2 Martha Q. Lacy, MD,1 Selina Cheng-Kiang, PhD,3 Vivek Roy, MD,4 David S. Jayabalan, MD,2 John A. Lust, MD, PhD,1 Thomas E. Witzig, MD,1 Rafael Fonseca, MD,5 Robert A. Kyle, MD,1 Philip R. Greipp, MD,1 A. Keith Stewart, MD, ChB,5 and Ruben Niesvizky, MD2
The objective of this case–matched study was to compare the efficacy and the toxicity of the addition of clarithromycin (Biaxin) to lenalidomide/low-dose dexamethasone (BiRd) vs lenalidomide/low-dose dexamethasone (Rd) for newly diagnosed myeloma. Data from 72 patients treated at the New York Presbyterian Hospital–Cornell Medical Center were retrospectively compared to an equal number of matched pair mates selected among patients seen at the Mayo Clinic who received Rd. Case matching was blinded and was performed according to age, gender, and transplant status. On intention-to-treat analysis, complete response (45.8% vs 13.9%, p<0.001) and very-good-partial-response or better (73.6% vs 33.3%, p<0.001) were significantly higher with BiRd. Time-to-progression (median 48.3 vs 27.5 months, p=0.071), and progression-free survival (median 48.3 vs 27.5 months, p=0.044) were higher with BiRd. There was a trend toward better OS with BiRd (3-year OS: 89.7% vs 73.0%, p=0.170). Main grade 3–4 toxicities of BiRd were hematological, in particular thrombocytopenia (23.6% vs 8.3%, p=0.012). Infections (16.7% vs 9.7%, p=0.218) and dermatological toxicity (12.5% vs 4.2%, p=0.129) were higher with Rd. Results of this case-control analysis suggest that there is a significant additive value when clarithromycin is added to Rd. Randomized phase III trials are needed to confirm these results.
33) Niesvizky, Ruben, et al. “BiRD (Biaxin [clarithromycin]/Revlimid [lenalidomide]/dexamethasone) combination therapy results in high complete-and overall-response rates in treatment-naive symptomatic multiple myeloma.” Blood 111.3 (2008): 1101-1109.
This trial determined the safety and efficacy of the combination regimen clarithromycin (Biaxin), lenalidomide (Revlimid), and dexamethasone (BiRD) as first-line therapy for multiple myeloma. Patients received BiRD in 28-day cycles. Dexamethasone (40 mg) was given orally once weekly, clarithromycin (500 mg) was given orally twice daily, and lenalidomide (25 mg) was given orally daily on days 1 to 21. Objective response was defined by standard criteria (ie, decrease in serum monoclonal protein [M-protein] by at least 50%, and a decrease in urine M-protein by at least 90%). Of the 72 patients enrolled, 65 had an objective response (90.3%). A combined stringent and conventional complete response rate of 38.9% was achieved, and 73.6% of the patients achieved at least a 90% decrease in M-protein levels. This regimen did not interfere with hematopoietic stem-cell harvest. Fifty-two patients who did not go on to receive transplants received continued therapy (complete response, 37%; very good partial response, 33%). The major adverse events were thromboembolic events, corticosteroid-related morbidity, and cytopenias. BiRD is an effective regimen with manageable side effects in the treatment of symptomatic, newly diagnosed multiple myeloma. This trial was registered at www.clinicaltrials.gov as #NCT00151203.
34) Niesvizky, Ruben, et al. “Clarithromycin, lenalidomide and dexamethasone combination therapy as primary treatment of multiple myeloma.” Journal of Clinical Oncology 24.18_suppl (2006): 7545-7545.
R. Niesvizky, D. S. Jayabalan, J. R. Furst, H. J. Cho, R. N. Pearse, F. Zafar, R. W. Lent, J. Tepler, M. W. Schuster, J. P. Leonard, M. ColemanNew York Presbyterian Hospital, Weill Cornell Medical Center, New York, NY
Background: Lenalidomide (Revlamid [R]) is the leading clinical compound in a new group of drugs called IMiDs. Our group demonstrated that clarithromycin (Biaxin [Bi]) augments tumor mass reduction and improves responses in patients (pts) receiving low-dose thalidomide and/or dexamethasone (D). We report the results of the combination of Bi plus R plus D (BiRD) in newly diagnosed MM. Methods: A phase II trial designed to accrue 50 pts. A 2-stage design rejects a CR rate of < 10% (alt >30%). Between Nov. 2004 and Jan. 2006, 46 pts have been accrued of which 40 pts are eligible for evaluation. R is given po at 25 mg daily on days 1–21 of a 28-day cycle. D is given po at 40 mg once weekly. Bi is given po at 500 mg bid. Pts receive low dose aspirin (ASA)(81mg) qd as thrombosis (TE) prophylaxis. Responses are defined according to modified EBMTR criteria. Analysis is by intent-to-treat. Patient Selection: Median age: 62.5 years (36–80), Male/Female 25/15, Hgb: 10.6 g/dL (7.2–15.1), Plt 234 k/uL (51–526), β2m: 3 mg/L (0.8–12.8), CRP: 0.6 mg/dL (0.12–14.2), creat: 1.1 mg/dL (0.6–3.1), albumin 3.5 g/dL (2.3–4.9). SD stage IIIa: 48%, stage IIIb: 10% and IIa: 42%. ISS stage I: 50%, stage II: 25% and stage III: 25%. Cytogenetics and FISH: trisomy 11 (10 pts), tetrasomy 11 (3 pts), del13q14 (14 pts), t (4,14) (1pt), t (11,14) (3 pts). Results: Of the 40 evaluable pts, 38 (95%) have achieved an objective response (>PR) within 3–4 months of Rx with the remaining pts continuing to respond. Seventeen pts (43%) had a >90% reduction of the initial paraprotein. Nearly one third of pts have achieved either a CR (10/40) or a nCR (2/40-continuing on Rx). CR has been confirmed in all pts by normalization of free light chain levels and ratio. The remaining 26 pts (65%) achieved a PR. Of those pts who achieved a PR, 5/26 pts (19%) had >90% reduction in the initial paraprotein. Nineteen pts have experienced grade ≥3 adverse events. Heme toxicities: anemia (11%), neutropenia (9%) and thrombocytopenia (9%). Non-heme toxicities (NHT) include TE in 7 patients (15%) 2 of them fatal. Four of the TE events were while off ASA. Other NHT include myopathy (6%), GI (4%), and mood (4%). Conclusions: BiRD therapy is a safe and highly effective primary therapy for symptomatic, treatment-naïve MM.
35) MORIYA, SHOTA, et al. “Macrolide antibiotics block autophagy flux and sensitize to bortezomib via endoplasmic reticulum stress-mediated CHOP induction in myeloma cells.” International Journal of Oncology 42.5 (2013): 1541.
The specific 26S proteasome inhibitor bortezomib (BZ) potently induces autophagy, endoplasmic reticulum (ER) stress and apoptosis in multiple myeloma (MM) cell lines (U266, IM-9 and RPMI8226). The macrolide antibiotics including concanamycin A, erythromycin (EM), clarithromycin (CAM) and azithromycin (AZM) all blocked autophagy flux, as assessed by intracellular accumulation of LC3B-II and p62. Combined treatment of BZ and CAM or AZM enhanced cytotoxicity in MM cell lines, although treatment with either CAM or AZM alone exhibited almost no cytotoxicity. This combination also substantially enhanced aggresome formation, intracellular ubiquitinated proteins and induced the proapoptotic transcription factor CHOP (CADD153). Expression levels of the proapoptotic genes transcriptionally regulated by CHOP (BIM, BAX, DR5 and TRB3) were all enhanced by combined treatment with BZ plus CAM, compared with treatment with each reagent alone. Like the MM cell lines, the CHOP+/+ murine embryonic fibroblast (MEF) cell line exhibited enhanced cytotoxicity and upregulation of CHOP and its transcriptional targets with a combination of BZ and one of the macrolides. In contrast, CHOP−/− MEF cells exhibited resistance against BZ and almost completely canceled enhanced cytotoxicity with a combination of BZ and a macrolide. These data suggest that ER stress-mediated CHOP induction is involved in pronounced cytotoxicity. Simultaneously targeting two major intracellular protein degradation systems such as the ubiquitin-proteasome system by BZ and the autophagy-lysosome system by a macrolide antibiotic enhances ER stress-mediated apoptosis in MM cells. This result suggests the therapeutic possibility of using a macrolide antibiotic with a proteasome inhibitor for MM therapy.
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