COX2 Inhibitor Celecoxib As Anti-Cancer Drug

Bernard 2008 COX2 Inhibitors for Hematologic Malignancy

COX2 Inhibitors As Anti-Cancer Agents

The COX2 (Cyclo-Oxygenase) pathway is upregulated in cancer, and COX2 inhibitors (celecoxib) can inhibit cell proliferation, tumor  invasiveness, and angiogenesis.  They can also overcome apoptosis resistance by BCL2, and overcome P-glycoprotein/MDR drug resistance, as well as restore immune response. (15) In this article, we examine the COX-2 inhibitor celecoxib as an anticancer agent.  Upper left image from Bernard 2008(2).

COX 5-LOX and WNT Inhibition

Dr. Jessica Roos in a 2016 study of leukemia cells reports that NSAIDS inhibit COX and WNT pathways.(1) Specifically, inhibition of the  the 5-LOX pathway can inhibit WNT.(1)  Note Disulfiram is a potent 5-LOX inhibitor. Celecoxib at high concentrations inhibits both 5-LOX and glutathione.(1,2)

Targeting COX2 in Hematologic Cancers

The inflammatory pathway, Cox-2, is frequently overexpressed in various cancers, especially hematologic cancers such as leukemia, multiple myeloma and lymphoma.(2) Dr Bernard says in his 2008 article (2):

“Malignant B cells, namely chronic lymphocytic leukemia (CLL), highly express Cox-2, which confers increased survival [2, 14]. Conversely, Cox-2 selective inhibitors increased apoptosis in B-CLL cells, indicating their potential to act as anti-malignant tumor therapeutic agents.”(2)

Dr. Bernard, in his 2008 article summarizes the effects of Cox2 inhibitors (such as celebrex)(20 :

  1. Inhibition of Angiogeneisis by reducing VEGF
  2. Reduce Invasion by reduction in MMP
  3. Inhibit Prolifration by reduction in NFKB, STAT3, MEK and Cyclins,upregulate p27
  4. Impair Survival by downregulating BCL2,NFKB, Glutathione,AKT, and by increasing ROS, caspase activity, Fas
  5. Glutathione Levels are significantly attenuated by Celecoxib
  6. Enhance Host Immune Function (NK/CTL) by increasing IFN-gamma, decreasing MHC-I
  7. Reducing T-Reg Cells

Dr Subhashini reported in Cancer Letter 2005, that celecoxib had anti-proliferative and apoptotic effects in leukemia cells in vitro.(3)  Celecoxib also regulated the anti-apoptotic protein BCL-2, and inhibited NF-KB activation.(3)

Attenuates Glutathione Levels

Dr Ryan from Rochester reported in 2008, celecoxib 400 mg per day attenuated glutathione levels in malignant B cells, and reduced B-CLL proliferation and survival.(4)

Blocking Akt Activation

Using a Prostate Cancer cell model, Dr Hsu reported in 2000, “celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2″.

Reduction in Stem Cell Markers

Working with Esophageal Cancer cells in vitro, Dr Pilar Jiménez reported in 2017 that (6)

“Treatment with celecoxib alone or in combination with 5-FU also resulted in a reduction of CD24 expression. Moreover, celecoxib inhibited the growth of tumor spheres. These findings showing a reduction in CSC (cancer stem cell) markers induced by celecoxib.” (6)

Inhibit MTor, Restore GSK3-B, Inhibit B-Cateninin

Dr Beatice Riva reported in OncoTarget 2016 using a CML and ALL model, showing (7):

“celecoxib rapidly activated AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2…. Treatment with celecoxib also restored GSK3ß function and led to down-regulation of ß-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph+ cell growth suppression by celecoxib.”(7)

Induction of Apoptosis

In 2011 Dr Justine Rudner studied the mechanism of celecoxib induced apoptosis in lymphoma cells, finding celecobib caused the depletion of Mcl-1 which was sufficient for apoptosis induction, which could not be blocked by  overexpression of Bcl-2.(8)(10)  Celecoxib induces apoptosis in cancer cells independent of BCL-2 (anti-apoptosis protein)  which may be upregulated in many cancers.(11,12)

Dr Cyril Sobolewski reported in 2011 working with leukemic and lymphoblastic cell models, that celecoxib prevents the G1/S transition (replication) with early down regulation of c-Myc leaving cells in the G0 phase (non-replicating).(9)

“These events are associated with a rapid down-regulation (within one hour) of c-Myc expression, accompanied by the up-regulation of p27 and the down-regulation of PCNA and cyclin D1.”(9)

P27_CMyc_Proliferation F6Left Image shows how elevated Akt activity increases c-Myc, decreases p27 and leads to cell proliferation.  Decreased Akt leads to decreased c-Myc, increased p27  and apoptosis.  Courtesy of (41) Reciprocal Control of Forkhead O3a and c-Myc via the Phosphatidylinositol 3-Kinase Pathway Coordinately Regulates p27Kip1 Levels  Vidyalakshmi Chandramohan et al J Immunol 2004,

Indeed, Dr Jendrossek from Essen  Germany says in Cancer Letter 2013, Celecoxib may be of specific value for the treatment of apoptosis-resistant tumors with overexpression of Bcl-2.”(24)

Immune Evasion by COX2

Dr Marc Hennequart reports in 2017, Cyclooxygenase-2 and mediates intrinsic immune resistance via IDO1 expression.(13)  “IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. “(14)  Celecoxib serves as a potent IDO inhibitor thus restoring host immune function, (13)   Thus, COX-2 inhibitors can increase the infiltration of CD4+and CD8+T cells to tumor sites, restoring immune response within the tumor microenvironment . (15)

In a tumor microenvironment study of breast cancer cells, Dr Li reported in Oncotarget 2015 that tumor associated macrophages (TAMs) express COX-2, which then feeds into the cancer cells as a promoting factor in a positive-feedback loop between macrophages and cancer cells.(26)  He says:

“COX-2+ TAMs promoted breast cancer cell proliferation and survival by increasing Bcl-2 and P-gp and decreasing Bax in cancer cells.”(26)

Obviously, COX2 inhibitor celecoxib in beneficial in disrupting this feedback loop in the tumor micro-environment.(26)

 

Overcoming Drug Resistance and Inducing Apoptosis

A recurring problem in conventional oncology is the repeated use of chemotherapy agents tends to induce a chemo-resistant cell type.  The COX-2 inhibitors such as celecoxib restore sensitivity to chemotherapy agents.(18,19)  Dr Vimal Patel reported in 2002, a direct link between Cox-2 expression and P-gp, the membrane pump protein responsible for drug resistance.(21)   The drugs get pumped out of the cell promptly by the  MDR1 efflux pump.(27-28).   COX-2 inhibitors down regulate the MDR gene, reducing  expression of P-glycoprotein (P-gp), thus downregulating the efflux pump.(22)

P-Glycoprotein Blocks Apoptosis

The  P-glycoprotein (P-gp) is also an anti-apoptotic protein which blocks release of cyctochrome C from the mitochondria thus inhibiting the intrinsic pathway.(23)  Dr Omella Fantappiè reported in 2007 low doses of celecoxib induced apoptosis in a Multi-Drug Resistance  hepatocellular cancer line.  She says:”10 micromol/L celecoxib reduced P-glycoprotein, Bcl-x(L), and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells.(23-25)

Synergy with Chemotherapy and Radiation Therapy

Cox 2 inhibitors have been shown to improve efficacy of chemotherapy and radiotherapy.(16-17)(29-40)

Synergy With CAR-T Therapy (44)

Celecoxib has been suggested by Dr Dinh in a 2017 article in combination with CAR T cell therapy for B Cell Lymphoma .(44)

COX-2 Inhibition Unwanted Adverse Effects – COX- 2 inhibitors may increase risk of cardiovasular disease.(2)

Conclusion: COX2 Inhibitors such as celecoxib are potent anti-cancer agents.  Hopefully, COX 2 inhibitors will soon be incorporated into routine use on the oncology wards.

Jeffrey Dach MD
7450 Griffin Road Suite 190
Davie, Florida 33314
954 792 4663

Links and References

COX and WNT signalling   

1) Regulation of Tumorigenic Wnt signaling by COX2 LOX5 in Cancer Cells Roos Jessica 2016  Roos, Jessica, et al. “Regulation of tumorigenic Wnt signaling by cyclooxygenase-2, 5-lipoxygenase and their pharmacological inhibitors: A basis for novel drugs targeting cancer cells?.” Pharmacology & therapeutics 157 (2016): 43-64.

Wnt signaling is of pivotal importance in the pathogenesis of cancer  and crucially affects tumor initiation, cancer cell proliferation, cancer cell apoptosis, and metastasis.  Several studies have shown that long-term administration of non-steroidal anti-inflammatory drugs protects against colon cancer and potentially other tumor types by interfering both with the COX and the Wnt pathway. Our own studies have shown that non-steroidal anti-inflammatory drugs suppress Wnt signaling by targeting the pro-inflammatory enzyme 5-lipoxygenase which is the key enzyme pathophysiologically involved in the synthesis of leukotrienes. Furthermore, we found a direct link between the 5-lipoxygenase and Wnt signaling pathways, which is essential for the maintenance of leukemic stem cells. Accordingly, genetic and pharmacological inhibition of 5-lipoxygenase led to an impairment of Wnt-dependent acute and chronic myeloid leukemic stem cells. We believe that 5-lipoxygenase inhibitors might represent a novel type of Wnt inhibitor activating a potentially naturally occurring novel mechanism of suppression of Wnt signaling that is non-toxic, at least in mice, and is potentially well tolerated in patients.

disulfiram inhibits 5-LOX (potent)

celecoxib at  high concentrations inhibits 5 LOX and glutathione levels

2) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2745246/
Bernard, M. P., et al. “Targeting cyclooxygenase-2 in hematological malignancies: rationale and promise.” Current pharmaceutical design 14.21 (2008): 2051-2060.–

There is much interest in the potential use of Cox-2 selective inhibitors in combination with other cancer therapeutics. Malignancies of hematopoietic and non-hematopoietic origin often have increased expression of cyclooxygenase-2 (Cox-2), a key modulator of inflammation. For example, hematological malignancies such as chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin’s lymphoma, non-Hodgkin’s lymphoma and multiple myeloma often highly express Cox-2, which correlates with poor patient prognosis. Expression of Cox-2 enhances survival and proliferation of malignant cells, while negatively influencing anti-tumor immunity. Hematological malignancies expressing elevated levels of Cox-2 potentially avoid immune responses by producing factors that enhance angiogenesis and metastases. Cellular immune responses regulated by natural killer cells, cytotoxic T lymphocytes, and T regulatory cells are also influenced by Cox-2 expression. Therefore, Cox-2 selective inhibitors have promising therapeutic potential in patients suffering from certain hematological malignancies.

Cox-2 selective inhibitor celecoxib, at a dose of 400 mg/day

More recently, our laboratory has examined the effects of both celecoxib and OSU03012 on B-CLL, as well as B cell lymphomas [21]. Treatment with either drug significantly attenuated glutathione levels. Glutathione controls damaging reactive oxygen species (ROS) production and low levels of glutathione were associated with decreased malignant B cell viability.

3) Cancer Lett. 2005 Jun 16;224(1):31-43. Epub 2004 Dec 13.
Anti-proliferative and apoptotic effects of celecoxib on human chronic myeloid leukemia in vitro.
Subhashini J1, Mahipal SV, Reddanna P.
Celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, is the only non-steroidal anti-inflammatory drug so far which has been approved by the FDA for adjuvant treatment of patients with familial adenomatous polyposis. The molecular mechanism responsible for the anti-cancer effects of celecoxib is not fully understood. There is little data on the potential role of COX-2 in lymphoma pathogenesis. In view of the reported induction of apoptosis in cancer cells by cyclooxygenase-2 inhibitors, the present study is undertaken to test the effect of celecoxib on human chronic myeloid leukemia cell line, K562 and other hematopoietic cancer cell lines like Jurkat (human T lymphocytes), HL60 (human promyelocytic leukemia) and U937 (human macrophage). Treatment of these cells with celecoxib (10-100 microM) dose-dependently, reduced cell growth with arrest of the cell cycle at G0/G1 phase and induction of apoptosis. Further mechanism of apoptosis induction was elucidated in detail in K562 cell line. Apoptosis was mediated by release of cytochrome c into the cytoplasm and cleavage of poly (ADP-ribose) polymerase-1 (PARP-1). This was followed by DNA fragmentation. The level of anti-apoptotic protein Bcl-2 was decreased without any change in the pro-apoptotic Bax. Celecoxib also inhibited NF-kB activation. Celecoxib thus potentiates apoptosis as shown by MTT assay, cytochrome c leakage, PARP cleavage, DNA fragmentation, Bcl-2 downregulation and possibly by inhibiting NF-kB activation.


Cox-2 selective inhibitor celecoxib, at a dose of 400 mg/day attenuated glutathione levels

4) Cancer Immunol Immunother. 2008 Mar;57(3):347-58.   Cyclooxygenase-2 independent effects of cyclooxygenase-2 inhibitors on oxidative stress and intracellular glutathione content in normal and malignant human B-cells.
Ryan EP1, Bushnell TP, Friedman AE, Rahman I, Phipps RP.
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Box 850, Rochester, NY 14642, USA.

We recently reported that inhibition of Cyclooxygenase-2 (Cox-2) reduced human B-CLL proliferation and survival. Herein, we investigated the mechanisms whereby small molecule Cox-2 selective inhibitors, SC-58125 (a Celebrex analog) and CAY10404 blunt survival of human B-cell lymphomas and chronic lymphocytic leukemia B-cells. SC-58125 and OSU03012 (a Celebrex analog that lacks Cox-2 inhibitory activity) both decreased intracellular glutathione (GSH) content in malignant human B-cells, as well as in Cox-2 deficient mouse B-cells. This new finding supports Cox-2 independent effects of SC-58125. Interestingly, SC-58125 also significantly increased B-cell reactive oxygen species (ROS) production, suggesting that ROS are a pathway that reduces malignant cell survival. Addition of GSH ethyl ester protected B lymphomas from the increased mitochondrial membrane permeability and reduced survival induced by SC-58125. Moreover, the SC-58125-mediated GSH depletion resulted in elevated steady-state levels of the glutamate cysteine ligase catalytic subunit mRNA and protein. These new findings of increased ROS and diminished GSH levels following SC-58125 exposure support novel mechanisms whereby a Cox-2 selective inhibitor reduces malignant B-cell survival. These observations also support the concept that certain Cox-2 selective inhibitors may have therapeutic value in combination with other drugs to kill malignant B lineage cells.

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induces apoptosis independent of BCL2 -prostate CA

5) http://www.jbc.org/content/275/15/11397.long
J Biol Chem. 2000 Apr 14;275(15):11397-403.
The cyclooxygenase-2 inhibitor celecoxib induces apoptosis by blocking Akt activation in human prostate cancer cells independently of Bcl-2. Hsu AL1, Ching TT, Wang DS, Song X, Rangnekar VM, Chen CS.

This study investigates the apoptotic activity of the cyclooxygenase-2 (COX-2) inhibitor celecoxib in prostate carcinoma cells. COX-2 is constitutively expressed in androgen-responsive LNCaP and androgen-nonresponsive PC-3 cells. Exposure of these cells to celecoxib induces characteristic features of apoptosis, including morphological changes, DNA laddering, and caspase-3 activation, whereas piroxicam, a COX-1-specific inhibitor, displays no appreciable effect on either cancer cell line even after prolonged exposure. Moreover, the potency of celecoxib in apoptosis induction is significantly higher than that of other COX-2 inhibitors examined despite the observation that these inhibitors exhibit similar IC(50) in COX-2 inhibition. It is noteworthy that normal human prostate epithelial cells, expressing a marginally detectable level of COX-2, are insensitive to the induction of apoptosis by celecoxib. These data suggest a correlation between COX-2 expression and sensitivity to the apoptotic effect of the COX-2 inhibitor. In an effort to delineate the underlying mechanism, we examined the effect of celecoxib on the expression of Bcl-2 as well as the activation of the key anti-apoptotic kinase Akt.

In contrast to an earlier report that attributed the apoptotic activity of NS398 in LNCaP cells to Bcl-2 down-regulation, we provide evidence that the induction of apoptosis by celecoxib in LNCaP and PC-3 cells is independent of Bcl-2. First, treatment with celecoxib does not alter the cellular Bcl-2 level in both cell lines. Second, enforced Bcl-2 expression in PC-3 cells does not confer protection against the induction of apoptosis by celecoxib. Our data show that celecoxib treatment blocks the phosphorylation of Akt. This correlation is supported by studies showing that overexpression of constitutively active Akt protects PC-3 cells from celecoxib-induced apoptosis. Nevertheless, how celecoxib down-regulates Akt is not clear because the drug does not adversely affect phosphoinositide 3-kinase activity in vivo and okadaic acid, a protein phosphatase 2A inhibitor, cannot rescue the inhibition. In summary, our data demonstrate that inhibition of Akt activation may play a crucial role in the induction of apoptosis by celecoxib.

novel mechanism for celecoxib: it selectively blocks the activation of Akt, thereby attenuating the activity of a major anti-apoptotic pathway.

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2017 – Reduction in stem cell markers with Celecoxib – esoph ca in vitro

6) Jiménez, Pilar, et al. “CD24 Expression Is Increased in 5-Fluorouracil-Treated Esophageal Adenocarcinoma Cells.” Frontiers in Pharmacology 8 (2017).
The cancer stem cell (CSC) model suggests that there are subsets of cells within a tumor with increased proliferation and self-renewal capacity, which play a key role in therapeutic resistance. The importance of cyclooxygenase-2 (COX-2) in carcinogenesis has been previously established and the use of COX-2 inhibitors as celecoxib has been shown to exert antitumor effects. The present study investigated whether treatment of esophageal adenocarcinoma (EAC) cells with 5-fluorouracil (5-FU) or the growth of tumor spheres increased the proportion of CSCs and also if treatment with celecoxib was able to reduce the putative CSC markers in this tumor. OE19 and OE33 EAC cells surviving 5-FU exposure exhibited an increase in CSC markers CD24 and ABCG2 and also an increased resistance to apoptosis. EAC cell lines had the capacity to form multiple spheres displaying typical CSC functionalities such as self-renewal and increased CD24 levels. In addition, after the induction of differentiation, cancer cells reached levels of CD24 similar to those observed in the parental cells. Treatment with celecoxib alone or in combination with 5-FU also resulted in a reduction of CD24 expression. Moreover, celecoxib inhibited the growth of tumor spheres. These findings showing a reduction in CSC markers induced by celecoxib suggest that the COX-2 inhibitor might be a candidate for combined chemotherapy in the treatment of EAC. However, additional clinical and experimental studies are needed.

2016-Inhibits CML via regulation of Beta-Catenin and mTorc

7) Riva, Beatrice, et al. “Celecoxib inhibits proliferation and survival of chronic myelogeous leukemia (CML) cells via AMPK-dependent regulation of ß-catenin and mTORC1/2.” Oncotarget 7.49 (2016): 81555.

CML is effectively treated with tyrosine kinase inhibitors (TKIs). However, the efficacy of these drugs is confined to the chronic phase of the disease and development of resistance to TKIs remains a pressing issue. The anti-inflammatory COX2 inhibitor celecoxib has been utilized as anti-tumour drug due to its anti-proliferative activity. However, its effects in hematological malignancies, in particular CML, have not been investigated yet. Thus, we tested biological effects and mechanisms of action of celecoxib in Philadelphia-positive (Ph+) CML and ALL cells.

We show here that celecoxib suppresses the growth of Ph+ cell lines by increasing G1-phase and apoptotic cells and reducing S- and G2-phase cells. These effects were independent of COX2 inhibition but required the rapid activation of AMP-activated protein kinase (AMPK) and the consequent inhibition mTORC1 and 2. Treatment with celecoxib also restored GSK3ß function and led to down-regulation of ß-catenin activity through transcriptional and post-translational mechanisms, two effects likely to contribute to Ph+ cell growth suppression by celecoxib.

Celecoxib inhibited colony formation of TKI-resistant Ph+ cell lines including those with the T315I BCR-ABL mutation and acted synergistically with imatinib (gleevec) in suppressing colony formation of TKI-sensitive Ph+ cell lines. Finally, it suppressed colony formation of CD34+ cells from CML patients, while sparing most CD34+ progenitors from healthy donors, and induced apoptosis of primary Ph+ ALL cells.

Together, these findings indicate that celecoxib may serve as a COX2-independent lead compound to simultaneously target the mTOR and ß-catenin pathways, key players in the resistance of CML stem cells to TKIs.

2011 Celecoxib induced apoptosis via intrinsic pathway not prevented by BCL2,  causes Rapid decline Mcl-1,

free pdf
8) Rudner, Justine, et al. “Anti-apoptotic Bcl-2 fails to form efficient complexes with pro-apoptotic Bak to protect from Celecoxib-induced apoptosis.” Biochemical pharmacology 81.1 (2011): 32-42.  Bcl2 fails to protect from Celecoxib-induced apoptosis Rudner Justine Biochemical pharmacology 2011

The non-steroidal anti-inflammatory drug Celecoxib is a specific inhibitor of cyclooxygenase-2. Apart from its inhibitor function, Celecoxib induces apoptosis through the intrinsic pathway which is controlled by the Bcl-2 family members. In Jurkat T lymphoma cells, treatment with Celecoxib results in a rapid decline of the anti-apoptotic Bcl-2-related protein Mcl-1. The depletion of Mcl-1 is sufficient for apoptosis induction and can be blocked by overexpression of Bcl-xL but not by the close homologue Bcl-2. The present investigation analyzed the mechanism by which Bcl-xL prevents apoptosis induction whereas Bcl-2 failed to. Our data show that the involvement of the orphan nuclear receptor Nur77/TR3 specifically targeting Bcl-2 but not Bcl-xL was not involved in Celecoxib-induced apoptosis. Surprisingly, BH3-only proteins Bid, Bim, and Puma of the Bcl-2 family were not needed either. However, unlike Bcl-2, Mcl-1, and Bcl-xL sequestered Bak preventing it from activation through a direct interaction. Thus, when abundantly expressed, Bcl-xL can substitute for the loss of Mcl-1 whereas Bcl-2, incapable of forming a high affinity complex with Bak, could not.

COX2 inhibitors Downregulate C-Myc

9) Sobolewski, Cyril, et al. “Cox-2 inhibitors induce early c-Myc downregulation and lead to expression of differentiation markers in leukemia cells.” Cell Cycle 10.17 (2011): 2978-2993.Cox2 inhibitors induce CMyc downregulation in leukemia cells Sobolewski Cyril Cell Cycle 2011

It is well described that cyclooxygenase-2 (COX-2) inhibitors counteract cancer cell proliferation by preventing the G1/S transition. This effect has been associated with the inhibition of COX-2 enzymatic activity but also as an off-target effect essentially in adherent cancer cell models. In this study, we investigated the effect of three COX-2 inhibitors (nimesulide, NS-398 and celecoxib) on cell proliferation of leukemic and lymphoblastic cells expressing COX-2 at high (U937, Jurkat, Hel and Raji) and very low (K562) protein levels. We found that the inhibitors reduce cell proliferation in all COX-2-expressing cells leading to an accumulation in the G0/G1 phase of the cell cycle. We provide evidence that this modulation corresponds to an accumulation of cells in G0 paralleled by the expression of cell differentiation markers in U937 (CD15) and Hel (CD41a and CD61) cells but not in the insensitive K562. These events are associated with a rapid down-regulation (within one hour) of c-Myc expression, accompanied by the up-regulation of p27 and the down-regulation of PCNA and cyclin D1. Our study suggests c-Myc as a crucial early target of COX-2 inhibitors.

10) Rudner, Justine, et al. “Differential effects of anti-apoptotic Bcl-2 family members Mcl-1, Bcl-2, and Bcl-xL on celecoxib-induced apoptosis.” Biochemical pharmacology 79.1 (2010): 10-20.  Differential effects of anti-apoptotic Mcl1 Bcl2 and BclxL on celecoxib-induced apoptosis Rudner Justine 2010

The cyclooxygenase-2 inhibitor Celecoxib is a potent inducer of apoptosis in tumor cells. In most cellular systems Celecoxib induces apoptosis via an intrinsic, mitochondrial apoptosis pathway.  We recently showed that in Bax-negative Jurkat cells expression of pro-apoptotic Bak is essential for Celecoxib-induced mitochondrial damage and apoptosis induction. Aim of the present study was to identify specific pro- and anti-apoptotic members of the Bcl-2 family involved in the regulation of Bak activation, and subsequent apoptosis upon treatment with Celecoxib in the Jurkat cell model. Our results show that apoptosis in response to Celecoxib required the presence of Noxa and downregulation of the anti-apoptotic protein Mcl-1. Celecoxib-induced Bak activation and subsequent apoptosis could be inhibited by overexpression of Bcl-xL but not by the very similar Bcl-2. In Bcl-xL-overexpressing cells neutralization of both, Mcl-1 and Bcl-xL, was prerequisite for an efficient induction of apoptosis. Our data reveal an important role of the Mcl-1/Noxa axis for Celecoxib-induced apoptosis and suggest that Celecoxib may be of value for treatment of tumors addicted to Mcl-1 and for combined treatment approaches targeting anti-apoptotic Bcl-2 family members.

The current review summarizes work that identifies the role of celecoxib in blocking the activity of Bcl-2.

11) Winfield, Leyte L., and Florastina Payton-Stewart. “Celecoxib and Bcl-2: emerging possibilities for anticancer drug design.” Future medicinal chemistry 4.3 (2012): 361-383.

Celecoxib is a multifaceted drug with promising anticancer properties. A number of studies have been conducted that implicate the compound in modulating the expression of Bcl-2 family members and mitochondria-mediated apoptosis. The growing data surrounding the role of celecoxib in the regulation of the mitochondrial death pathway provides a platform for ongoing debate. Studies that describe celecoxib’s properties as a BH3 mimic or as a direct inhibitor of Bcl-2 are not available. The motivations for this review are: to provide the basis for the development of novel compounds that modulate Bcl-2 expression using celecoxib as a structural starting point and to encourage additional biological studies (such as binding and enzymatic assays) that would provide information regarding celecoxib’s role as a Bcl-2 antagonist. The current review summarizes work that identifies the role of celecoxib in blocking the activity of Bcl-2.

induces cell death entirely independent of bcl-2 expression.

12) https://www.ncbi.nlm.nih.gov/pubmed/15454489
Blood. 2005 Mar 15;105(6):2504-9. Epub 2004 Sep 28. A novel celecoxib derivative, OSU03012, induces cytotoxicity in primary CLL cells and transformed B-cell lymphoma cell line via a caspase- and Bcl-2-independent mechanism.Johnson AJ1, Smith LL, Zhu J, Heerema NA, Jefferson S, Mone A, Grever M, Chen CS, Byrd JC.

Chronic lymphocytic leukemia (CLL) is an incurable adult leukemia characterized by disrupted apoptosis. OSU03012 is a bioavailable third-generation celecoxib derivative devoid of cyclooxygenase-2 inhibitory activity that potently induces apoptosis in prostate cancer cell lines and is being developed as an anticancer therapy in the National Cancer Institute (NCI) Rapid Access to Intervention Development (RAID) program. We assessed the ability of OSU03012 to induce apoptosis in primary CLL cells and the mechanism by which this occurs. The LC50 (lethal concentration 50%) of OSU03012 at 24 hours was 7.1 microM, and this decreased to 5.5 microM at 72 hours. Additionally, we have demonstrated that OSU03012 mediates apoptosis by activation of the intrinsic, mitochondrial pathway of apoptosis but also activates alternative cell death pathways that are caspase independent. The early activation of both caspase-dependent and -independent pathways of apoptosis is novel to OSU03012 and suggests it has great potential promise for the treatment of CLL. Moreover, unlike the great majority of therapeutic agents used to treat leukemia or other forms of cancer, OSU03012 induces cell death entirely independent of bcl-2 expression. Overall, these data provide justification for further preclinical development of OSU03012 as a potential therapeutic agent for CLL.

Immune Evasion – COX2

13) Marc Hennequart, Luc Pilotte, Stefania Cane, Delia Hoffmann, Vincent Stroobant, Etienne De Plaen, Benoît J. Van den Eynde. Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance. Cancer Immunology Research, 2017; article in SCience Daily

Marc Hennequart, et al.. Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance. Cancer Immunology Research, 2017

COX-2 drives tumor-induced immunosuppression through constitutive expression of IDO1.  IDO becomes activated during tumor development, helping malignant cells escape eradication by the immune system.  Immunodeficient mice reconstituted with human lymphocytes and bearing human ovarian tumor xenografts with constitutive IDO1 expression responded to celecoxib as well as the IDO1 inhibitor, epacadostat.

14) Curr Med Chem. 2011;18(15):2263-71. The interplay between indoleamine 2,3-dioxygenase 1 (IDO1) and cyclooxygenase (COX)-2 in chronic inflammation and cancer.  Cesario A1, Rocca B, Rutella S.

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) degrades the essential amino acid tryptophan into kynurenine and other downstream metabolites that suppress effector T-cell function and favor the differentiation of regulatory T cells. IDO1 is traditionally viewed as a general suppressor of T-cell activation and mediator of immune escape in cancer. Recently, evidence has emerged to support a greater functional complexity of IDO1 as modifier of pathogenic inflammation. For instance, IDO1 activity may sustain autoantibody production by B cells, and elicit the development of cancer in the context of chronic inflammation. Cyclooxygenase (COX)-2 metabolizes the first enzymatic step in the conversion of arachidonic acid into prostanoids. In particular, prostaglandin (PG)E2 generated at sites of inflammation and/or immune response is mainly COX-2-derived and has pro-inflammatory and immune regulatory activities. Pharmacological blockade of COX-2 in animal models of cancer translates into down-regulation of IDO1 expression at tumor sites and decreased levels of kynurenine in the circulation, underpinning the view that IDO1 might be downstream of COX-2. This article reviews preclinical studies focusing on IDO1 and COX-2 as inter-related molecular targets for therapeutic intervention in chronic inflammation and cancer. COX-2 inhibition might, in principle, be pursued in cancer-associated inflammation characterized by IDO1 hyper-activity, with the foreseeable aim at altering the immune response within the tumor microenvironment.

15) Murphy, J. “Anti-Cancer Therapy: Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) in Combination with Immunotherapy.” MOJ Immunol 5.3 (2017): 00156.  AntiCancer Therapy NonSteroidal AntiInflammatory Drugs NSAIDS with Immunotherapy Murphy J MOJ Immunol 2017

some studies have shown that specific COX-2 inhibitors can increase the infiltration of CD4+and CD8+T cells to tumor sites,

16) Hohenforst-Schmidt, Wolfgang, et al. “COX-2 Inhibitors, a Potential Synergistic Effect with Antineoplastic Drugs in Lung Cancer.”  Oncomedicine 2017; 2:28-36  The synergistic effect of the combination of COX-2 inhibitors and chemotherapeutic agents has been demonstrated. Our suggestion is that COX-2 inhibitors could be added as maintenance treatment in lung cancer patients.

17) Sobolewski, Cyril, et al. “The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies.” International journal of cell biology 2010 (2010).  cyclooxygenase2 COX2 in cell proliferation death in human malignancies Sobolewski Cyril Int j cell biology 2010

celecoxib [11], which is now approved by the   Food and Drug Administration’s Oncologic Drugs Advisory Committee as an adjuvant in FAP therapy. Prostanoids (prostaglandins and thromboxanes) are immediately released from the cells, where it is believed that they act locally in an autocrine and paracrine manner

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Overcomes drug Resistance

18) Lim, Jong Seung, et al. “Co-treatment with Celecoxib or NS398 Strongly Sensitizes Resistant Cancer Cells to Antimitotic Drugs Independent of P-gp Inhibition.” Anticancer research 36.10 (2016): 5063-5070.ANTICANCER RESEARCH 36: 5063-5070 (2016)

These results suggest that antimitotic drug-resistant cancer cells can be strongly sensitized by co-treatment with COX-2 inhibitors, without P-gp inhibitory activity. Conclusion: These findings provide important information regarding the sensitization of drug-resistant cells and indicate that COX-2 inhibitors may be used for potentially resistant cancer patients, without the toxic effects of P-gp inhibition.

19) Xia, Wenhong, et al. “Celecoxib enhanced the sensitivity of cancer cells to anticancer drugs by inhibition of the expression of P-glycoprotein through a COX-2-Independent Manner.” Journal of cellular biochemistry 108.1 (2009): 181-194.

The P-glycoprotein (p170, P-gp) encoded by human MDR1 gene functions as a pump to extrude anticancer drugs from cancer cells. Over-expression of p170 is closely related to primary and induced drug resistance phenotype of tumor cells. Recent studies have demonstrated that expression of cyclooxygenase-2 (COX-2) is positively correlated with the p170 level, suggesting a potential of COX-2 specific inhibitors in regulation of cytotoxicity of anticancer agents. Celecoxib is one of the specific inhibitors of COX-2 and has been widely used in clinic. However, its function in the response of cancer cells to anticancer drugs and the related mechanism are still waiting to be investigated. To explore the correlation of celecoxib and the p170-mediated drug resistance, the role of celecoxib in drug response of cancer cells was analyzed with flow cytometry, high performance liquid chromatography (HPLC), and colony formation experiments. Celecoxib (50 microM) was found to significantly enhance the sensitivity of MCF-7 and JAR/VP16 cells to tamoxifen and etoposide, respectively, by inhibition of p170 expression and increase in intracellular accumulation of the drugs. However, celecoxib did not affect pump function of p170. Enzyme activity and methylation analyses demonstrated that the inhibitory effect of celecoxib on p170 was independent on COX-2 but closely related to hypermethylation of MDR1 gene promoter. Our study suggested that celecoxib was a potential agent for enhancement of the sensitivity of cancer cells to anticancer drugs. It also provided a links between epigenetic change of MDR1 and drug response of cancer cells.

20) Roy, Karnati R., et al. “Celecoxib inhibits MDR1 expression through COX-2-dependent mechanism in human hepatocellular carcinoma (HepG2) cell line.” Cancer chemotherapy and pharmacology 65.5 (2010): 903-911.
The role of COX-2 in the regulation of the expression of MDR1, a P-glycoprotein involved in hepatocellular carcinoma cell line, HepG2, was studied in the present investigation. Celecoxib, a selective inhibitor of COX-2, at 25 microM concentration increased the accumulation of doxorubicin in HepG2 cells and enhanced the sensitivity of the cells to doxorubicin by tenfold. The induction of MDR1 expression by PGE2 and its downregulation by celecoxib or by COX-2 knockdown suggests that the enhanced sensitivity of HepG2 cells to doxorubicin by celecoxib is mediated by the downregulation of MDR1 expression, through COX-2-dependent mechanism. present study thus demonstrates the usefulness of COX-2 intervention in overcoming the drug resistance in HepG2 cells.

21) Patel, Vimal A., Michael J. Dunn, and Andrey Sorokin. “Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2.” Journal of Biological Chemistry 277.41 (2002): 38915-38920.

We employed cDNA expression microarrays and observed an increase in P-gp gene expression within cells with enforced expression of Cox-2. This translated to increased protein expression and functional activity of P-gp. This is the first report that has found a direct link between Cox-2 expression and P-gp,

22) Zrieki, A., R. Farinotti, and M. Buyse. “Cyclooxygenase inhibitors down regulate P-glycoprotein in human colorectal Caco-2 cell line.” Pharmaceutical research 25.9 (2008): 1991.

Elevated expression of the ABC transporters P-glycoprotein (P-gp), and breast cancer resistance protein (BCRP) seems to correlate with multidrug resistance of cancer cells. In this study we investigated the effect of COX inhibitors in modulating P-gp and BCRP expression and P-gp activity in Caco-2 cells.
METHODS:mRNA and protein expression of MDR1 and BCRP were evaluated by real time PCR and western blot respectively. The activity of P-gp was measured by intracellular accumulation of rhodamine123 or 3H-Digoxin.
RESULTS:The chronic exposure of Caco-2 to indomethacin heptyl ester (indo HE) (0.4 muM) or nimesulide (10 muM) (selective COX-2 inhibitors) and naproxen (6 muM) (non selective inhibitor COX-1/COX-2) significantly decreased the expression and activity of P-gp.
CONCLUSION:Our observations suggest a possible down regulation of P-gp by COX inhibitors, which may enhance the accumulation of chemotherapy agents.

23) Fantappiè, Ornella, et al. “P-glycoprotein mediates celecoxib-induced apoptosis in multiple drug-resistant cell lines.” Cancer research 67.10 (2007): 4915-4923.

In several neoplastic diseases, including hepatocellular carcinoma, the expression of P-glycoprotein and cyclooxygenase-2 (COX-2) are often increased and involved in drug resistance and poor prognosis. P-glycoprotein, in addition to drug resistance, blocks cytochrome c release, preventing apoptosis in tumor cells. Because COX-2 induces P-glycoprotein expression, we evaluated the effect of celecoxib, a specific inhibitor of COX-2 activity, on P-glycoprotein-mediated resistance to apoptosis in cell lines expressing multidrug resistant (MDR) phenotype. Experiments were done using MDR-positive and parental cell lines at basal conditions and after exposure to 10 or 50 micromol/L celecoxib. We found that 10 micromol/L celecoxib reduced P-glycoprotein, Bcl-x(L), and Bcl-2 expression, and induced translocation of Bax from cytosol to mitochondria and cytochrome c release into cytosol in MDR-positive hepatocellular carcinoma cells. This causes the activation of caspase-3 and increases the number of cells going into apoptosis. No effect was shown on parental drug-sensitive or on MDR-positive hepatocellular carcinoma cells after transfection with MDR1 small interfering RNA. Interestingly, although inhibiting COX-2 activity, 50 micromol/L celecoxib weakly increased the expression of COX-2 and P-glycoprotein and did not alter Bcl-x(L) and Bcl-2 expression. In conclusion, these results show that relatively low concentrations of celecoxib induce cell apoptosis in MDR cell lines. This effect is mediated by P-glycoprotein and suggests that the efficacy of celecoxib in the treatment of different types of cancer may depend on celecoxib concentration and P-glycoprotein expression.

24) Cancer Lett. 2013 May 28;332(2):313-24. Targeting apoptosis pathways by Celecoxib in cancer.Jendrossek V1. Institute for Cell Biology (Cancer Research), Department of Molecular Cell Biology, University of Duisburg-Essen Medical School, Virchowstrasse 173, 45122 Essen, Germany.

Celecoxib is a paradigmatic selective inhibitor of cyclooxygenase-2 (COX-2). This anti-inflammatory drug has potent anti-tumor activity in a wide variety of human epithelial tumor types, such as colorectal, breast, non-small cell lung, and prostate cancers. Up to now, the drug found application in cancer prevention in patients with familial adenomatous polyposis. Moreover, the use of Celecoxib is currently tested in the prevention and treatment of pancreatic, breast, ovarian, non-small cell lung cancer and other advanced human epithelial cancers. Induction of apoptosis contributes to the anti-neoplastic activity of Celecoxib. In most cellular systems Celecoxib induces apoptosis independently from its COX-2 inhibitory action via a mitochondrial apoptosis pathway which is however, not inhibited by overexpression of Bcl-2. In addition, Celecoxib exerts antagonistic effects on the anti-apoptotic proteins Mcl-1 and survivin. Consequently, the use of Celecoxib may be of specific value for the treatment of apoptosis-resistant tumors with overexpression of Bcl-2, Mcl-1, or survivin as single drug or in combination with radiotherapy, chemotherapy, or targeted pro-apoptotic drugs that are inhibited by survivin, Bcl-2 or Mcl-1. As COX-2 inhibition has been associated with cardiovascular toxicity, the value of drug derivatives without COX-2 inhibitory action should be validated for prevention and treatment of human epithelial tumors to reduce the risk for heart attack or stroke. However, its additional COX-2 inhibitory action may qualify Celecoxib for a cautious use in COX-2-dependent epithelial tumors, where the drug could additionally suppress COX-2-mediated growth and survival promoting signals from the tumor and the stromal cells.

25) Zatelli, Maria Chiara, et al. “Cyclooxygenase-2 inhibitors prevent the development of chemoresistance phenotype in a breast cancer cell line by inhibiting glycoprotein p-170 expression.” Endocrine-related cancer 14.4 (2007): 1029-1038.

Immune Evasion – COX2 express in TAMs

26) Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells

Li, Hongzhong, et al. “Cyclooxygenase-2 in tumor-associated macrophages promotes breast cancer cell survival by triggering a positive-feedback loop between macrophages and cancer cells.” Oncotarget 6.30 (2015): 29637.

Tumor-associated macrophages (TAMs) play an important role in cancer cell survival,  In this study, we found that COX-2 was abundantly expressed in breast TAMs, which was correlated to poor prognosis in breast cancer patients. Ectopic over-expression of COX-2 in TAMs enhanced breast cancer cell survival both in vitro and in vivo. COX-2 in TAMs was determined to be essential for the induction and maintenance of M2-phenotype macrophage polarity    (Th2 immune response). COX-2+ TAMs promoted breast cancer cell proliferation and survival by increasing Bcl-2 and P-gp and decreasing Bax in cancer cells. Furthermore, COX-2 in TAMs induced the expression of COX-2 in breast cancer cells, which in turn promoted M2 macrophage polarization. Inhibiting PI3K/Akt pathway in cancer cells suppressed COX-2+ TAMs-induced cancer cell survival. These findings suggest that COX-2, functions as a key cancer promoting factor by triggering a positive-feedback loop between macrophages and cancer cells, which could be exploited for breast cancer prevention and therapy.

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27) Inhibition of Bacterial Multidrug Resistance by Celecoxib, a Cyclooxygenase-2 Inhibitor  Arunasree M. Kalle1,* and Arshad Rizvi2
Multidrug resistance (MDR) is a major problem in the treatment of infectious diseases and cancer. Accumulating evidence suggests that the cyclooxygenase-2 (COX-2)-specific inhibitor celecoxib would not only inhibit COX-2 but also help in the reversal of drug resistance in cancers by inhibiting the MDR1 efflux pump. Here, we demonstrate that celecoxib increases the sensitivity of bacteria to the antibiotics ampicillin, kanamycin, chloramphenicol, and ciprofloxacin by accumulating the drugs inside the cell, thus reversing MDR in bacteria.

28) Patel, V. A., M. J. Dunn, and A. Sorokin. “Regulation of MDR-1 (P-glycoprotein) by cyclooxygenase-2.” The Journal of biological chemistry 277.41 (2002): 38915.

=======================================================

Discusses Benefits of COX2 inhibitors with rad tx

Cox 2 inhibitors plus radiation synergy Radiation Protection

29) Drug Discov Today. 2016 Apr;21(4):654-62.
The use of cyclooxygenase-2 inhibitors for improvement of efficacy of radiotherapy in cancers.  Salehifar E1, Hosseinimehr SJ2.
Cyclooxygenase-2 (COX-2) is overexpressed in cancer cells and is associated with carcinogenesis and maintenance of progressive tumour growth as well as resistance of cancer cells to ionising radiation (IR). COX-2 inhibitors can attenuate tumour growth and expression of markers of cell proliferation as well as induce apoptosis in tumour cells. These agents can have a synergistic effect with IR in the killing of cancer cells. In this review, we discuss the rational basis and molecular mechanisms regarding the usefulness of COX-2 inhibitors in cancer therapy, and also their potential role in increasing the therapeutic index of chemoradiation by protecting normal cells and sensitizing tumor cells to radiotherapy.

30) Laube, Markus, Torsten Kniess, and Jens Pietzsch. “Development of Antioxidant COX-2 Inhibitors as Radioprotective Agents for Radiation Therapy—A Hypothesis-Driven Review.” Antioxidants 5.2 (2016): 14.

31) https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-016-0306-8
Rahmanian, Najmeh, Seyed Jalal Hosseinimehr, and Ali Khalaj. “The paradox role of caspase cascade in ionizing radiation therapy.” Journal of biomedical science 23.1 (2016): 88.

32) Davis, Thomas W., et al. “Synergy between celecoxib and radiotherapy results from inhibition of cyclooxygenase-2-derived prostaglandin E2, a survival factor for tumor and associated vasculature.” Cancer research 64.1 (2004): 279-285.

33) Davis, Thomas W., et al. “COX-2 inhibitors as radiosensitizing agents for cancer therapy.” American journal of clinical oncology 26.4 (2003): S58-S61.

34) Nakata, Eiko, et al. “Potentiation of tumor response to radiation or chemoradiation by selective cyclooxygenase-2 enzyme inhibitors.” International Journal of Radiation Oncology* Biology* Physics 58.2 (2004): 369-375.

Cyclooxygenase-2 (COX-2) is an enzyme expressed primarily in pathologic states, such as inflammatory disorders and cancer, where it mediates prostaglandin production. Its overexpression is associated with more aggressive biologic tumor behavior and adverse patient outcome. Increasing evidence shows that agents that selectively inhibit COX-2 enhance tumor response to radiation or chemotherapeutic agents. This article gives an overview of some of this evidence. In addition, we describe new results showing that celecoxib, a selective COX-2 inhibitor, enhanced response of A431 human tumor xenografts in nude mice to radiation by an enhancement factor (EF) of 1.43 and to the chemotherapeutic agent docetaxel by an EF of 2.07. Celecoxib also enhanced tumor response when added to the combined docetaxel plus radiation treatment (EF = 2.13). Further experiments showed that selective COX-2 inhibitors enhanced tumor cell sensitivity to ionizing radiation, involving inhibition of cellular repair from radiation damage and cell cycle redistribution as mechanisms for some cell types. The results show that selective COX-2 inhibitors have the potential to improve tumor radiotherapy or radiochemotherapy, and this therapeutic strategy is currently under clinical testing.

35) Shin, You Keun, et al. “Radiosensitivity enhancement by celecoxib, a cyclooxygenase (COX)-2 selective inhibitor, via COX-2–dependent cell cycle regulation on human cancer cells expressing differential COX-2 levels.” Cancer research 65.20 (2005): 9501-9509.

36) Davis, Thomas W., et al. “Synergy between celecoxib and radiotherapy results from inhibition of cyclooxygenase-2-derived prostaglandin E2, a survival factor for tumor and associated vasculature.Cancer research 64.1 (2004): 279-285.

Taken together, these data suggest that celecoxib synergizes with radiotherapy by inhibiting COX-2-derived PGE2 production, which leads to greater antitumor efficacy by preventing the survival of the tumor neovasculature.

37) Kishi, Kazushi, et al. “Preferential enhancement of tumor radioresponse by a cyclooxygenase-2 inhibitor.” Cancer research 60.5 (2000): 1326-1331.

37) Petersen, Cordula, et al. “Enhancement of intrinsic tumor cell radiosensitivity induced by a selective cyclooxygenase-2 inhibitor.” Clinical Cancer Research 6.6 (2000): 2513-2520.

38) Choy, Hak, and Luka Milas. “Enhancing radiotherapy with cyclooxygenase-2 enzyme inhibitors: a rational advance?.” Journal of the National Cancer Institute 95.19 (2003): 1440-1452.

39) Raju, Uma, et al. “In vitro enhancement of tumor cell radiosensitivity by a selective inhibitor of cyclooxygenase-2 enzyme: mechanistic considerations.” International Journal of Radiation Oncology* Biology* Physics 54.3 (2002): 886-894.

40) Sminia, P., et al. “COX-2 inhibitors act as radiosensitizer in tumor treatment.” Biomedicine & pharmacotherapy 59 (2005): S272-S275.

Since cyclooxygenase-2 (COX-2) is overexpressed in malignant tissues, the COX-2 mediated signaling pathway has been recognized as potential target for therapeutic intervention. In most human tumors, COX-2 overexpression has been associated with tumor aggressiveness and poor clinical outcome. In vitro studies show inhibition of cell proliferation by selective COX-2 inhibitors alone, and enhancement of the response to irradiation. In vivo experimental reports demonstrate enhanced tumor response and impediment of tumor neovascularization following radiotherapy combined with COX-2 inhibition. Clinical studies on the combination of irradiation with COX-2 inhibitors are emerging. Taken together, the perspective for the combined approach of radiotherapy with COX-2 inhibition yields clinical significance since preclinical data demonstrate selective COX-2 inhibitors to act as radiosensitizer in tumor treatment.

41) Reciprocal Control of Forkhead box O 3a and c-Myc via the Phosphatidylinositol 3-Kinase Pathway Coordinately Regulates p27Kip1 Levels
Vidyalakshmi Chandramohan, Sébastien Jeay, Stefania Pianetti and Gail E. Sonenshein J Immunol May 1, 2004, 172 (9) 5522-5527;
B cell receptor (BCR) engagement of murine WEHI 231 immature B lymphoma cells leads sequentially to a drop in NF-κB and c-Myc, and induction of the p27Kip1 cyclin-dependent kinase inhibitor, which promotes growth arrest and apoptosis. BCR engagement was recently shown to induce a drop in phosphatidylinositol 3-kinase (PI3K)/Akt signaling, preceding the increase in p27.

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Dipyridamole Inhibits COX2

42) https://www.ncbi.nlm.nih.gov/pubmed/20940016
Eur J Pharmacol. 2011 Jan 10;650(1):445-50. Dipyridamole inhibits lipopolysaccharide-induced cyclooxygenase-2 and monocyte chemoattractant protein-1 via heme oxygenase-1-mediated reactive oxygen species reduction in rat mesangial cells.
Chen YC1, Chen CH, Ko WS, Cheng CY, Sue YM, Chen TH.

Dipyridamole contributes to its beneficial effects on inflammatory responses in many cell types. The anti-inflammatory mechanisms of dipyridamole on glomerular mesangial cells are mostly uncharacterized. In this study, we monitored the influence of dipyridamole on the expression levels of cyclooxygenase-2 (COX-2) and monocyte chemoattractant protein-1 (MCP-1) in rat mesangial cells stimulated with lipopolysaccharide. Dipyridamole was found to inhibit lipopolysaccharide-induced COX-2 and MCP-1 expression, and reduced lipopolysaccharide-induced reactive oxygen species generation in rat mesangial cells. This inhibitory effect of dipyridamole is independent on cyclic AMP and cyclic GMP increase. Tin protoporphyrin IX (SnPP), a heme oxygenase-1(HO-1) inhibitor, blocked the inhibitory effect of dipyridamole on lipopolysaccharide-induced COX-2 and MCP-1 expression. By applying specific inhibitors in rat mesangial cells, ERK1/2 and p38 MAPK signaling pathways were demonstrated to be involved in the lipopolysaccharide-induced inflammatory responses, and were inhibited by SnPP and N-acetylcysteine treatment. Additionally, dipyridamole was also found to upregulate HO-1 in rat mesangial cells. Therefore, our data suggest that dipyridamole inhibits the expression of COX-2 and MCP-1 in lipopolysaccharide-treated rat mesangial cells via HO-1-mediated reactive oxygen species reduction.

43) Reciprocal Control of Forkhead box O 3a and c-Myc via the Phosphatidylinositol 3-Kinase Pathway Coordinately Regulates p27Kip1 Levels
Vidyalakshmi Chandramohan, Sébastien Jeay, Stefania Pianetti and Gail E. Sonenshein
J Immunol May 1, 2004, 172 (9) 5522-5527;
B cell receptor (BCR) engagement of murine WEHI 231 immature B lymphoma cells leads sequentially to a drop in NF-κB and c-Myc, and induction of the p27Kip1 cyclin-dependent kinase inhibitor, which promotes growth arrest and apoptosis. BCR engagement was recently shown to induce a drop in phosphatidylinositol 3-kinase (PI3K)/Akt signaling, preceding the increase in p27.

44)  Dinh, Tam NM, Alexandra S. Onea, and Ali R. Jazirehi. “Combination of celecoxib (Celebrex®) and CD19 CAR-redirected CTL immunotherapy for the treatment of B-cell non-Hodgkin’s lymphomas.” Am J Clin Exp Immunol 6.3 (2017): 27-42.

In a phase II clinical trial, patients with relapsed and refractory MM were given thalidomide with celecoxib at doses ranging from 200 to 800 mg/day [19]. The results were promising: those who took doses greater than 400 mg/day had greater progression-free survival than those who took doses equal to or less than 400 mg/day (12.7 months compared to 4.6 months). Patients who took higher doses also had a better overall survival rate (OSR) than those who took the lesser dose (29.6 months compared to 18.9 months). However, adverse effects (AEs), such as peripheral edema and renal complication, were observed in some patients [19].

Celecoxib is also an effective drug to use in treatment of patients with NHL. In a phase II study, 35 patients with relapsed or refractory NHL were treated with high doses of celecoxib (400 mg p.o.bi.d) [20]. The median progression-free rate was 4.7 months and median overall survival rate was 14.4 months with 8.4 months median follow-up. Even though celecoxib was used in high doses, the AEs observed were minimal. Gastrointestinal toxicity was observed with no interference with compliance. Most AEs were grade 1 and 2, including nausea, hypertension, and fatigue. Pharmacokinetics data showed that celecoxib was stable for a prolonged period. Per a preclinical model of Kerbel and colleagues, a plasma concentration having more than 500 μg/L was antiangiogenic [21].

In Jurkatt T lymphoma cells treated with celecoxib, there was a sharp decline of Mcl-1, allowing Bak to trigger apoptosis.

45) Neurosurg Focus. 2006 Nov 15;21(5):E14.
Efficacy of celecoxib in the treatment of CNS lymphomas: an in vivo model.  Wang W1, Kardosh A, Su YS, Schonthal AH, Chen TC.

The incidence of primary central nervous system lymphomas (PCNSLs) has increased over the past several decades. Unfortunately, even with the most effective therapeutic regimen (that is, methotrexate with wholebrain radiation therapy), PCNSL recurs within a few years in more than half of the treated patients and is eventually fatal. Because PCNSL usually occurs in older patients and in those with acquired immunodeficiency syndrome, combination treatments in which both chemo- and radiation therapy are used is often poorly tolerated and results in a significant reduction in the quality of life. Recently, it has been demonstrated that the selective cyclooxygenase- 2 inhibitor celecoxib (Celebrex), can block the growth of lymphoma cells in vitro.
METHODS:  To create an experimental animal model in vivo for the PCNSL study, the authors intracranially injected a human B-cell lymphoma cell line into nude mice. Their data demonstrate that this experimental model is an excellent one for human PCNSL with brain and leptomeningeal involvement. They also evaluated the feasibility of using celecoxib as a therapeutic agent in the treatment of PCNSL. Nude mice with intracranial lymphomas were treated with celecoxib contained in the animal chow. The treated animals demonstrated significantly prolonged survival times compared with the untreated animals.
CONCLUSIONS:  Based on the authors’ data, celecoxib may be a promising therapeutic agent for the treatment of PCNSL.

 

 

 

 

 

 

 

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Summary
COX2 Inhibitor Celecoxib As Anti-Cancer Drug
Article Name
COX2 Inhibitor Celecoxib As Anti-Cancer Drug
Description
COX2 Inhibitor Celecoxib As Anti-Cancer Drug
Author
jeffrey dach md
  • Jonas Moses

    With utmost respect, Dr. Dach, there is no point to employ antianiogenesis agents in treatment of tumors. Our lab, followed by hundreds of others – In validation of our research – demonstrated, unequivocally, tumors not only do not create their own blood supply (angiogenesis) they do not require vasculature, at all, due to the fact that we showed (again, many hundreds of other studies, since, verify this) tumors developdevelop their own back-to-back, loops of microchannels (that my colleague named “vasculogenic mimicry”), which are not lined with endothelial cells…rather, they are lined with Lamimin I.

    If you wish to learn more, you are welcome to contact me, as we are already connected via LinkedIn.

    Respectfully,

    Dr. Jonas Moses

    • arthur wolf

      Dr Moses;
      If this is not a route for potential treatments has your lab discovered any new viable or potential options in treating this affliction

      • Clayton Stern

        This sounds like an offline conversation, Sir. I can be found on LinkedIn, if you wish to continue. I am certainly willing to share what I/we have learned. Thank you.

      • Jonas Moses

        Sir, I am delighted to respond, offline. In order to continue this conversation, please reach out, via LinkedIn. My profile is https://www.linkedin.com/in/jonasmoses/ and I will certainly discuss this, in detail. Respectfully, Dr. Jonas Moses