https://europepmc.org/articles/PMC4710172?pdf=render

NFAT as cancer target: mission possible?

Ion channels are key regulators of cancer cell pathophysiology. They contribute to a variety of processes such as maintenance of cellular osmolarity and membrane potential, motility (via interactions with the cytoskeleton), invasion, signal transduction, transcriptional activity and cell cycle progression, leading to tumour progression and metastasis. Ion channels thus represent promising targets for cancer therapy. Ion channels are attractive targets because many of them are expressed at the plasma membrane and a broad range of existing inhibitors are already in clinical use for other indications. However, many of the ion channels identified in cancer cells are also active in healthy normal cells, so there is a risk that certain blockers may have off-target effects on normal physiological function. This review describes recent research advances into ion channel inhibitors as anticancer therapeutics. A growing body of evidence suggests that a range of existing and novel Na+, K+, Ca2+ and Cl- channel inhibitors may be effective for suppressing cancer cell proliferation, migration and invasion, as well as enhancing apoptosis, leading to suppression of tumour growth and metastasis, either alone or in combination with standard-of-care therapies. The majority of evidence to date is based on preclinical in vitro and in vivo studies, although there are several examples of ion channel-targeting strategies now reaching early phase clinical trials. Given the strong links between ion channel function and regulation of tumour growth, metastasis and chemotherapy resistance, it is likely that further work in this area will facilitate the development of new therapeutic approaches which will reach the clinic in the future.

/pdf/targeting-ion-channels-for-cancer-treatment-current-progress-256jb8vole.pdf

Targeting Ion Channels for Cancer Treatment: Current Progress and Future Challenges

Purpose Hypertension and cancer are frequently found comorbidity occurring in same individual. This study was intended to evaluate the anticancer effects of commonly used antihypertensive medications and chemotherapy on chemoresistant lung cancer cells. Methods Calcium channel blockers (CCBs), including Verapamil, Diltiazem, and Nifedipine, either alone or combined with docetaxel (DOC) or vincristine (VCR) were used to treat A549 lung adenocarcinoma chemoresistant sublines. Cell viability was determined by MTT assay, and colony formation assay was used to demonstrate the long-term effect of CCBs on proliferation of the sublines. Apoptosis was evaluated by Annexin V assay and autophagy intensity was quantitated from acidic vesicular organelle formation. Pan-caspase inhibitor, shATG5 interference and chloroquine were applied to study the roles of Verapamil on apoptosis and autophagy, with related proteins verified by Western blot analysis. Results Results show that 10 μM of Verapamil and Diltiazem, but not Nifedipine, differentially induce autophagy in DOC-resistant or VCR-resistant A549 cells, respectively. When CCBs are combined with DOC or VCR to treat the sublines, 10 μM of Verapamil induces autophagy more significantly than Diltiazem and Nifedipine, respectively, in DOC-resistant (54.91±0.76, 18.03±0.69, 7.05±0.30) or VCR-resistant A549 (32.41±1.04, 21.51±0.63, 7.14±0.24) cells. Inhibition of apoptosis by pan-caspase inhibitor partly reduced cell death indicates association of caspase-dependent cell death but with persistence of autophagy. Inhibition of autophagy by interfering ATG5 expression reduced c-PARP level and apoptotic cells suggest a pro-death role of autophagy. Chloroquine treatment enhanced autophagosome accumulation and cell death but with reduced c-PARP level suggests that mechanism of caspase-independent cell death also contributes to Verapamil/chemotherapy-induced anticancer effects. Conclusion Verapamil combined with DOC or VCR induces chemoresistant lung cancer cells to death through autophagy burst and apoptosis more strongly than Diltiazem and Nifedipine. Administering Verapamil or Diltiazem individually with chemotherapy, but not Nifedipine, can be considered in lung cancer patients with hypertension.

/pdf/anticancer-effects-of-antihypertensive-l-type-calcium-42z6dehd4m.pdf

Anticancer Effects of Antihypertensive L-Type Calcium Channel Blockers on Chemoresistant Lung Cancer Cells via Autophagy and Apoptosis.

The relationship between calcium channel blockers and prostate cancer has been an area of increased interest to investigators. Calcium channel blockers have been shown to influence cell proliferation, differentiation, and apoptosis. Clinically, the association between calcium channel blockers and the development of prostate cancer has been controversial. However, on a basic science level, there is evidence that calcium channel blockers induce cytotoxicity in androgen receptor positive cell lines and may offer an innovative strategy for the treatment of castration-resistant prostate cancer.

Calcium channel blockers and prostate cancer

https://www.internationaljournalofcardiology.com/article/S0167-5273(15)30277-1/pdf

No evidence for increased prostate cancer risk among calcium channel blockers user

Diltiazem is a calcium channel blocker used to treat cardiovascular ailments. In addition, reports suggest that diltiazem induces cell death, which could make it a drug of choice for the treatment of cancer associated with hypertension. The goal of this research was to determine whether diltiazem is capable of inducing apoptosis in prostate cancer cells, either alone or in combination with the proteasome inhibitors, lactacystin and bortezomib (Velcade). Bortezomib is approved for the treatment of multiple myeloma; unfortunately, it has side effects that limit its utility. Presumably these side effects could be decreased by reducing its dose in combination with another drug. We have previously shown that lactacystin induces apoptosis in LNCaP cells; here, we show that this effect was enhanced by diltiazem. Furthermore, in proteasome inhibitor-resistant DU145 cells, diltiazem alone did not induce apoptosis but decreased cytosolic calcium levels and induced mitochondrial fission; likewise, lactacystin did not induce apoptosis but up-regulated the proapoptotic protein Bik. However, increasing concentrations of diltiazem in combination with lactacystin or bortezomib induced apoptosis in a dose-dependent and synergistic manner. The combination of diltiazem and lactacystin also up-regulated the levels of Bik and released Bak from Bcl-xL, indicating the involvement of the Bcl2 family pathway in this apoptosis. In addition, the drug combination up-regulated GRP78, suggesting also the involvement of endoplasmic reticulum stress in the apoptotic response. Thus, our results demonstrate a potential therapeutic advantage of combining a frequently used calcium channel blocker with proteasome inhibitors in the treatment of prostate cancer.

https://jpet.aspetjournals.org/content/jpet/early/2012/03/05/jpet.111.188151.full.pdf

Manal El Gaish

Papers

Diltiazem Enhances the Apoptotic Effects of Proteasome Inhibitors to Induce Prostate Cancer Cell Death