title: Diltiazem enhances the apoptotic effects of proteasome inhibitors to induce prostate cancer cell death.
abstract: 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.
authors.affiliation: Charlie Norwood VA Medical Center, One Freedom Way, Augusta, GA 30904, USA. ismail.kaddour-djebbar@va.gov
authors.forename: Ismail
authors.initials: I
authors.lastname: Kaddour-Djebbar
authors.forename: Vivek
authors.initials: V
authors.lastname: Choudhary
authors.forename: Vijayabaskar
authors.initials: V
authors.lastname: Lakshmikanthan
authors.forename: Robert
authors.initials: R
authors.lastname: Shirley
authors.forename: Manal
authors.initials: M
authors.lastname: El Gaish
authors.forename: Mohamed
authors.initials: M
authors.lastname: Al-Shabrawey
authors.forename: Belal
authors.initials: B
authors.lastname: Al-Husein
authors.forename: Roger
authors.initials: R
authors.lastname: Zhong
authors.forename: Michael
authors.initials: M
authors.lastname: Davis
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bollag
authors.forename: M Vijay
authors.initials: MV
authors.lastname: Kumar
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000627:therapeutic use; D000069286:Bortezomib; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004357:Drug Synergism; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D011480:Protease Inhibitors / Q000627:therapeutic use*; D011719:Pyrazines / Q000627:therapeutic use; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
chemical_list: D001897:Boronic Acids; D002121:Calcium Channel Blockers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D011480:Protease Inhibitors; D011719:Pyrazines; C067713:lactacystin; D000069286:Bortezomib; D004110:Diltiazem; D002118:Calcium; D000111:Acetylcysteine