Diltiazem enhances the apoptotic effects of proteasome inhibitors to induce prostate cancer cell death

Ismail Kaddour-Djebbar, Vivek Choudhary, Vijayabaskar Lakshmikanthan, Robert Shirley, Manal El Gaish, Mohamed Al-Shabrawey, Belal Al-Husein, Roger Zhong, Michael Davis, Zheng Dong, Wendy B Bollag, M. Vijay Kumar

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)646-655
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume341
Issue number3
DOIs
StatePublished - Jun 1 2012

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Proteasome Inhibitors
Diltiazem
Prostatic Neoplasms
Cell Death
Apoptosis
Calcium Channel Blockers
Mitochondrial Dynamics
Endoplasmic Reticulum Stress
Second Primary Neoplasms
Drug Combinations
Multiple Myeloma
Pharmaceutical Preparations
lactacystin
Hypertension
Calcium
Bortezomib
Research

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Diltiazem enhances the apoptotic effects of proteasome inhibitors to induce prostate cancer cell death. / Kaddour-Djebbar, Ismail; Choudhary, Vivek; Lakshmikanthan, Vijayabaskar; Shirley, Robert; El Gaish, Manal; Al-Shabrawey, Mohamed; Al-Husein, Belal; Zhong, Roger; Davis, Michael; Dong, Zheng; Bollag, Wendy B; Kumar, M. Vijay.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 341, No. 3, 01.06.2012, p. 646-655.

Research output: Contribution to journalArticle

Kaddour-Djebbar, Ismail ; Choudhary, Vivek ; Lakshmikanthan, Vijayabaskar ; Shirley, Robert ; El Gaish, Manal ; Al-Shabrawey, Mohamed ; Al-Husein, Belal ; Zhong, Roger ; Davis, Michael ; Dong, Zheng ; Bollag, Wendy B ; Kumar, M. Vijay. / Diltiazem enhances the apoptotic effects of proteasome inhibitors to induce prostate cancer cell death. In: Journal of Pharmacology and Experimental Therapeutics. 2012 ; Vol. 341, No. 3. pp. 646-655.
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