NDLI: Subverting ER-Stress towards Apoptosis by Nelfinavir and Curcumin Coexposure Augments Docetaxel Efficacy in Castration Resistant Prostate Cancer Cells

Content Provider	PubMed Central
Author	Mathur, Aditi Abd, Elmageed Zakaria Y. Liu, Xichun Kostochka, Mikhail L. Zhang, Haitao Abdel-mageed, Asim B. Mondal, Debasis
Editor	Gao, Allen
Copyright Year	2014
Abstract	Despite its side-effects, docetaxel (DTX) remains a first-line treatment against castration resistant prostate cancer (CRPC). Therefore, strategies to increase its anti-tumor efficacy and decrease its side effects are critically needed. Targeting of the constitutive endoplasmic reticulum (ER) stress in cancer cells is being investigated as a chemosensitization approach. We hypothesized that the simultaneous induction of ER-stress and suppression of PI3K/AKT survival pathway will be a more effective approach. In a CRPC cell line, C4-2B, we observed significant (p<0.005) enhancement of DTX-induced cytotoxicity following coexposure to thapsigargin and an AKT-inhibitor. However, since these two agents are not clinically approved, we investigated whether a combination of nelfinavir (NFR) and curcumin (CUR), known to target both these metabolic pathways, can similarly increase DTX cytotoxicity in CRPC cells. Within 24 hrs post-exposure to physiologic concentrations of NFR (5 µM) and CUR (5 µM) a significantly (p<0.005) enhanced cytotoxicity was evident with low concentration of DTX (10 nM). This 3-drug combination rapidly increased apoptosis in aggressive C4-2B cells, but not in RWPE-1 cells or in primary prostate epithelial cells (PrEC). Comparative molecular studies revealed that this 3-drug combination caused a more pronounced suppression of phosphorylated-AKT and higher induction in phosphorylated-eIF2α in C4-2B cells, as compared to RWPE-1 cells. Acute exposure (3–9 hrs) to this 3-drug combination intensified ER-stress induced pro-apoptotic markers, i.e. ATF4, CHOP, and TRIB3. At much lower concentrations, chronic (3 wks) exposures to these three agents drastically reduced colony forming units (CFU) by C4-2B cells. In vivo studies using mice containing C4-2B tumor xenografts showed significant (p<0.05) enhancement of DTX’s (10 mg/kg) anti-tumor efficacy following coexposure to NFR (20 mg/kg) & CUR (100 mg/kg). Immunohistochemical (IHC) analyses of tumor sections indicated decreased Ki-67 staining and increased TUNEL intensity in mice exposed to the 3-drug combination. Therefore, subverting ER-stress towards apoptosis using adjuvant therapy with NFR and CUR can chemosensitize the CRPC cells to DTX therapy.
Related Links	http://dx.doi.org/10.1371/journal.pone.0103109
Starting Page	103109
File Format	PDF
ISSN	19326203
e-ISSN	19326203
Journal	PLoS ONE
Issue Number	8
Volume Number	9
Language	English
Publisher	Public Library of Science
Publisher Date	2014-08-01
Access Restriction	Open
Rights Holder	Public Library of Science
Subject Keyword	Biochemistry, Genetics and Molecular Biology(all) Agricultural and Biological Sciences(all) Medicine(all) Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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