Subverting ER-stress towards apoptosis by nelfinavir and curcumin coexposure augments docetaxel efficacy in castration resistant prostate cancer cells.

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.

• Authors: Aditi Mathur, Zakaria Y Abd Elmageed, Xichun Liu, Mikhail L Kostochka, Haitao Zhang, Asim B Abdel-Mageed, Debasis Mondal
• Journal: PloS one (PLoS One) Vol. 9 Issue 8 Pg. e103109 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 25121735 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Taxoids
• Docetaxel
• Thapsigargin
• Phosphatidylinositol 3-Kinases
• Proto-Oncogene Proteins c-akt
• Nelfinavir
• Curcumin

Topics

• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• Curcumin (pharmacology)
• Docetaxel
• Endoplasmic Reticulum Stress (drug effects)
• Epithelial Cells (metabolism)
• Humans
• Male
• Mice
• Mice, Nude
• Nelfinavir (pharmacology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy)
• Proto-Oncogene Proteins c-akt (metabolism)
• Taxoids (pharmacology)
• Thapsigargin (pharmacology)