title: 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.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Aditi
authors.initials: A
authors.lastname: Mathur
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Zakaria Y
authors.initials: ZY
authors.lastname: Abd Elmageed
authors.affiliation: Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Xichun
authors.initials: X
authors.lastname: Liu
authors.affiliation: Peptide Research Laboratories, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Mikhail L
authors.initials: ML
authors.lastname: Kostochka
authors.affiliation: Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Urology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Asim B
authors.initials: AB
authors.lastname: Abdel-Mageed
authors.affiliation: Department of Pharmacology, Tulane University School of Medicine, New Orleans, Louisiana, United States of America.
authors.forename: Debasis
authors.initials: D
authors.lastname: Mondal
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D000077143:Docetaxel; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D004847:Epithelial Cells / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D019888:Nelfinavir / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043823:Taxoids / Q000494:pharmacology*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D043823:Taxoids; D000077143:Docetaxel; D019284:Thapsigargin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019888:Nelfinavir; D003474:Curcumin