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Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells.
Biochimie. 2016 May; 124:53-64.B

Abstract

Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 μM vs. 32.4 μM). Coexposures to NFV could significantly (p < 0.05) decrease DOX-IC50 in MCF-7/Dox cells. Multiple exposures to physiologic concentrations of NFV (2.25 μM or 6.75 μM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p < 0.01) than either agent alone. Immunohistochemical (IHC) analysis revealed decreased p-AKT and Ki-67 levels. Thus, NFV overcomes MDR in breast cancer cells and should be tested as an adjunct to chemotherapy.

Authors+Show Affiliations

Department of Pharmacology, Tulane University Medical Center, USA.Department of Pharmacology, Tulane University Medical Center, USA.Department of Pharmacology, Tulane University Medical Center, USA.Department of Pharmacology, Tulane University Medical Center, USA.Department of Pharmacology, Tulane University Medical Center, USA.Department of Urology, Tulane University Medical Center, USA.Department of Biostatistics, Tulane University School of Public Health and Tropical Medicine, USA.Department of Urology, Tulane University Medical Center, USA.Department of Pharmacology, Tulane University Medical Center, USA. Electronic address: dmondal@tulane.edu.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26844637

Citation

Chakravarty, Geetika, et al. "Nelfinavir Targets Multiple Drug Resistance Mechanisms to Increase the Efficacy of Doxorubicin in MCF-7/Dox Breast Cancer Cells." Biochimie, vol. 124, 2016, pp. 53-64.
Chakravarty G, Mathur A, Mallade P, et al. Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells. Biochimie. 2016;124:53-64.
Chakravarty, G., Mathur, A., Mallade, P., Gerlach, S., Willis, J., Datta, A., Srivastav, S., Abdel-Mageed, A. B., & Mondal, D. (2016). Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells. Biochimie, 124, 53-64. https://doi.org/10.1016/j.biochi.2016.01.014
Chakravarty G, et al. Nelfinavir Targets Multiple Drug Resistance Mechanisms to Increase the Efficacy of Doxorubicin in MCF-7/Dox Breast Cancer Cells. Biochimie. 2016;124:53-64. PubMed PMID: 26844637.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Nelfinavir targets multiple drug resistance mechanisms to increase the efficacy of doxorubicin in MCF-7/Dox breast cancer cells. AU - Chakravarty,Geetika, AU - Mathur,Aditi, AU - Mallade,Pallavi, AU - Gerlach,Samantha, AU - Willis,Joniece, AU - Datta,Amrita, AU - Srivastav,Sudesh, AU - Abdel-Mageed,Asim B, AU - Mondal,Debasis, Y1 - 2016/02/01/ PY - 2015/07/15/received PY - 2016/01/29/accepted PY - 2016/2/5/entrez PY - 2016/2/5/pubmed PY - 2016/12/17/medline KW - Breast cancer KW - Chemosensitization KW - Doxorubicin KW - MDR KW - Nelfinavir KW - Tumor xenograft SP - 53 EP - 64 JF - Biochimie JO - Biochimie VL - 124 N2 - Development of multidrug resistance (MDR) remains a significant problem in cancer chemotherapy and underscores the importance of using chemosensitizers. Well known MDR mechanisms include: (i) upregulation of drug-efflux; (ii) increased signaling via AKT; and (iii) decreased apoptosis. Therefore, chemosensitizers should target multiple resistance mechanisms. We investigated the efficacy of nelfinavir (NFV), a clinically approved anti-HIV drug, in increasing doxorubicin (DOX) toxicity in a MDR breast cancer cell line, MCF-7/Dox. As compared to parental MCF-7 cells, the MCF-7/Dox were 15-20 fold more resistant to DOX-induced cytotoxicity at 48 h post-exposure (DOX IC50 = 1.8 μM vs. 32.4 μM). Coexposures to NFV could significantly (p < 0.05) decrease DOX-IC50 in MCF-7/Dox cells. Multiple exposures to physiologic concentrations of NFV (2.25 μM or 6.75 μM) decreased DOX-IC50 by 21-fold and 50-fold, respectively. Interestingly, although single exposure to NFV transiently induced P-glycoprotein (P-gp) levels, multiple treatments with NFV inhibited both P-gp expression and efflux function, which increased intracellular DOX concentrations. Single exposure to NFV augmented the markers of cell-survival (AKT) and autophagy (LC3-II), whereas multiple exposures enabled suppression of both total AKT (t-AKT) and insulin like growth factor-1 (IGF-1)-induced phosphorylated AKT (p-AKT) levels. Multiple exposures to NFV also resulted in increased unfolded protein response (UPR) transducers, e.g. Grp78, p-PERK, p-eIF2α, and ATF-4; and endoplasmic reticulum (ER) stress induced death sensors, e.g. CHOP & TRIB-3. Multiple exposures to NFV also abrogated the mitogenic effects of IGF-1. In mice carrying MCF-7/Dox tumor xenografts, intraperitoneal (i.p.) injection of NFV (20 mg/kg/day) and DOX (2 mg/kg/twice/wk) decreased tumor growth more significantly (p < 0.01) than either agent alone. Immunohistochemical (IHC) analysis revealed decreased p-AKT and Ki-67 levels. Thus, NFV overcomes MDR in breast cancer cells and should be tested as an adjunct to chemotherapy. SN - 1638-6183 UR - https://www.unboundmedicine.com/medline/citation/26844637/Nelfinavir_targets_multiple_drug_resistance_mechanisms_to_increase_the_efficacy_of_doxorubicin_in_MCF_7/Dox_breast_cancer_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0300-9084(16)00042-0 DB - PRIME DP - Unbound Medicine ER -