Combination of sorafenib and enzalutamide as a potential new approach for the treatment of castration-resistant prostate cancer.
Enzalutamide, a novel androgen receptor (AR) antagonist, prolongs overall survival of patients with castration-resistant prostate cancer (CRPC); however, patients eventually progress with enzalutamide resistance. We studied the efficacy of sorafenib combined with enzalutamide in a CRPC model and explored a potential strategy to improve enzalutamide efficacy in vitro and in LNCaP xenografts. The results indicated that enzalutamide combined with sorafenib potently decreased cell proliferation and induced apoptosis in the prostate cancer cell lineLNCaP. In castrate-resistant LNCaP xenografts, the combination of enzalutamide with sorafenib significantly suppressed tumor growth compared with eachsingle agent. Western blots and immunohistochemical staining assay showed that the expression of AR was down-regulated, and the extracellular signal-regulated kinase (ERK) signaling pathway was inhibited after combination treatment, suggesting a synergistic inhibitory effect on the AR and ERK pathways. These results demonstrated that sorafenib therapy improved the efficacy of enzalutamide in the CRPC model, indicating a promising therapeutic strategy for clinical CRPC patients.
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
Hongxi
H
Wu
Department of Toxicology, The Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing 211166, Jiangsu, China.
Lulu
L
Zhang
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
Xiaofang
X
Gao
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
Xiuna
X
Zhang
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
Jingjing
J
Duan
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
Linjun
L
You
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China.
Yan
Y
Cheng
Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore.
Jinsong
J
Bian
Department of Urology, Jiangsu Province Hospital of TCM, Nanjing 210029, China. Electronic address: zhuqy1971@126.com.
Qingyi
Q
Zhu
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 211198, China. Electronic address: yy@cpu.edu.cn.
Yong
Y
Yang
D000726:Androgen Antagonists / Q000494:pharmacology*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D013997:Time Factors; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C410798:AR protein, human; D000726:Androgen Antagonists; D001549:Benzamides; D009570:Nitriles; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; D009536:Niacinamide; C540278:enzalutamide; D000077157:Sorafenib; D048049:Extracellular Signal-Regulated MAP Kinases
Androgen receptor; Castration-resistant prostate cancer; Enzalutamide; Sorafenib; Tyrosine kinase