Abstract
The present study investigated the effects of Isorhamnetin on two types of prostate cancer cells (androgen-independent and androgen-dependent) and explored its possible mechanisms underlying such effects. Treatment with Isorhamnetin significantly inhibited cell growth and induced lactate dehydrogenase (LDH) release of androgen-independent DU145 and PC3 prostate cancer cells, but exhibited almost no toxicity effect on androgen-dependent LNCaP prostate cancer cell line or normal human prostate epithelial PrEC cells, which was achieved by the induction of apoptosis in a mitochondrion-dependent intrinsic apoptotic pathway. Furthermore, Isorhamnetin inhibited cell migration and invasion in concentration-dependent manners by enhancing mesenchymal−epithelial transition (MET) and inhibiting matrix metalloproteinase (MMP) 2 (MMP-2) and MMP-9 overexpression. In addition, Isorhamnetin also down-regulated the expression of phosphorylated PI3K (p-P13K), Akt (p-Akt), and mTOR (p-mTOR) proteins in both cancer cells, revealing Isorhamnetin to be a selective PI3K–Akt–mTOR pathway inhibitor. In summary, these findings propose that Isorhamnetin might be a novel therapeutic candidate for the treatment of androgen-independent prostate cancer.
Highlights
Prostate cancer represents as one of the most commonly diagnosed cancer in the United States and remains the second leading cause of cancer deaths in men, trailing only lung cancer [1,2]
Monoclonal antibodies against Bax, Bcl-2, cytoplasmic cytochrome-c, cleaved-caspase 9, cleaved-caspase 3, cleaved-PARP protein, E-cadherin, Vimentin, N-cadherin, matrix metalloproteinase (MMP) 2 (MMP-2), MMP-9, phosphor(p)-PI3K (p85), PI3K (p85), phosphorylated Akt (p-Akt) (Thr308), Akt (Thr308), phosphorylated mTOR (p-mTOR), mTOR, and β-actin were purchased from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, U.S.A.)
Consistent with MTT assay, the lactate dehydrogenase (LDH) release was increased in the culture surpernatant of androgen-independent DU145 and PC3 cells following Isorhamnetin (5, 10, and 20 μM) treatment for 48 h in a concentration-dependent manner, which was obviously significant from the control group (P
Summary
Prostate cancer represents as one of the most commonly diagnosed cancer in the United States and remains the second leading cause of cancer deaths in men, trailing only lung cancer [1,2]. Strong evidence suggests prostate cancer cells cannot grow or differentiate without androgens, androgen ablation therapy can be considered as one of the preventive approaches employed to manage prostate cancers [3]. Though this therapy is effective, most of these patients inevitably established the resistance to androgen deprivation, developing into androgen-independent prostate cancer [4]. These tumors are highly aggressive, more resistant to currently used chemotherapeutic agents, and more likely to metastasize from the primary site to distant tissues than other tumor types [5,6]. Taking into consideration that chemotherapy has severe side effects and usually a poor outcome, there is a growing demand for the development of safer and more therapeutic agents to improve the treatment outcomes of hormone-refractory prostate cancer
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