Palmer Hannah, Nimick Mhairi, Mazumder Aloran, Taurin Sebastien, Rana Zohaib, Rosengren Rhonda J
Department of Pharmacology and Toxicology, University of Otago, Dunedin 9016, New Zealand.
Department of Biochemistry, University of Otago, Dunedin 9016, New Zealand.
Biomedicines. 2022 Apr 5;10(4):853. doi: 10.3390/biomedicines10040853.
Androgen receptor (AR)-castrate-resistant prostate cancer (CRPC) is an aggressive form of prostate cancer that does not have clinically approved targeted treatment options. To this end, the cytotoxic potential of raloxifene and the synthetic curcumin derivative 2,6-bis (pyridin-4-ylmethylene)-cyclohexanone (RL91) was examined in AR-(PC3 and DU145) cells and AR+ (LnCaP) CRPC cells. The results showed that both raloxifene and RL91 elicited significant cytotoxicity across three cell lines with the lowest EC values in PC3 cells. Additionally, the two drugs were synergistically cytotoxic toward the PC3, DU-145 and LNCaP cell lines. To determine the effect of the drug combination in vivo, an orthotopic model of CRPC was used. Male mice were injected with PC3 prostate cancer cells and then treated with vehicle (5 mL/kg), raloxifene (8.5 mg/kg, po), RL91 (8.5 mg/kg, po) or a combination of raloxifene and RL91 for six weeks. Sham animals were subjected to the surgical procedure but were not implanted with PC3 cells. The results showed that raloxifene decreased tumor size and weight as well as metastasis to renal lymph nodes. However, combination treatment reversed the efficacy of raloxifene as tumor volume and metastasis returned to control levels. The results suggest that raloxifene has tumor suppressive and anti-metastatic effects and has potential for further clinical use in AR-CRPC.
雄激素受体（AR）去势抵抗性前列腺癌（CRPC）是一种侵袭性前列腺癌，目前尚无临床批准的靶向治疗方案。为此，研究了雷洛昔芬和合成姜黄素衍生物2,6-双（吡啶-4-基亚甲基）-环己酮（RL91）在AR-（PC3和DU145）细胞和AR+（LnCaP）CRPC细胞中的细胞毒性潜力。结果表明，雷洛昔芬和RL91在三种细胞系中均引发了显著的细胞毒性，其中PC3细胞中的EC值最低。此外，这两种药物对PC3、DU-145和LNCaP细胞系具有协同细胞毒性。为了确定药物组合在体内的作用，使用了CRPC原位模型。雄性小鼠注射PC3前列腺癌细胞，然后用溶剂（5 mL/kg）、雷洛昔芬（8.5 mg/kg，口服）、RL91（8.5 mg/kg，口服）或雷洛昔芬与RL91的组合治疗六周。假手术动物接受手术操作，但未植入PC3细胞。结果表明，雷洛昔芬可减小肿瘤大小和重量以及向肾淋巴结的转移。然而，联合治疗逆转了雷洛昔芬的疗效，因为肿瘤体积和转移恢复到了对照水平。结果表明，雷洛昔芬具有肿瘤抑制和抗转移作用，在AR-CRPC中具有进一步临床应用的潜力。
