Department of Rehabilitation Medicine and Laboratory of Liver Surgery, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China; Key Laboratory of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, China.
Department of Rehabilitation Medicine and Laboratory of Liver Surgery, Sichuan University-University of Oxford Huaxi Joint Centre for Gastrointestinal Cancer, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Pharmacol Res. 2021 Jan;163:105295. doi: 10.1016/j.phrs.2020.105295. Epub 2020 Nov 8.
Targeted therapies and immunotherapy have brought substantial benefits to patients with melanoma. However, brain metastases remain the biggest threat to the survival and quality of life of melanoma patients. One of the major challenges to an effective therapy is the inability of drugs to penetrate the blood-brain barrier (BBB). Anti-schizophrenic drugs can cross the BBB, and many of them have demonstrated anti-cancer effects. Repurposing existing drugs for new clinical indications is an alluring strategy for anticancer drug discovery. Herein, we applied this strategy and screened a small collection of existing anti-schizophrenic drugs to use as anti-melanoma agents. Among them, trifluoperazine dihydrochloride (TFP) exhibited promising potencies for suppressing the growth and metastasis of melanoma, both in vitro and in vivo. TFP obviously suppressed the viability of melanoma cells within the micromolar range and inhibited the growth of melanoma in the subcutaneous mice models. Notably, intraperitoneal (i.p.) administration of TFP (40 mg/kg/day) obviously inhibited the growth of intra-carotid-injection established melanoma brain metastasis and extended the survival of brain metastasis-bearing mice. Moreover, TFP significantly suppressed lung metastasis and bone metastasis of melanoma in preclinical metastasis models. Mechanistically, TFP caused G0/G1 cell cycle arrest and mitochondrial-dependent intrinsic apoptosis of melanoma cells. In addition, TFP treatment increased the expression of microtubule associated protein 1 light chain 3 beta-II (LC3B-II) and p62 in vitro, suggesting an inhibition of autophagic flux. TFP decreased LysoTracker Red uptake after treatment, indicating impaired acidification of lysosomes. Moreover, the colocalization of LC3 with lysosomal-associated membrane protein 1 (LAMP1), a lysosome marker, was also suppressed after TFP treatment, suggesting that TFP might block the fusion of autophagosomes with lysosomes, which led to autophagosome accumulation. Taken together, our data highlight the potential of repurposing TFP as a new adjuvant drug for treating melanoma patients with brain, lung, and bone metastases.
靶向治疗和免疫疗法为黑色素瘤患者带来了显著的获益。然而，脑转移仍然是黑色素瘤患者生存和生活质量的最大威胁。有效的治疗方法面临的主要挑战之一是药物无法穿透血脑屏障（BBB）。抗精神分裂症药物可以穿透 BBB，其中许多药物已显示出抗癌作用。将现有药物重新用于新的临床适应症是一种诱人的抗癌药物发现策略。在此，我们应用该策略筛选了一小部分现有的抗精神分裂症药物，将其用作抗黑色素瘤药物。其中，盐酸三氟拉嗪（TFP）在体外和体内均表现出抑制黑色素瘤生长和转移的潜力。TFP 在微摩尔范围内明显抑制黑色素瘤细胞的活力，并抑制皮下小鼠模型中黑色素瘤的生长。值得注意的是，TFP（40mg/kg/天）腹腔内给药明显抑制了颈动脉内注射建立的黑色素瘤脑转移的生长，并延长了脑转移荷瘤小鼠的生存时间。此外，TFP 还显著抑制了黑色素瘤在临床前转移模型中的肺转移和骨转移。在机制上，TFP 导致黑色素瘤细胞发生 G0/G1 细胞周期停滞和线粒体依赖性内在细胞凋亡。此外，TFP 处理后体外增加微管相关蛋白 1 轻链 3β-II（LC3B-II）和 p62 的表达，提示自噬流受到抑制。TFP 处理后 LysoTracker Red 摄取减少，表明溶酶体酸化受损。此外，LC3 与溶酶体相关膜蛋白 1（LAMP1）（溶酶体标志物）的共定位在 TFP 处理后也受到抑制，表明 TFP 可能阻止自噬体与溶酶体融合，从而导致自噬体积累。综上所述，我们的数据强调了将 TFP 重新用作治疗有脑、肺和骨转移的黑色素瘤患者的新辅助药物的潜力。
