Department of Burn and Plastic Surgery, The First Affiliated Hospital of Chongqing Medical University, 400016 Chongqing, China.
Department of Rehabilitation Medicine, Rehabilitation Medical Center, West China Hospital, Sichuan University, 610041 Chengdu, Sichuan, China.
Front Biosci (Landmark Ed). 2024 Mar 29;29(4):132. doi: 10.31083/j.fbl2904132.
The incidence of melanoma brain metastasis (MBM) is high and significantly compromises patient survival and quality of life. Effective treatment of MBM is made difficult by the blood-brain barrier (BBB), since it restricts the entry of drugs into the brain. Certain anti-psychotic drugs able to cross the BBB have demonstrated efficacy in suppressing brain metastasis in preclinical studies. However, the activity of zuclopenthixol against MBM is not yet clear.
Cell viability assays were employed to investigate the potential of zuclopenthixol in the treatment of MBM. Subsequently, the mechanism of action was investigated by RNA-sequencing (RNAseq), flow cytometry-based cell cycle and apoptosis assays, protein expression analysis, and autophagy flux detection. Additionally, the efficacy of zuclopenthixol against tumor growth was investigated , including MBM models.
Zuclopenthixol inhibited the proliferation of various melanoma cell lines at minimal doses by causing cell cycle arrest in the G0/G1 phase and mitochondrial-mediated intrinsic apoptosis. Zuclopenthixol also induced cytoprotective autophagy, and inhibition of autophagy enhanced the anti-melanoma effects of zuclopenthixol. Furthermore, zuclopenthixol inhibited the growth of human melanoma tumors in nude mice, as well as the growth of intracranial metastases in a mouse model of MBM.
These results demonstrate that zuclopenthixol has significant potential as an effective therapeutic agent for MBM.
黑色素瘤脑转移（MBM）的发病率很高，严重影响了患者的生存和生活质量。血脑屏障（BBB）使得有效治疗 MBM 变得困难，因为它限制了药物进入大脑。某些能够穿过血脑屏障的抗精神病药物在临床前研究中已被证明能抑制脑转移。然而，齐拉西酮对 MBM 的活性尚不清楚。
采用细胞活力测定法研究齐拉西酮治疗 MBM 的潜力。随后，通过 RNA 测序（RNAseq）、基于流式细胞术的细胞周期和凋亡测定、蛋白质表达分析和自噬通量检测来研究其作用机制。此外，还研究了齐拉西酮对肿瘤生长的疗效，包括 MBM 模型。
齐拉西酮以最小剂量抑制了各种黑色素瘤细胞系的增殖，导致细胞周期停滞在 G0/G1 期，并通过线粒体介导的内在凋亡。齐拉西酮还诱导了细胞保护性自噬，并且自噬的抑制增强了齐拉西酮的抗黑色素瘤作用。此外，齐拉西酮抑制了裸鼠中人类黑色素瘤肿瘤的生长以及 MBM 小鼠模型中颅内转移的生长。
这些结果表明，齐拉西酮具有作为 MBM 有效治疗剂的巨大潜力。
