Antipsychotic Zuclopenthixol Inhibits Melanoma Growth and Brain Metastasis by Inducing Apoptosis and Cell Cycle Arrest.

Abstract

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 in vivo, 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.