Repurposing chlorpromazine for the treatment of triple-negative breast cancer growth and metastasis based on modulation of mitochondria-mediated apoptosis and autophagy/mitophagy.

BACKGROUND: Triple-negative breast cancer (TNBC) presents significant challenges due to its aggressive nature and high propensity for brain metastasis, often exhibiting resistance to standard treatments. In this study, we conducted a preliminary screening of potential therapeutic agents and identified chlorpromazine (CPZ) as a promising candidate for treating TNBC and its brain metastases. METHODS: The inhibitory activities of CPZ and its combination with several standard treatment drugs were evaluated in preclinical TNBC models. The mechanism of CPZ on TNBC was elucidated using TMT-labeled quantitative proteomics analysis. RESULTS: In vivo experiments demonstrated that CPZ robustly suppressed tumor growth and metastasis, particularly in lung and brain models. Importantly, CPZ enhanced the efficacy of standard therapeutic agents such as vinorelbine (NVB) and anti-PD-1 antibody. Mechanistically, CPZ induced G2/M phase arrest and triggered mitochondria-mediated intrinsic apoptosis in TNBC cells. Furthermore, CPZ triggered incomplete autophagy and activated PINK1-Parkin-mediated mitophagy. Inhibiting autophagy/mitophagy augmented CPZ's anticancer effects, indicating these processes may have cell protective roles. CONCLUSIONS: Our study highlights the dual function of CPZ in suppressing TNBC growth and metastasis, positioning it as a promising candidate for treating this aggressive cancer. Additionally, targeting autophagy/mitophagy may serve as an effective strategy to enhance anticancer therapies against TNBC.