Elucidating the Multimodal Anticancer Mechanism of an Organometallic Terpyridine Platinum(II) N-Heterocyclic Carbene Complex against Triple-Negative Breast Cancer In Vitro and In Vivo

Treatment of triple-negative breast cancer (TNBC) has long been a medical challenge because of the lack of effective therapeutic targets. Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option in view of three heterogeneous metabolic-pathway-based TNBC subtypes. Here, we present a multimodal anticancer platinum(II) complex, named Pt(II)caffeine, with a novel mode of action involving simultaneous mitochondrial damage, inhibition of lipid, carbohydrate, and nucleotide metabolic pathways, and promotion of autophagy. All these biological processes eventually result in a strong suppression of TNBC MDA-MB-231 cell proliferation both in vitro and in vivo. The results indicate that Pt(II)caffeine, influencing cellular metabolism at multiple levels, is a metallodrug with increased potential to overcome the metabolic heterogeneity of TNBC.

Automated summary

Targeting lipid, carbohydrate, and nucleotide metabolism pathways has recently been proven as a promising option for the treatment of triple-negative breast cancer (TNBC). In this study, a multimodal anticancer platinum(II) complex, Pt(II)caffeine, was developed, which simultaneously damages mitochondria, inhibits metabolic pathways, and promotes autophagy, resulting in strong suppression of TNBC cell proliferation both in vitro and in vivo. These findings highlight the potential of Pt(II)caffeine as a metallodrug to overcome the metabolic heterogeneity of TNBC.