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.

三阴性乳腺癌（triple-negative breast cancer, TNBC）因缺乏有效治疗靶点，长期以来一直是临床治疗的棘手难题。鉴于三类基于异质性代谢通路划分的三阴性乳腺癌亚型，靶向脂质、碳水化合物及核苷酸代谢通路的策略，近期被证实为颇具前景的治疗方案。在此，我们报道一种名为Pt(II)caffeine的多模态抗癌铂(II)配合物（platinum(II) complex），其具备全新的作用机制：可同时介导线粒体损伤、抑制脂质、碳水化合物与核苷酸代谢通路，并促进细胞自噬。上述多种生物学效应最终可在体外与体内实验中，强效抑制三阴性乳腺癌MDA-MB-231细胞的增殖活性。研究结果表明，可多层面调控细胞代谢的Pt(II)caffeine，是一款具备克服三阴性乳腺癌代谢异质性潜力的金属抗肿瘤药物。