Boosting Energy Deprivation via Synchronous Interventions of Oxidative Phosphorylation and Glycolysis for Cancer Therapy with 1,8-Naphthyridine-Piperazine-Dithiocarbamate Ruthenium(II) Polypyridyl Complexes

Bioenergetic therapy targeting mitochondrial bioenergy
is a promising
therapeutic strategy for cancer. However, its clinical efficacy is
limited by the metabolic adaptability of tumor cells, as they can
switch between glycolytic and oxidative phosphorylation metabolic
phenotypes to maintain energy homeostasis. In this study, we discovered
1,8-naphthyridine-piperazine-dithiocarbamate ruthenium(II) polypyridyl
complexes (RuL1) that enhanced energy deprivation by
inhibiting the activity of mitochondrial complex I and III, thereby
disrupting oxidative phosphorylation. Simultaneously, RuL1 inhibits glycolysis while unexpectedly activating antitumor immunity.
This dual metabolic–immunological targeting resulted in enhanced
anticancer activity against MGC-803 cells. To the best of our knowledge, RuL1 is the first ruthenium polypyridyl complex reported to
achieve high anticancer activity through dual metabolic inhibition.