Mitochondria-targeting natural product rhein conjugated with dichloroacetate as the dual inhibitor of glycolysis and oxidative phosphorylation to off energize cancer cells and induce ROS storm.

Metabolic reprogramming emerges as a remarkable hallmark of cancer cells and exhibits potential in the development of metabolic modulators. Numerous small-molecule inhibitors mainly target reversing the dominant-glycolysis pathway. However, energy metabolic adaptation that facilitates the alternation of metabolic phenotypes from glycolysis to oxidative phosphorylation (OXPHOS) undermines treatment efficacy. Thus, small molecular therapeutic agents, concurrently cutting off the cellular energy metabolism of glycolysis and OXPHOS and trigger oxidative stress damage, hold promise for cancer therapy. Herein, natural product rhein with the capacity of mitochondria-targeting was conjugated with pyruvate dehydrogenase kinase (PDK) inhibitor dichloroacetate (DCA) to form a multifunction small molecule drug Rhein-DCA conjugate. The ATP production inhibition, oxidative stress damage and antitumor efficacy of Rhein-DCA conjugate were evaluated both and . Rhein unit not only led to the effective accumulation of Rhein-DCA conjugate in mitochondria, but also promoted the binding of DCA and PDK1, enhancing typical inhibition of glycolysis by DCA PDK-PDH axis. Unlike classical PDK inhibitors, which restrained glycolysis and restored OXPHOS, rhein within the conjugate further suppressed mitochondrial respiratory chain complex and induced sustained opening of mitochondrial permeability transition pore, destroying intractable OXPHOS. Importantly, rhein component in the conjugate elevated the reactive oxygen species (ROS) level to further disrupt OXPHOS, and thus ROS triggered the release of damage associated molecular patterns. Simultaneously, the conjugate weakened lactate-mediated immunosuppression by reducing lactate levels in the tumor microenvironment. Eventually, the polarization state of tumor-associated macrophages could be effectively reversed following oral administration. This study designed a small-molecule dual-inhibitor of glycolysis and OXPHOS to circumvent metabolic adaptations and simultaneously induce immunogenic cell death for macrophages repolarization, thereby synergistically promoting antitumor efficacy.