Ginsenoside Rh2 pretreatment and withdrawal reactivated the pentose phosphate pathway to ameliorate intracellular redox disturbance and promoted intratumoral penetration of adriamycin

Improving the limited penetration, accumulation and therapeutic effects of antitumor drugs in the avascular region of the tumor mass is crucial during chemotherapy. P-gp inhibitors have achieved little success despite significant efforts. Excessive P-gp inhibition disturbed the kinetic balance between intracellular accumulation and intercellular penetration, thus resulting in a more inhomogeneous distribution of substrate drugs. Here, we found that ginsenoside Rh2 pretreatment mildly downregulated P-gp expression through reactivating the pentose phosphate pathway and rebalancing redox status. This mild P-gp inhibition not only significantly increased the growth inhibition effect and accumulation profile of adriamycin (ADR) throughout the multicellular tumor spheroid (MCTS) but also had unique advantages in improving drug penetration. Furthermore, we developed a novel individual-cell-based PK-PD integrated model and proved that metabolic reprogramming and redox rebalancing-based P-gp regulation was sufficient to increase the ADR effect in both central and peripheral cells of MCTS. Thus, a “ginsenoside Rh2-ADR” sequential regimen was proposed and exhibited a potent antitumor effect in vivo. This novel P-gp inhibition via metabolic reprogramming and redox rebalancing provided a new idea for achieving better antitumor effects in the tumor avascular region during chemotherapy.