Jatrophane diterpenes from Euphorbia Sororia enhance chemotherapy drugs sensitivities in P-gp-induced multidrug resistance cells

Investigating P-glycoprotein modulators with pharmacology effects and low toxicity to enhance P-gp-mediated chemotherapeutic drugs sensitivity against drug resistance cells is considered as one of the most feasible strategies to overcome multidrug resistance (MDR). Jatrophane diterpenes obtained from the fructus of Euphorbia Sororia have demonstrated to exhibit MDR reversal abilities with low toxicity. In this study, we developed a method for purifying and enriching Jatrophane diterpenes, and evaluated the toxicity and MDR reversal potential. Component I primarily consists of eight jatrophane diterpenes with a total content reaching up to 92.3 %, as quantified by HPLC analysis. Component I exhibited superior efficacy and lower toxicity compared to component G and E. Our results suggest that Component I may act as a P-gp substrate, directly inhibiting the P-gp-mediated efflux of its substrates and stimulating P-gp ATPase activity, thereby increasing intracellular drug accumulation in both MCF-7/ADR and HCT-8/T cell lines. Component I inhibited PI3K/NF-κB pathway in MCF-7/ADR cells which contributed to the reduction of P-gp. Component I enhanced ROS levels in DOX-resistant MCF-7/ADR cells, although this effect was attenuated in HCT-8/T cells. These effects ultimately resulted in increased cell apoptosis and restored sensitivity to P-gp substrate chemotherapeutic agents in both MDR cell lines.