A myrsinol diterpene isolated from Euphorbia prolifera reverses multidrug resistance in breast cancer cells.

P-glycoprotein (P-gp), a member of ATP-Binding Cassette transporter superfamily, can expel a variety of anti-cancer drugs so that it impairs the effect of cancer chemotherapy and results in multidrug resistance (MDR). The P-gp inhibitors are important to circumvent MDR and improve efficacy of cancer chemotherapy. The dried root of Euphorbia prolifera Buch.-Ham. has been used to treat cancer and inflammation in Chinese folk medicine for several hundred years. A myrsinol diterpene derived from Euphorbia prolifera Buch.-Ham. (J196-9-4) could modulate multidrug resistance. Cytotoxicity assays were performed to measure the reversal efficiency of J196-9-4. Efflux assay and ATPase assay were used to elucidate the mechanism of the chemical. J196-9-4 potentiated cytotoxicity of anti-cancer drugs in the P-gp over-expressing resistant breast cancer cell line MCF-7/Adr as compared to MCF-7 cells. Concentrations of 5 and 10 μM J196-9-4 could reverse the resistance to daunorubicin, vincristine, and topotecan significantly. Since J196-9-4 inhibited P-gp mediated efflux and stimulated ATP hydrolysis, J196-9-4 was a substrate of P-gp. Thus J196-9-4 is a competitive inhibitor of P-gp and reverses multidrug resistance induced by the transporter.