Triterpenoids with modified A-ring as modulators of P-gp-dependent drug-resistance in cancer cells

Semi-synthetic A-cycle modified triterpenic derivatives with A-cycle condensed with a heterocyclic fragment (compound 1 ) and fragmented A-ring (compound 2 ) were tested for cytotoxicity against several tumor cell cultures and doxorubicin (Dox)-resistant cell lines. The equal cytotoxicity of the tested compounds to the parental tumor cell lines (HBL-100, K562) and their resistant subclones (HBL-100/Dox, K562/i-S9) was revealed. The overexpression of ABCB1 (MDR1) gene and P-glycoprotein (P-gp) was confirmed for both resistant subclones of tumor cells. Compounds 1 and 2 were shown to inhibit the ABC-transporter gene expression ( MDR1 , MRP , MVP , and BCRP ) and the transport of well-known P-gp substrate Rhodamine 123 from resistant cells. The docking of triterpenoids 1 and 2 into the drug binding site of P-gp revealed a similarity between the conformation of the tested triterpenoids and that of classical inhibitor verapamil , thus assuming these compounds to be more likely the inhibitors than the substrates of P-gp. Any tested triterpenic derivatives, when combined at non-toxic concentrations with doxorubicin, improved cytotoxic effect of the therapeutic drug against resistant subclones of tumor cells. • Compounds 1 , 2 showed cytotoxicity against cancer and MDR cells. • 1 , 2 greatly enhanced the cytotoxicity of Dox against MDR cells. • 1 , 2 inhibit the MDR1 , MRP , MVP , and BCRP genes expression. • 1 , 2 could inhibit P-gp activity via non-competitive interaction. • According to docking, 1 , 2 bounded to the P-gp binding site as verapamil.