Rapid development of multiple drug resistance against current
therapies is a major barrier in the treatment of
cancer. Therefore,
anticancer agents that can overcome acquired drug resistance in
cancer cells are of great importance. Previously, we have demonstrated that ethyl 2-amino-4-(2-ethoxy-2-oxoethyl)-6-phenyl-4H-chromene-3-carboxylate (5a,
sHA 14-1), a stable analogue of
ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (6,
HA 14-1), mitigates drug resistance and synergizes with a variety of
cancer therapies in
leukemia cells. Structure-activity relationship (SAR) studies of 5a guided the development of ethyl 2-amino-6-(3',5'-dimethoxyphenyl)-4-(2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (5q,
CXL017), a compound with low micromolar cytotoxicity against a wide-range of hematologic and solid
tumor cells. More excitingly, our studies of 5q in
camptothecin (CCRF-CEM/C2) and
mitoxantrone (HL-60/MX2) resistant
cancer cells highlight its ability to selectively kill
drug-resistant cells over parent
cancer cells. 5q inhibits
tumor cell growth through the induction of apoptosis, with detailed mechanism of its selectivity toward
drug-resistant
cancer cells under investigation. These results suggest that 5q is a promising candidate for treatment of
cancers with multiple drug resistance.