Quercetin inhibits Multidrug Resistance by down-regulation of CYR61 in human gastric adenocarcinoma AGS cells

Abstract

ABSTRACT The cysteine-rich angiogenic inducer 61 (CYR61), an extracellular matrix-associated protein, is involved in survival, tumorigenesis, angiogenesis, and drug resistance. There is an increasing demand for developing agents that target CYR61. We study here the effects of flavones against CYR61-overexpressing human gastric adenocarcinoma AGS (AGS-cyr61) cells. AGS-cyr61 cells exhibit resistance to 5-fluorouracil, adriamycin, tamoxifen, paclitaxel, and docetaxel. Overexpression of CYR61 in AGS cells leads to up-regulation of MRP1 (Multidrug resistance-associated protein 1, encoded by ABCC1, ATP-binding cassette sub-family C member 1), poly (ADP-ribose) polymerase (PARP), and nuclear factor-kappa B (p65). Treatment with 5-Fluorouracil at 25-50 μM or Adriamycin at 125-250 nM showed the dramatic cleavage of PARP in AGS cells but AGS-cyr61 cells. Among the various flavones, quercetin had lowest IC50 value of 27.3 ± 15.1 μM and it reduced the viability of AGS-cyr61 cells more than that of AGS cells. Quercetin down-regulates CYR61 and MRP1 in AGS-cyr61 cells and the multidrug resistance observed in AGS-cyr61 cells is revered by either the treatment of quercetin or CYR61 siRNA. In addition, quercetin synergizes actions of standard chemotherapeutics 5-Fluorouracil and adriamycin. Our results demonstrate for the first time that CYR61 can be potential regulator of ABC transporters and quercetin can be the novel agent that improves the efficacy of anticancer drugs by down-regulating CYR61 and ABC transporters.