Paeoniflorin sensitizes imatinib mesylate-resistant chronic myeloid leukemia cells via the inhibition of Cyr61 production

Imatinib mesylate (IM) is a first-line therapy for chronic myeloid leukemia (CML) and exhibits good therapeutic effects, but not in all patients with CML owing to drug resistance. Our previous study showed that Cyr61 plays a key role in IM resistance in CML cells. Paeoniflorin (PF) is a bioactive compound isolated from the traditional Chinese medicine Paeonia lactiflora Pall that displays anticancer activity. Little is, however, known regarding the role of PF in IM-resistant CML cells. This study aimed to evaluate whether PF could decrease Cyr61 production and improve IM-resistant CML cell sensitivity to IM and to investigate the underlying mechanisms. CML cell lines (K562 and KCL22) and IM-resistant cell lines (K562G and KCL22R) were used as CML study models. Cyr61 expression was assessed in both parental and IM-resistant CML cells by western blotting, real-time quantitative PCR , and ELISA. Lentiviral vectors were used to induce the knockdown of Cyr61 expression, followed by a comprehensive evaluation of cell proliferation and apoptosis. The results showed that PF decreased the production of Cyr61 in the presence of IM by inhibiting extracellular regulated protein kinases 1/2 activation. PF significantly decreased the IC50 value of IM and increased IM-induced apoptosis of IM-resistant CML cells. Importantly, PF also improved the sensitivity of CML cells to bosutinib and dasatinib via inhibition of Cyr61 production. In conclusion, we report for the first time that PF may effectively improve the sensitivity of IM-resistant CML cells to IM, bosutinib, and dasatinib, at least in part, by subsequently downregulating Cyr61.