Potential anti-MDR agents based on the podophyllotoxin scaffold: synthesis and antiproliferative activity evaluation against chronic myeloid leukemia cells by activating MAPK signaling pathways

Abstract

One of the main causes for chemotherapeutic failure is the development of multidrug resistance (MDR), which is also one of the major obstacles to successful cancer chemotherapy. To overcome multidrug resistance, in this study, we synthesized several acrylic esters of podophyllotoxin and evaluated their antiproliferative activities in sensitive and resistant human chronic myeloid leukemia cells, K562 and K562/ADR, by CCK-8 method in vitro. All of the synthesized compounds demonstrated potent anticancer effects with IC₅₀ values in the nM range. In particular, compound 9k exhibited the most potent activity towards drug-resistant K562/ADR cells with an IC₅₀ value of 0.055 ± 0.014 μM, which was more effective than podophyllotoxin, doxorubicin and etoposide. Furthermore, flow cytometry results revealed that 9k could obviously induce cell cycle arrest in the G2/M phase in K562/ADR cells. Meanwhile, it was found that 9k could induce apoptosis in K562/ADR cells by up-regulating the expression of Bax, caspase-3 and p53, and inhibiting the expression of Bcl-2 and survivin. Western blot analysis revealed that 9k significantly inhibited Pgp protein expression in K562/ADR cells. Additionally, further studies demonstrated that 9k could dose-dependently stimulate the MAPK signaling pathways in K562/ADR cells by up-regulating the expression levels of p-ERK1/2, p-JNK and p-p38. The results indicate that 9k has the potential to be a novel MDR reversal agent in human chronic myeloid leukemia therapy.