A selenium-containing selective estrogen receptor modulator to overcome drug resistance of chronic myeloid leukemia.

Chemotherapy failure caused by adriamycin (ADM) and imatinib (IM) resistance remains a critical challenge in the treatment of chronic myeloid leukemia (CML). In this study, a novel compound 4, 4’-(selenophene-2, 5-diyl)bis(3-fluorophenol) (Se-1) with estrogen receptor regulation and selenium anticancer activity was applied to reverse drug resistance of CML. Se-1 exhibited superior inhibitory activity against resistant K562/ADM cells compared to sensitive K562 cells. The growth of K562/ADM in xenograft mouse was suppressed by Se-1 treatment. The anti-leukemia mechanism of Se-1 was tested by western-blot, flow cytometry, molecular docking and fluorescence imaging. The apoptosis rate was increasing after Se-1 treatment, meanwhile proteins of Cleaved PARP and Cleaved Caspase3 were up-regulated and Bcl-2 was down-regulated. In addition, the autophagy was activated through increasing of autophagy vesicles and proteins of LC3-II and P62, and inactivating of mTOR protein. Moreover, estrogen receptor α (ERα), ERK and P38 were activated, the proteins of PI3K and AKT1 were decreased. Overall, Se-1 exerted anti-CML effects through multi-mechanism interaction, which was expected to advance the research in reversing ADM and IM resistance of chronic myeloid leukemia.