Sitravatinib enhances doxorubicin cytotoxicity in doxorubicin‐resistant K562 / ADM cells

Abstract Drug resistance remains a major obstacle in leukemia treatment, and combination therapy has emerged as an effective strategy to overcome this limitation. This study aimed to identify compounds with potent anticancer activity in multidrug‐resistant leukemia cells through a drug repositioning–based screening of clinical‐phase compounds. Among 3120 screened compounds, sitravatinib was identified as a promising hit compound exhibiting significant cytotoxic activity in doxorubicin‐resistant K562/ADM cells. When combined with doxorubicin, sitravatinib showed a synergistic effect, enhancing caspase‐dependent apoptosis and amplifying DNA damage signaling through CHK1 phosphorylation at Ser317. Taken together, this study highlights the therapeutic potential of sitravatinib to be used as a partner drug in doxorubicin combination therapy and provides an effective drug combination strategy for overcoming multidrug resistance in leukemia.