Resistance to doxorubicin (DOX) is a major clinical challenge in triple-negative breast cancer (TNBC), which is highly diverse in different patients with variable outcomes. Apatinib is a new antiangiogenic agent, which has been reported to induce apoptosis. Nevertheless, the potential role and underlying mechanisms of apatinib in reversing DOX resistance of TNBC remain unknown. This work aims to evaluate the effects of apatinib on improving the sensitivity of TNBC cells to DOX and its underlying molecular basis. Our data indicate that apatinib treatment sensitizes DOX-resistant breast cancer cells to DOX, which is accompanied by significantly increased apoptosis. Additionally, this increased induction of apoptosis is associated with an enhancement of reactive oxygen species (ROS) accumulation. Importantly, it was found that followed by DOX treatment, apatinib could inhibit NF-κB signaling pathways, which have been validated to increase ROS production and reverse DOX resistance. Moreover, our in vivo results indicate the combination of DOX and apatinib exerted increased antitumor effects on TNBC cell xenograft models. Taken together, our study suggests that apatinib sensitizes TNBC cells to DOX in vitro and in vivo through inactivation of NF-κB signaling pathways, providing a rationale for the combined use of apatinib and DOX in TNBC chemotherapy.
Keywords: Apatinib; NF-κB; ROS; apoptosis; chemoresistance; doxorubicin.
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