Eupatilin-derived compounds enhance antitumor activity and doxorubicin efficacy in triple-negative breast cancer.

PURPOSE: Triple-negative breast cancer (TNBC) has limited therapeutic options. We evaluated the anticancer activities of the Eupatilin derivatives ONG41008 and ONG41003 and their potential to enhance doxorubicin efficacy.

MATERIALS AND

METHODS

Anticancer activity was evaluated in TNBC cells using viability, cell-cycle, apoptosis, migration, and invasion assays. Drug interactions with doxorubicin and paclitaxel were assessed using dose-response curves and the Loewe model. Doxorubicin accumulation and ABCB1 and ABCG2 mRNA expression were analyzed. ONG41003 efficacy was further evaluated in an orthotopic TNBC xenograft model.

RESULTS

Both derivatives induced G2/M arrest and apoptosis and inhibited migration and invasion. ONG41008 showed an apparent reduction in the fitted doxorubicin IC50 at 60 μM and clear synergy with doxorubicin. ONG41003 did not consistently reduce the doxorubicin IC50 and showed a modest positive interaction. Neither compound showed meaningful synergy with paclitaxel. Combination treatment increased doxorubicin accumulation and attenuated doxorubicin-induced ABCB1 expression. In vivo, ONG41003 enhanced doxorubicin efficacy without detectable systemic toxicity.

CONCLUSION

ONG41008 and ONG41003 exerted anticancer effects and enhanced the response to doxorubicin through distinct interactions. Increased doxorubicin accumulation may be associated with attenuation of ABCB1 expression, supporting further investigation of these compounds as partners for anthracycline-based chemotherapy.