F-α-DDB-derivative, a novel synthetic of bifendate, plus epirubicin improves antitumor efficacy against triple negative breast cancer without additional cardiotoxicity

Triple negative breast cancer (TNBC) refers to a molecular subtype of breast cancers (BC) with high rate of distant metastases and poor prognosis. Epirubicin (EPI) is widely used for the therapy of TNBC but it's limited in clinical use due to cardiotoxicity and chemotherapy resistance. We previously identified F-α-DDB-derivative, a novel synthetic of bifendate, as a potential agent to improve the therapeutic efficacy of TNBC in combination with EPI since F-α-DDB-derivative inhibited MDA-MB-468, but not as much as EPI. In this study, we investigated the antitumor activity of F-α-DDB-derivative in combination with EPI against TNBC in vitro and in vivo and whether co-treatment would induce additional cardiotoxicity. In human TNBC MDA-MB-468 cells, application of F-α-DDB-derivative (11.5, 23.0, 46.0 μg/ml) in combination with EPI (1.5, 3.0, 6.0 μg/ml) exhibited great inhibition on cell viability and cell proliferation. Additionally, F-α-DDB-derivative (5.75, 11.5, 23.0, 46.0 μg/ml) interacted with EPI (0.75, 1.5, 3.0, 6.0 μg/ml) synergistically to induce apoptosis in MDA-MB-468 cells. This suggests that F-α-DDB-derivative may be more sensitive to apoptotic pathways. Furthermore, we revealed that co-administration of EPI and F-α-DDB-derivative (ip, once every other day for 14 days) significantly increased the therapeutic efficacy of EPI (2.0 mg/kg) or F-α-DDB-derivative (20.0 mg/kg) in mice harboring MDA-MB-468 cell xenografts without additional cardiotoxicity compared to that in EPI monotherapy group. These results implicate that co-treatment of EPI and F-α-DDB-derivative may be a potential therapeutic approach for the treatment of TNBC.