Anthocyanidins Inhibit Growth and Chemosensitize Triple-Negative Breast Cancer via the NF-κB Signaling Pathway

SIMPLE SUMMARY: Breast cancer is the most common female cancer diagnosed in the U.S. and the second most common cause of cancer death in women. Chemotherapeutics used to treat breast cancer often have side effects, which are sometimes life-threatening. Moreover, the tumors can develop resistance over time, making breast cancer treatment challenging. In this paper, we show that the oral administration of colored pigments isolated from bilberry/blueberry, called anthocyanidins (Anthos), significantly decrease MDA-MB-231 orthoxenograft tumor volume, inhibit the growth and metastasis of breast cancer, sensitize drug-resistant tumor cells, and exhibit a lower rate of lymph node and lung metastasis, compared to control. Our results also suggest regulation of cell-cycle progression and inhibition of NF-κB activation as mechanisms underpinning the anti-proliferative activity of Anthos in breast cancer. These mechanistic insights are expected to be valuable for clinical translation of berry Anthos, either alone or as adjuvant to chemotherapy, for the treatment of breast cancer patients. ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to the lack of drug-targetable receptors, chemotherapy is the only systemic treatment option. Although chemotherapeutic drugs respond initially in TNBC, many patients relapse and have a poor prognosis. Poor survival after metastatic relapse is largely attributed to the development of resistance to chemotherapeutic drugs. In this study, we show that bilberry-derived anthocyanidins (Anthos) can inhibit the growth and metastasis of TNBC and chemosensitize paclitaxel (PAC)-resistant TNBC cells by modulating the NF-κB signaling pathway, as well as metastatic and angiogenic mediators. Anthos administered orally significantly decreased MDA-MB-231 orthoxenograft tumor volume and led to lower rates of lymph node and lung metastasis, compared to control. Treatment of PAC-resistant MDA-MB-231Tx cells with Anthos and PAC in combination lowered the IC(50) of PAC by nearly 20-fold. The combination treatment also significantly (p < 0.01) decreased the tumor volume in MDA-MB-231Tx orthoxenografts, compared to control. In contrast, Anthos and PAC alone were ineffective against MDA-MB-231Tx tumors. Our approach of using Anthos to inhibit the growth and metastasis of breast cancers, as well as to chemosensitize PAC-resistant TNBC, provides a highly promising and effective strategy for the management of TNBC.