Overcoming ABT-737 resistance in triple-negative breast cancer: C-phycocyanin-mediated myeloid cell leukemia-1 downregulation enhances apoptotic sensitivity.

BACKGROUND: Triple-negative breast cancer (TNBC) remains an aggressive disease with few targeted therapies. The BH3-mimetic ABT-737 faces clinical resistance largely due to Mcl-1-mediated compensatory survival signaling. C-Phycocyanin is a natural compound known to trigger apoptosis. Therefore, we aimed to evaluate whether C-Phycocyanin enhances ABT-737 sensitivity in MDA-MB-468 TNBC cells by downregulating Mcl-1 and modulating the intrinsic apoptotic cascade.

METHODS: Cells were treated with C-phycocyanin, ABT-737, or their combination. Viability (MTT), proliferation (trypan blue), migration (wound healing), clonogenicity, apoptosis (ELISA), and caspase-3 activity were evaluated. Expression of Mcl-1, Bcl-2, Bak, and p53 was measured by qRT-PCR and Western blot. Synergy was analyzed using the Combination Index (CI) method.

RESULTS: IC₅₀ values for C-phycocyanin and ABT-737 were 5.62 µM and 32.47 µM, respectively; combination therapy reduced the IC₅₀ to 3.71 µM and demonstrated synergy (CI < 1). C-Phycocyanin downregulated Mcl-1 and Bcl-2 while upregulating Bak and p53. ABT-737 alone increased Mcl-1 expression by ~ 40%, an effect effectively counteracted by co-treatment. The combination significantly inhibited migration and colony formation and enhanced caspase-3 activation compared to monotherapies.

CONCLUSIONS: C-Phycocyanin synergistically enhances ABT-737 efficacy in MDA-MB-468 TNBC cells by suppressing compensatory Mcl-1 upregulation and modulating apoptotic regulators. This natural-product-based combination offers a promising strategy to overcome BH3-mimetic resistance, although further validation in additional TNBC cell lines is warranted.