Synchronizing activity of Biobran/MGN-3 with exosomes: Therapeutic targeting of hypoxia pathway to inhibit angiogenesis and proliferation of breast invasive ductal carcinoma

Hypoxia-inducible factors (HIFs) are crucial for understanding and treating breast cancer, as low oxygen levels within tumors are key factors driving cancer progression, metastasis, and therapy resistance. We studied the possible role of exosomes in combination with Biobran/MGN-3, an arabinoxylan rice bran, in the HIF pathway via its pathogenesis and resistance to VEGF or Ang-2 inhibitors. Primary cultures of human breast cancer (BC) (invasive ductal carcinoma) and normal epithelial breast tissues were established. Primary BC cells were treated with the IC50 of Biobran and exosomes and exposed to moderate (5% O2) and severe (0.02% O2) hypoxic conditions. The mRNA expression of HIF-1a, VEGF, and Ang-2 and the protein levels of Bcl-2, p53, and caspase-3 were examined. Molecular docking in situ was also performed to predict and assess the affinity of Biobran for hypoxia-related targets: VHL, PHD, CBP, FIH, and VEGFR-2. Treatment with Biobran or its combination with exosomes attenuated the severe elevation of HIF-1a, VEGF, and Ang-2 levels and upregulation of both p53 and caspase-3 expression in tumor cells, while downregulating Bcl-2 expression. Molecular docking data revealed that PHD protein is the strongest binder to Biobran, with the strength of protein binding being PHD > VHL > CBP > VEGFR-2 > FIH. The present study demonstrates that both Biobran and exosomes enhance anti-tumor activity, suggesting the design of analogs for HIF-1a, VEGF, Ang-2, and Bcl-2 receptors for new anticancer therapies, offering potential for targeted cancer treatment.