Computational development of mushroom-6-glucan/paclitaxel as a synergistic complementary medicine for breast cancer therapy.

Abstract

Background: Breast cancer is chemo-resistant and highly metastatic, often resulting in patient mortality. One of the primary factors contributing to the metastasis and chemotherapy resistance is the presence of cancer stem-like cells. We posited that the natural polysaccharide known as 6-glucans, derived from Pleurotus ostreatus, could effectively counteract the chemotherapy resistance associated with cancer stem-like cells in breast cancer.

Methods: We computationally developed a specific dual combinatorial therapy involving 6-glucans and Paclitaxel (PTX) and tested on preclinical 3D mammosphere human tumor models representing receptor-positive and receptor-negative breast cancer. Using this preclinical 3D spheroid technology, we tested the anti-cancer properties of these predicted treatment combinations on mammospheres containing human breast cancer stem cells.

Results: Among the 40 distinct combinations examined, computational prediction revealed that the addition of 2.0 mg/mL of 6-glucans to a low dose of 3.0 µg/mL PTX was the sole combination demonstrating a synergistic effect. This optimized synergistic combination therapy displayed a significant inhibitory impact on human cancer epithelial and stem cell migration, evasion, and colony formation. The inclusion of 6-glucans also augmented apoptosis in both breast cancer cells and stem cells, leading to a six-fold reduction in BrdU labeled cells and an increased arrest of cells in the sub-G0 phase. These effects were mediated through mitochondrial dysfunction and the downregulation of associated oncogenes.

Conclusion: Our study revealed that the computationally predicted 6-glucans-based binary complementary medicine exhibited sequence- and concentration-dependent anticancer synergistic effects.