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

Abstract

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.