Breast cancer, like other solid cancers, contains cell populations known as breast cancer stem cells (BCSCs) that are carcinogenic, pluripotent, and self-renewing. The presence of BCSC is responsible for the occurrence of metastasis, resistance to treatment, recurrence of cancer and have CD24- / CD44 + surface antigen markers. Breast cancer stem cells (BCSCs) express high levels of the anti-apoptotic protein, survivin. The affinity between andrographolide {natural terpenoids} and survivin was found to be higher than that with caspase-9 and caspase-3. Survivin is an inhibitor of the apoptosis protein family (Inhibitor Protein… IAP) that blocks the endogenous apoptosis pathway by binding to caspase-9 or caspase-3.
Phosphorylation of survivin increases the binding of this protein to caspase-9, leading to inhibition of the interaction of the two caspases. This protein is rarely present in normal cells, but is highly expressed in cancer cells. Human CD24- / CD44 + BCSCs were treated with andrographolide in vitro for 24 hours. The expression of survivin, caspase-9 and caspase-3 mRNA was analyzed using qRT-PCR, the levels of phosphorylated survivin by ELISA, and by flow cytometry the apoptotic activity of andrographolide. Previous studies have shown that human BCSCs (CD24- / CD44 +) have higher viability compared to the corresponding non-BCSCs (CD24- / CD44-) due to the high expression of survival, regulated by the Wnt pathway.
The results show that andrographolide reduced survivin and phosphorylated survivin, thereby inhibiting survivin activation in BCSCs, with no cytotoxic effect on MSCs. In conclusion, andrographolide can be considered a compound that targets BCSCs due to its molecular interactions with survivin, caspase-9 and caspase-3, which cause apoptosis.
Therefore, targeting survival inhibition is a promising treatment strategy for apoptosis-based treatment for BCSCs using natural active compounds from medicinal plants.
SOURCE: Survivin and CsCs, PLOS ONE, November 2020.
