Abstract
Breast cancer stem cells (BCSCs) express high levels of the anti-apoptotic protein, survivin. This study aimed to discover a natural active compound with anti-cancer properties that targeted survivin in human breast cancer stem cells. From the seven examined compounds, andrographolide was selected as a lead compound through in silico molecular docking with survivin, caspase-9, and caspase-3. We found that the affinity between andrographolide and survivin is higher than that with caspase-9 and caspase-3. Human CD24-/CD44+ BCSCs were treated with andrographolide in vitro for 24 hours. The cytotoxic effect of andrographolide on BCSCs was compared to that on human mesenchymal stem cells (MSCs). The expression of survivin, caspase-9, and caspase-3 mRNA was analyzed using qRT-PCR, while Thr34-phosphorylated survivin and total survivin levels were determined using ELISA and Immunoblotting assay. Annexin-V/PI flow cytometry assays were performed to evaluate the apoptotic activity of andrographolide. Our results demonstrate that the CC50 of andrographolide in BCSCs was 0.32mM, whereas there was no cytotoxic effect in MSCs. Moreover, andrographolide decreased survivin and Thr34-phosphorylated survivin, thus inhibiting survivin activation and increasing survivin mRNA in BCSCs. The apoptotic activity of andrographolide was revealed by the increase of caspase-3 mRNA and protein, as well as the increase in both the early and late phases of apoptosis. In conclusion, andrographolide can be considered an anti-cancer compound that targets BCSCs due to its molecular interactions with survivin, caspase-9, and caspase-3, which induce apoptosis. We suggest that the binding of andrographolide to survivin is a critical aspect of the effect of andrographolide.
Highlights
Breast cancer, like other solid cancers, contains cell populations known as breast cancer stem cells (BCSCs) which have tumorigenic, pluripotent, and self-renewal properties
This study demonstrates that the addition of 0.6 mM andrographolide to BCSCs significantly increased the expression of survivin mRNA (p
We examined the anti-cancer potential of andrographolide, a natural active compound, through its in silico molecular interactions with survivin, caspase-9, and caspase-3 and the increased intrinsic apoptosis activity of human BCSCs in vitro
Summary
Like other solid cancers, contains cell populations known as breast cancer stem cells (BCSCs) which have tumorigenic, pluripotent, and self-renewal properties. The phosphorylation of survivin on Thr residue increases the binding of this protein to initiator caspase-9, leading to the inhibition of caspase-9 and caspase-3 interaction [2,3,4]. This protein is rarely present in normal cells but is highly expressed in cancer cells [5, 6]. Targeting survivin inhibition is a promising strategy for apoptosis-based cancer therapy, in cancer stem cells This could possibly be done by reducing the expression of survivin in human breast cancer stem cells (BCSCs) using natural active compounds from medicinal plants
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