Physalin A induces apoptotic cell death and protective autophagy in HT1080 human fibrosarcoma cells
Hao He1, Ling-He Zang, Yong-Sheng Feng
1Department of Natural Products Chemistry, School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang, People's Republic of China.
Abstract:
Physalin A (1) is a withanolide isolated from Physalis alkekengi var. franchetii. In this study, the selective growth inhibitory effects on tumor cells induced by 1 were screened, and the mechanism was investigated on 1-induced growth inhibition, including apoptosis and autophagy, in human fibrosarcoma HT1080 cells. Apoptosis induced by 1 in HT1080 cells was associated with up-regulation of caspase-3 and caspase-8 expression. However, there were no significant changes in caspase-9, Bid, Bax, and Bcl-2 expression, indicating that 1-induced apoptosis in HT1080 cells occurs mainly through activation of the death receptor-associated extrinsic apoptotic pathways. Autophagy induced by 1 was found to antagonize apoptosis in HT1080 cells. This effect was enhanced by rapamycin and suppressed by the autophagy inhibitor 3-methyladenine (3MA). Loss of beclin 1 (as an autophagic regulator) function led to similar results to 3MA. However, 1 did not show inhibitory effects on normal human cells (human peripheral blood mononuclear cells). Taken together, these results suggest that 1 may be a promising agent for the treatment of cancer.
Insights
Physalin A selectively inhibits tumor cell growth by inducing apoptosis via the extrinsic pathway. It also triggers autophagy, which counteracts apoptosis, suggesting potential as a novel cancer therapeutic.
Area of Science:
- Natural Products Chemistry
- Molecular Biology
- Cancer Research
Background:
- Physalin A is a withanolide derived from Physalis alkekengi var. franchetii.
- Withanolides are known for their diverse biological activities.
- Understanding the mechanisms of action of natural compounds is crucial for drug discovery.
Purpose of the Study:
- To investigate the selective growth inhibitory effects of Physalin A on human fibrosarcoma HT1080 cells.
- To elucidate the underlying mechanisms of Physalin A-induced growth inhibition, focusing on apoptosis and autophagy.
- To evaluate the potential of Physalin A as an anti-cancer agent by assessing its effects on both tumor and normal cells.
Main Methods:
- Screening of selective growth inhibitory effects of Physalin A on HT1080 cells.
- Analysis of apoptosis markers, including caspase-3, caspase-8, caspase-9, Bid, Bax, and Bcl-2 expression.
- Investigation of autophagy induction and its interplay with apoptosis using rapamycin and 3-methyladenine (3MA).
- Assessment of Physalin A's cytotoxicity on normal human peripheral blood mononuclear cells.
Main Results:
- Physalin A demonstrated selective growth inhibition of HT1080 tumor cells without affecting normal human cells.
- Apoptosis induction by Physalin A in HT1080 cells was linked to the upregulation of caspase-3 and caspase-8, indicating activation of extrinsic apoptotic pathways.
- Physalin A also induced autophagy, which appeared to antagonize the apoptotic process, an effect modulated by rapamycin and 3MA.
- Loss of beclin 1 function mimicked the effects of the autophagy inhibitor 3MA.
Conclusions:
- Physalin A exhibits selective anti-cancer properties by inducing apoptosis through the extrinsic pathway in fibrosarcoma cells.
- Autophagy plays a counter-regulatory role in Physalin A-induced apoptosis, suggesting complex cellular responses.
- Physalin A represents a potential therapeutic candidate for cancer treatment due to its targeted cytotoxicity and distinct mechanism of action.
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