Withaferin A induces apoptosis by ROS-dependent mitochondrial dysfunction in human colorectal cancer cells
Shuxian Xia1, Yinglei Miao2, Side Liu3
1Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Gastroenterology, The First Affiliated Hospital of Kunming Medical University, Yunnan Institute of Digestive Disease, Kunming 650032, Yunnan Province, China.
Abstract:
Withaferin A (WA) is an active steroidal lactone derived from the herbal plant Withania somnifera, which exhibits antitumor activity with reactive oxygen species (ROS) modulating in a variety of cancer models, such as breast cancer, lung cancer and pancreatic cancer. However, to the best of our knowledge, the direct effect and mechanism of WA on CRC cells has not been previously determined. The present study investigated the anti-tumor effects of WA on CRC cells in vitro, and explored the mechanisms of action. The flow cytometry was applied for detecting the accumulation of ROS with the treatment of withaferin A. We performed the flow cytometry and western blot to evaluate the withaferin A induced apoptosis and cell cycle arrest in human colon cancer cells. And to verify the ROS accumulation induced mitochondrial dysfunction after the treatment of withaferin A, fluorescence microscope and western blot were applied. WA exerted a dose-dependent cytotoxic effect on HCT-116 and RKO cells. The effect was associated with ROS-mediated cell cycle arrest and the expression of apoptotic proteins. In addition, WA promoted ROS production and decreased mitochondrial membrane potential accompanying with mitochondrial dysfunction. Taken together, these results strongly indicated that WA directly inhibits cell growth and induces apoptosis in CRC cells through ROS-mediated mitochondrial dysfunction and JNKs pathway, and WA may be a promising potential candidate for therapeutic application of CRC.
Insights
Withaferin A (WA) shows anti-tumor effects on colon cancer cells by inducing cell cycle arrest and apoptosis. This natural compound promotes reactive oxygen species (ROS) production, leading to mitochondrial dysfunction and potential CRC therapy.
Area of Science:
- Pharmacology
- Cancer Biology
- Cell Biology
Background:
- Withaferin A (WA), a steroidal lactone from Withania somnifera, has demonstrated antitumor properties in various cancer models.
- The specific mechanisms of WA action on colorectal cancer (CRC) cells remain largely undetermined.
Purpose of the Study:
- To investigate the in vitro anti-tumor effects of WA on human colon cancer cells (HCT-116 and RKO).
- To elucidate the underlying mechanisms, focusing on reactive oxygen species (ROS) generation, apoptosis, cell cycle arrest, and mitochondrial function.
Main Methods:
- Flow cytometry was used to assess ROS accumulation, apoptosis, and cell cycle arrest.
- Western blot analysis was employed to evaluate apoptotic protein expression and JNKs pathway activation.
- Fluorescence microscopy was utilized to examine mitochondrial membrane potential and ROS production.
Main Results:
- WA exhibited a dose-dependent cytotoxic effect on CRC cell lines.
- Treatment with WA led to increased ROS production, cell cycle arrest, and apoptosis.
- WA induced mitochondrial dysfunction, evidenced by decreased mitochondrial membrane potential.
Conclusions:
- WA directly inhibits CRC cell growth and induces apoptosis via ROS-mediated mitochondrial dysfunction and activation of the JNKs pathway.
- Withaferin A presents a promising therapeutic candidate for colorectal cancer treatment.
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