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Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
- Source :
- Cancers, Volume 11, Issue 7, Cancers, Vol 11, Iss 7, p 1003 (2019)
- Publication Year :
- 2019
-
Abstract
- Low response rate and recurrence are common issues in lung cancer<br />thus, identifying a potential compound for these patients is essential. Utilizing an in silico screening method, we identified withaferin A (WA), a cell-permeable steroidal lactone initially extracted from Withania somnifera, as a potential anti&ndash<br />lung cancer and anti&ndash<br />lung cancer stem-like cell (CSC) agent. First, we demonstrated that WA exhibited potent cytotoxicity in several lung cancer cells, as evidenced by low IC50 values. WA concurrently induced autophagy and apoptosis and the activation of reactive oxygen species (ROS), which plays an upstream role in mediating WA-elicited effects. The increase in p62 indicated that WA may modulate the autophagy flux followed by apoptosis. In vivo research also demonstrated the anti-tumor effect of WA treatment. We subsequently demonstrated that WA could inhibit the growth of lung CSCs, decrease side population cells, and inhibit lung cancer spheroid-forming capacity, at least through downregulation of mTOR/STAT3 signaling. Furthermore, the combination of WA and chemotherapeutic drugs, including cisplatin and pemetrexed, exerted synergistic effects on the inhibition of epidermal growth factor receptor (EGFR) wild-type lung cancer cell viability. In addition, WA can further enhance the cytotoxic effect of cisplatin in lung CSCs. Therefore, WA alone or in combination with standard chemotherapy is a potential treatment option for EGFR wild-type lung cancer and may decrease the occurrence of cisplatin resistance by inhibiting lung CSCs.
- Subjects :
- 0301 basic medicine
Cancer Research
withaferin A
lcsh:RC254-282
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
synergistic effect
medicine
Epidermal growth factor receptor
Lung cancer
PI3K/AKT/mTOR pathway
Cisplatin
biology
business.industry
Cancer
respiratory system
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
medicine.disease
respiratory tract diseases
030104 developmental biology
Pemetrexed
Oncology
chemistry
non-small-cell lung cancer
Apoptosis
Withaferin A
030220 oncology & carcinogenesis
Cancer research
biology.protein
business
connectivity map
medicine.drug
Subjects
Details
- ISSN :
- 20726694
- Volume :
- 11
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Cancers
- Accession number :
- edsair.doi.dedup.....662fddeb9cb680567b9a18c8672f0694