Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
Open accessAbstract
Low response rate and recurrence are common issues in lung cancer; 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–lung cancer and anti–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.
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Withaferin-A blocks NFkappaB activation by specifically targeting cysteine 179 in the catalytic site of IKK-b.
“In addition to that, withaferin-A could block the NFκB activation by specifically targeting cysteine 179 in the catalytic site of the inhibitor of nuclear factor kappa-B (IKK-b) [130].”
From Withania somnifera (L.) Dunal (Ashwagandha): A comprehensive review on ethnopharmacology, pharmacotherapeutics, biomedicinal and toxicological aspects (2021) · cites this paper as [130]
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- Authors
- Hsu, J. H.-M., Chang, P. M.-H., Cheng, T.-S., Kuo, Y.-L., Wu, A. T.-H., Tran, T.-H., Yang, Y.-H., Chen, J.-M., Tsai, Y.-C., Chu, Y.-S., Huang, T. H., Huang, C.-Y. F., & Lai, J.-M.
- Affiliations
- National Yang Ming University (TW)
- Taipei Veterans General Hospital (TW)
- National Taiwan University (TW)
- Taipei Medical University (TW)
- Fu Jen Catholic University (TW)
- Graduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, Taiwan
- Chang Gung University of Science and Technology (TW)
- Corresponding author
- Huang, Tse- Hung
- Huang, Chi-Ying F.
- Lai, Jin-Mei
- ORCID
- Venue
- Cancers
- Publisher
- MDPI AG
- Published
- 2019-07-17
- Volume
- 11
- Issue
- 7
- Pages
- 1003
- ISSN
- 2072-6694 (ISSN-L)
- PMC
- PMC6678286
- OpenAlex
- W2956425051
- Cited by
- 68
- References
- 62
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 11 · 2023: 7 · 2022: 10 · 2021: 13 · 2020: 14 · 2019: 1
- FWCI
- 12.24
- Type
- journal article
- Language
- en
- Open access
- gold
- dx.doi.org
- Licence
- Locations
- Cancers (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Ministry of Science and Technology, Taiwan (MOST-106-2627-M-075-001, MOST107-2320-B-010-040-MY3, MOST-106-2627-M-030-001)
- Topics
- Health Sciences › Medicine › Complementary and alternative medicine › Phytochemicals and Medicinal Plants
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Sesquiterpenes and Asteraceae Studies
- Keywords
- withaferin A, non-small cell lung cancer, lung cancer stem cells, autophagy, apoptosis, reactive oxygen species, cisplatin resistance, pemetrexed, cisplatin combination therapy, chemosensitization, side population cells, Withania somnifera, steroidal lactones, cytotoxicity
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