Identification of withaferin a as a potential candidate for anti-cancer therapy in non-small cell lung cancer

Jade H.M. Hsu, Peter M.H. Chang, Tai Shan Cheng, Yu Lun Kuo, Alexander T.H. Wu, Thu Ha Tran, Yun Hsuan Yang, Jing Ming Chen, Yu Chen Tsai, Yeh Shiu Chu, Tse Hung Huang, Chi Ying F. Huang, Jin Mei Lai

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article number1003
JournalCancers
Volume11
Issue number7
DOIs
Publication statusPublished - Jul 1 2019

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
Neoplasms
Cisplatin
Therapeutics
Autophagy
Epidermal Growth Factor Receptor
Lung
Pemetrexed
Side-Population Cells
Withania
withaferin A
Apoptosis
Neoplastic Stem Cells
Lactones
Computer Simulation
Inhibitory Concentration 50
Reactive Oxygen Species
Cell Survival
Down-Regulation

Keywords

  • Connectivity map
  • Non-small-cell lung cancer
  • Synergistic effect
  • Withaferin A

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hsu, J. H. M., Chang, P. M. H., Cheng, T. S., Kuo, Y. L., Wu, A. T. H., Tran, T. H., ... Lai, J. M. (2019). Identification of withaferin a as a potential candidate for anti-cancer therapy in non-small cell lung cancer. Cancers, 11(7), [1003]. https://doi.org/10.3390/cancers11071003

Identification of withaferin a as a potential candidate for anti-cancer therapy in non-small cell lung cancer. / Hsu, Jade H.M.; Chang, Peter M.H.; Cheng, Tai Shan; Kuo, Yu Lun; Wu, Alexander T.H.; Tran, Thu Ha; Yang, Yun Hsuan; Chen, Jing Ming; Tsai, Yu Chen; Chu, Yeh Shiu; Huang, Tse Hung; Huang, Chi Ying F.; Lai, Jin Mei.

In: Cancers, Vol. 11, No. 7, 1003, 01.07.2019.

Research output: Contribution to journalArticle

Hsu, JHM, Chang, PMH, Cheng, TS, Kuo, YL, Wu, ATH, Tran, TH, Yang, YH, Chen, JM, Tsai, YC, Chu, YS, Huang, TH, Huang, CYF & Lai, JM 2019, 'Identification of withaferin a as a potential candidate for anti-cancer therapy in non-small cell lung cancer', Cancers, vol. 11, no. 7, 1003. https://doi.org/10.3390/cancers11071003
Hsu, Jade H.M. ; Chang, Peter M.H. ; Cheng, Tai Shan ; Kuo, Yu Lun ; Wu, Alexander T.H. ; Tran, Thu Ha ; Yang, Yun Hsuan ; Chen, Jing Ming ; Tsai, Yu Chen ; Chu, Yeh Shiu ; Huang, Tse Hung ; Huang, Chi Ying F. ; Lai, Jin Mei. / Identification of withaferin a as a potential candidate for anti-cancer therapy in non-small cell lung cancer. In: Cancers. 2019 ; Vol. 11, No. 7.
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AU - Tran, Thu Ha

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