Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer
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 <i>Withania somnifera...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2019-07-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/7/1003 |
| _version_ | 1797722564987977728 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Jade H.-M. Hsu |
| collection | DOAJ |
| description | 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 <i>Withania somnifera</i>, 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 IC<sub>50</sub> 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. |
| first_indexed | 2024-03-12T09:49:10Z |
| format | Article |
| id | doaj.art-83f0268e0a96453db65ed194d41ef0b7 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T09:49:10Z |
| publishDate | 2019-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-83f0268e0a96453db65ed194d41ef0b72023-09-02T12:39:15ZengMDPI AGCancers2072-66942019-07-01117100310.3390/cancers11071003cancers11071003Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung CancerJade H.-M. Hsu0Peter M.-H. Chang1Tai-Shan Cheng2Yu-Lun Kuo3Alexander T.-H. Wu4Thu-Ha Tran5Yun-Hsuan Yang6Jing-Ming Chen7Yu-Chen Tsai8Yeh-Shiu Chu9Tse- Hung Huang10Chi-Ying F. Huang11Jin-Mei Lai12Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, TaiwanDivision of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei 112, TaiwanInstitute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, TaiwanDepartment of Computer Science and Information Engineering, National Taiwan University, Taipei 106, TaiwanThe Ph.D. Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei 110, TaiwanInstitute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, TaiwanThe Ph.D. Program in Pharmaceutical Biotechnology, College of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanGraduate Institute of Applied Science and Engineering, College of Science and Engineering, Fu Jen Catholic University, New Taipei City 242, TaiwanDepartment of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, TaiwanBrain Research Center, National Yang-Ming University, Taipei 112, TaiwanGraduate Institute of Traditional Chinese Medicine, School of Traditional Chinese Medicine, Chang Gung University, Taoyuan 333, TaiwanDepartment of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei 112, TaiwanThe Ph.D. Program in Pharmaceutical Biotechnology, College of Medicine, Fu Jen Catholic University, New Taipei City 242, TaiwanLow 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 <i>Withania somnifera</i>, 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 IC<sub>50</sub> 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.https://www.mdpi.com/2072-6694/11/7/1003non-small-cell lung cancerwithaferin Aconnectivity mapsynergistic effect |
| spellingShingle | 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 Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer Cancers non-small-cell lung cancer withaferin A connectivity map synergistic effect |
| title | Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer |
| title_full | Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer |
| title_fullStr | Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer |
| title_full_unstemmed | Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer |
| title_short | Identification of Withaferin A as a Potential Candidate for Anti-Cancer Therapy in Non-Small Cell Lung Cancer |
| title_sort | identification of withaferin a as a potential candidate for anti cancer therapy in non small cell lung cancer |
| topic | non-small-cell lung cancer withaferin A connectivity map synergistic effect |
| url | https://www.mdpi.com/2072-6694/11/7/1003 |
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