A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer
In a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work conf...
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MDPI AG
2023-02-01
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| Online Access: | https://www.mdpi.com/1424-8247/16/2/244 |
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| author | Rangru Liu Zhuo Chen Gaoyun Hu Zutao Yu Qianbin Li Danqi Liu Ling Li Zhaoqian Liu |
| author_facet | Rangru Liu Zhuo Chen Gaoyun Hu Zutao Yu Qianbin Li Danqi Liu Ling Li Zhaoqian Liu |
| author_sort | Rangru Liu |
| collection | DOAJ |
| description | In a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work confirmed the anti-proliferation and pro-apoptosis effects of YZT in NSCLC cells. Furthermore, YZT promotes autophagy and provokes complete autophagic flux in NSCLC cells. Notably, compared with YZT alone, the combination of YZT with the autophagy inhibitor chloroquine (CQ) or 3-methyladenine (3-MA) markedly strengthened the anti-proliferative and pro-apoptotic actions, suggesting that YZT-induced autophagy is cytoprotective. We further found that YZT-induced autophagy may exert a cytoprotective function by preserving the integrity of mitochondria and decreasing mitochondrial apoptosis. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that PDK1 is an upstream protein of the Akt/mTOR axis and western blotting verified that YZT induces autophagy by the PDK1/Akt/mTOR signaling axis. Finally, YZT plus CQ significantly enhanced the anticancer activities compared to YZT alone in an animal study and immunohistochemistry showed that the level of LC3 was increased by YZT, which is in line with the in vitro results. In short, our study provides reliable experimental basis for developing Compound YZT as a new chemotherapeutic drug candidate and suggests that combined administration of YZT with CQ is a potential therapy against NSCLC. |
| first_indexed | 2024-03-11T08:18:25Z |
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| last_indexed | 2024-03-11T08:18:25Z |
| publishDate | 2023-02-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-e63b6aae63044a18bb73a4fb48ea60f52023-11-16T22:37:01ZengMDPI AGPharmaceuticals1424-82472023-02-0116224410.3390/ph16020244A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung CancerRangru Liu0Zhuo Chen1Gaoyun Hu2Zutao Yu3Qianbin Li4Danqi Liu5Ling Li6Zhaoqian Liu7Department of Clinical Pharmacology, National Clinical Research Center for Geriatric Disorders, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaDepartment of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaDepartment of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaDepartment of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, ChinaDepartment of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, ChinaDepartment of Pharmacy, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai 519000, ChinaDepartment of Clinical Pharmacology, National Clinical Research Center for Geriatric Disorders, Hunan Key Laboratory of Pharmacogenetics, Xiangya Hospital, Central South University, Changsha 410008, ChinaIn a preliminary study, we synthesized a series of new PDK1/MEK dual inhibitors. Antitumor activity screening showed that Compound YZT exerts a strong inhibitory action in A549 cells. However, the specific mechanism of YZT against non-small cell lung cancer (NSCLC) is largely unknown. This work confirmed the anti-proliferation and pro-apoptosis effects of YZT in NSCLC cells. Furthermore, YZT promotes autophagy and provokes complete autophagic flux in NSCLC cells. Notably, compared with YZT alone, the combination of YZT with the autophagy inhibitor chloroquine (CQ) or 3-methyladenine (3-MA) markedly strengthened the anti-proliferative and pro-apoptotic actions, suggesting that YZT-induced autophagy is cytoprotective. We further found that YZT-induced autophagy may exert a cytoprotective function by preserving the integrity of mitochondria and decreasing mitochondrial apoptosis. Moreover, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that PDK1 is an upstream protein of the Akt/mTOR axis and western blotting verified that YZT induces autophagy by the PDK1/Akt/mTOR signaling axis. Finally, YZT plus CQ significantly enhanced the anticancer activities compared to YZT alone in an animal study and immunohistochemistry showed that the level of LC3 was increased by YZT, which is in line with the in vitro results. In short, our study provides reliable experimental basis for developing Compound YZT as a new chemotherapeutic drug candidate and suggests that combined administration of YZT with CQ is a potential therapy against NSCLC.https://www.mdpi.com/1424-8247/16/2/244compound YZTa PDK1/MEK dual inhibitorthe PDK1/Akt pathwayautophagyapoptosis |
| spellingShingle | Rangru Liu Zhuo Chen Gaoyun Hu Zutao Yu Qianbin Li Danqi Liu Ling Li Zhaoqian Liu A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer Pharmaceuticals compound YZT a PDK1/MEK dual inhibitor the PDK1/Akt pathway autophagy apoptosis |
| title | A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer |
| title_full | A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer |
| title_fullStr | A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer |
| title_full_unstemmed | A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer |
| title_short | A Novel PDK1/MEK Dual Inhibitor Induces Cytoprotective Autophagy via the PDK1/Akt Signaling Pathway in Non-Small Cell Lung Cancer |
| title_sort | novel pdk1 mek dual inhibitor induces cytoprotective autophagy via the pdk1 akt signaling pathway in non small cell lung cancer |
| topic | compound YZT a PDK1/MEK dual inhibitor the PDK1/Akt pathway autophagy apoptosis |
| url | https://www.mdpi.com/1424-8247/16/2/244 |
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