PMID- 31004362 OWN - NLM STAT- MEDLINE DCOM- 20200615 LR - 20220418 IS - 1097-4652 (Electronic) IS - 0021-9541 (Linking) VI - 234 IP - 11 DP - 2019 Nov TI - 9za plays cytotoxic and proapoptotic roles and induces cytoprotective autophagy through the PDK1/Akt/mTOR axis in non-small-cell lung cancer. PG - 20728-20741 LID - 10.1002/jcp.28679 [doi] AB - Non-small-cell lung cancer (NSCLC) is an aggressive subtype of pulmonary carcinomas with high mortality. However, chemotherapy drug resistance and high recurrence rates hinder the curative effect of platinum-based first-line chemotherapy, which makes it urgent to develop new antitumor drugs for NSCLC. 9za, a new candidate drug synthesized by our research group, has been verified with potent antilung cancer activity in preliminary experiments. However, the underlying molecular mechanism of 9za remains largely vague. This work revealed that 9za could play important cytotoxic and proapoptotic roles in NSCLC cells. Moreover, 9za could induce autophagy and promote autophagy flux. Interestingly, the cytotoxic and proapoptotic roles were significantly dependent on 9za-induced cytoprotective autophagy. That is, the coadministration of 9za with an autophagy inhibitor such as chloroquine or 3-methyladenine exhibited increased cytotoxic and proapoptotic effects compared with 9za treatment alone. In addition, 9za exposure suppressed the phosphorylation of phosphoinositide-dependent protein kinase 1 (PDK1), protein kinase B (Akt), mammalian targets of rapamycin (mTOR), p70 S6 kinase, and 4E binding protein 1 by a dose-dependent way, manifesting that the Akt/mTOR axis was implicated in 9za-induced autophagy. In addition, the overexpression of PDK1 resulted in increased phosphorylation of PDK1 and Akt and blocking of 9za-mediated autophagy. These data showed that the PDK1/Akt/mTOR pathway was involved in 9za-induced autophagy. Hence, this work provides a theoretical basis for exploiting 9za as a new antilung cancer candidate drug and hints that the combination of 9za with an autophagy inhibitor is a feasible alternative approach for the therapy of NSCLC. CI - (c) 2019 Wiley Periodicals, Inc. FAU - Liu, Rangru AU - Liu R AUID- ORCID: 0000-0002-5076-5146 AD - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China. AD - Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. AD - Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China. FAU - Chen, Zhuo AU - Chen Z AD - Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China. FAU - Yi, Xinan AU - Yi X AD - The United Laboratory for Neurosciences of Hainan Medical University and the Fourth Military Medical University, Haikou, Hainan, China. FAU - Huang, Fengying AU - Huang F AD - Key Laboratory of Tropical Diseases and Translational Medicine of the Ministry of Education, Hainan Provincial Key Laboratory of Tropical Medicine, Hainan Medical University, Haikou, Hainan, China. FAU - Hu, Gaoyun AU - Hu G AD - Department of Medicinal Chemistry, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, China. FAU - Liu, Danqi AU - Liu D AD - Department of Pharmacy, Xiangya Hospital, Department of Pharmacy, Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Li, Xi AU - Li X AD - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China. AD - Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Zhou, Honghao AU - Zhou H AD - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China. AD - Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. FAU - Liu, Zhaoqian AU - Liu Z AD - Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, China. AD - Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center of Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Retracted Publication DEP - 20190419 PL - United States TA - J Cell Physiol JT - Journal of cellular physiology JID - 0050222 RN - 0 (Aniline Compounds) RN - 0 (Antineoplastic Agents) RN - 0 (Benzodioxoles) RN - 0 (Indoles) RN - 0 (PDK1 inhibitor 9za) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (3-Phosphoinositide-Dependent Protein Kinases) RN - EC 2.7.11.1 (PDPK1 protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM RIN - J Cell Physiol. 2022 May;237(5):2600. PMID: 35434811 MH - 3-Phosphoinositide-Dependent Protein Kinases/genetics/*metabolism MH - Aniline Compounds/chemistry/*pharmacology/therapeutic use MH - Antineoplastic Agents/chemistry/*pharmacology/therapeutic use MH - Autophagy/drug effects MH - Benzodioxoles/chemistry/*pharmacology/therapeutic use MH - Carcinoma, Non-Small-Cell Lung/*drug therapy MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Fibroblasts/drug effects MH - Gene Expression Regulation, Neoplastic/drug effects MH - Humans MH - Indoles/chemistry/*pharmacology/therapeutic use MH - Lung Neoplasms/*drug therapy MH - Molecular Structure MH - Proto-Oncogene Proteins c-akt/genetics/*metabolism MH - TOR Serine-Threonine Kinases/genetics/*metabolism OTO - NOTNLM OT - 9za OT - PDK1/Akt/mTOR signaling pathway OT - autophagy OT - cytotoxicity OT - non-small-cell lung cancer EDAT- 2019/04/21 06:00 MHDA- 2020/06/17 06:00 CRDT- 2019/04/21 06:00 PHST- 2018/11/03 00:00 [received] PHST- 2019/03/24 00:00 [revised] PHST- 2019/04/02 00:00 [accepted] PHST- 2019/04/21 06:00 [pubmed] PHST- 2020/06/17 06:00 [medline] PHST- 2019/04/21 06:00 [entrez] AID - 10.1002/jcp.28679 [doi] PST - ppublish SO - J Cell Physiol. 2019 Nov;234(11):20728-20741. doi: 10.1002/jcp.28679. Epub 2019 Apr 19.