title: A novel and promising therapeutic approach for NSCLC: recombinant human arginase alone or combined with autophagy inhibitor.
abstract: Recombinant human arginase (rhArg), an enzyme capable of depleting arginine, has been shown to be an effective therapeutic approach for various cancers. Non-small-cell lung cancer (NSCLC), a histological subtype of pulmonary carcinoma, has a high rate of morbidity and mortality in the world. Thus, the need for novel and more effective treatment is urgent. In this study, it is the first time to report that rhArg could induce significant cytotoxicity and caspase-dependent apoptosis in NSCLC cells. Subsequently, our research revealed that rhArg dramatically stimulated autophagic response in NSCLC cells, which was proved by the formation and accumulation of autophagosomes and the conversion of microtubule-associated protein light chain 3 (LC3) from LC3-I to LC3-II. Furthermore, blocking autophagy by chloroquine or LY294002 remarkably enhanced rhArg-induced cytotoxicity and caspase-dependent apoptosis, suggesting that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells. Further experiments showed that two signaling pathways including the Akt/mTOR and extracellular signal-regulated kinase pathway, and mitochondrial-derived reactive oxygen species (ROS) production were involved in rhArg-induced autophagy and apoptosis. Meanwhile, N-acetyl-L-cysteine, a common antioxidant, was employed to scavenge ROS, and we detected that it could significantly block rhArg-induced autophagy and cytotoxicity, indicating that ROS played a vital role in arginine degradation therapy. Besides, xenograft experiment showed that combination with autophagy inhibitor potentiated the anti-tumor efficacy of rhArg in vivo. Therefore, these results provided a novel prospect and viewpoint that autophagy acted a cytoprotective role in rhArg-treated NSCLC cells, and treatment with rhArg alone or combined with autophagy inhibitor could be a novel and promising therapeutic approach for NSCLC in vivo and in vitro.
authors.affiliation: Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Weitao
authors.initials: W
authors.lastname: Shen
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Xuyao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Fu
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jiajun
authors.initials: J
authors.lastname: Fan
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Jingyun
authors.initials: J
authors.lastname: Luan
authors.affiliation: Department of Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Zhonglian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Department of Instrumental Analysis Center, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Department of Research Center for Clinical Pharmacology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Zhongyuan
authors.initials: Z
authors.lastname: Xu
authors.affiliation: Department of Microbiological and Biochemical Pharmacy & The Key Laboratory of Smart Drug Delivery, Ministry of Education, School of Pharmacy, Fudan University, Shanghai 201203, China.
authors.forename: Dianwen
authors.initials: D
authors.lastname: Ju
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001119:Arginase / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002738:Chloroquine / Q000494:pharmacology*; D002867:Chromones / Q000494:pharmacology*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology*; D009363:Neoplasm Proteins / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D002867:Chromones; C477012:MAP1LC3A protein, human; D008869:Microtubule-Associated Proteins; D009025:Morpholines; D009363:Neoplasm Proteins; D011994:Recombinant Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D002738:Chloroquine; D001119:Arginase