title: Anoikis induction and metastasis suppression by a new integrin αvβ3 inhibitor in human melanoma cell line M21.
abstract: Integrin αvβ3 plays a critical role in the survival and metastasis process of cancer cells. It is therefore desirable to develop new types of small molecule inhibitors of integrin αvβ3. IH1062 (3, 5-dichloro-phenylbiguanide) is a novel small molecule inhibitor of integrin αvβ3 that we have recently discovered. In this study, we investigated the induction effects of anoikis in human melanoma cell line M21 by IH1062, by detecting caspase activity, measuring the expression levels of apoptosis-related proteins, and performing the AnnexinV/PI apoptosis assay. Furthermore, we established a melanoma pulmonary metastasis mouse model in order to evaluate the suppression of metastasis by IH1062 in vivo. Our results demonstrate that IH1062 triggered human melanoma M21 cells to undergo anoikis by interrupting the attachment of M21 cells to extracellular matrix, reducing the phosphorylation of focal adhesion kinase, decreasing survivin and the ratio of Bcl-2/Bax proteins, and activating caspase cascades in vitro. Additionally, IH1062 showed markedly anti-metastatic effects in the pulmonary metastasis model in vivo, which makes it a promising lead to develop new drugs for anti-metastasis therapies.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, 300020, People's Republic of China.
authors.forename: Yongci
authors.initials: Y
authors.lastname: Zhang
authors.forename: Ming
authors.initials: M
authors.lastname: Yang
authors.forename: Qing
authors.initials: Q
authors.lastname: Ji
authors.forename: Dongmei
authors.initials: D
authors.lastname: Fan
authors.forename: Hui
authors.initials: H
authors.lastname: Peng
authors.forename: Chunzheng
authors.initials: C
authors.lastname: Yang
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Xiong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhou
mesh_terms: D000818:Animals; D023102:Anoikis / Q000187:drug effects*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001645:Biguanides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D019096:Vitronectin / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001645:Biguanides; C561027:IH1062; D039302:Integrin alphaVbeta3; D019096:Vitronectin; D051416:Focal Adhesion Protein-Tyrosine Kinases; D020169:Caspases