title: CA-1H, a novel oxazole bearing analogue of combretastatin A-4, disrupts the tumor vasculatures and inhibits the tumor growth via inhibiting tubulin polymerization.
abstract: Vascular disrupting agents destroy established tumor vasculatures selectively, and have achieved encouraging antitumor activity in both pre-clinical and clinical trials. In the present study, we reported the vascular disruption and antitumor effects of CA-1H and its prodrug CA-1HP, oxazole bearing analogues of combretastatin A-4 (CA4). CA-1H was a tighter binder of tubulin than CA4 with the same binding site to chochcine and CA4, and inhibited tubulin polymerization both in cell free system and in human umbilical vein endothelial cells (HUVECs). Furthermore, CA-1H significantly disrupted the microtubulin skeleton in proliferating HUVECs rather than the quiescent ones, damaged the HUVECs-preformed tubes markedly, and lead to necrosis in tumor tissues in NCI-H1975 xenograft mice. Continuous administration for 19 days, CA-1HP could inhibit the NCI-H1975 xenograft tumor growth significantly without obvious weight loss and normal tissue damage, in addition, CA-1HP also inhibited the tumor growth in H22 hepatocellular carcinoma bearing mice; and combination CA-1HP with cisplatin showed more potent antitumor activity than used alone. Taken together, our present investigation suggested that CA-1H was a potential vascular disrupting agent for further development of antitumor drugs.
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Fuguo
authors.initials: F
authors.lastname: Han
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Wang
authors.affiliation: Southern Research Institute, 2000 9th Avenue South, Birmingham, AL 35205, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Gaomi Municipal Hospital of Shandong Province, Gaomi 261500, China.
authors.forename: Qun
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. Electronic address: qxhin@163.com.
authors.forename: Xin
authors.initials: X
authors.lastname: Qi
authors.affiliation: Key Laboratory of Marine Drugs, Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao 266003, China. Electronic address: lmouc@hotmail.com.
authors.forename: Ming
authors.initials: M
authors.lastname: Liu
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000473:pathology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D062105:Molecular Docking Simulation; D009336:Necrosis; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010080:Oxazoles / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D058105:Polymerization; D013267:Stilbenes / Q000737:chemistry*; D014404:Tubulin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D010080:Oxazoles; D013267:Stilbenes; D014404:Tubulin; C058728:fosbretabulin
keywords: Combretastatin A-4; Oxazole; Tumor; Vascular disrupting agents