title: Synergic antitumor effect of SKLB1002 and local hyperthermia in 4T1 and CT26.
abstract: A de novo VEGFR2-inhibited compound SKLB1002 which is independently developed in our laboratory has been described for antiangiogenesis and displays a potent antitumor activity in vivo and in vitro. In the present investigation, we aim to prove that combination therapy of SKLB1002 with hyperthermia plays a synergy as an antitumor agent in solid tumor. In this study, we analyzed their synergetic inhibitory action on human umbilical vein endothelial cells (HUVEC), murine mammary cancer 4T1, murine colon carcinoma CT26 in vitro. Multiply-table tournament was performed to detect cell proliferation in vitro. 4T1 implantation and CT26 implantation in BALB/c mice were used to examine the activity of combination therapy of SKLB1002 with hyperthermia in vivo. Vascular density was determined by CD31 immunohistochemistry. TUNEL was used to measure apoptosis in tumor tissue. Metastasis assay was investigated via measurement of pulmonary metastasis nodules under the microscope. Potential toxicity of combination therapy was observed by histologic analysis of main organs stained with H&E. In vitro, the combination therapy significantly inhibited cell proliferation of HUVEC, 4T1 and CT26. In vivo, 4T1 and CT26 model experiments showed that combination therapy remarkably inhibited tumor growth and prolonged life span. When compared with controls, combination therapy reached 61 % inhibition index of tumor growth against CT26 and 51 % against 4T1. Moreover, it reduced angiogenesis and increased tumor apoptosis and necrosis. It was further found that combination therapy could efficiently prevent tumor from metastasizing to lung. Importantly, it had no toxicity to main organs including heart, liver, spleen, lung and kidney. Combination treatment has been proved to be a novel and strong strategy in clinical antitumor therapy. Our findings suggest that the combination therapy of SKLB1002 with hyperthermia has a synergistic antiangiogenesis, anticancer and promotion of apoptosis efficacy compared with controls. These findings could pave a new way in clinical tumor therapy.
authors.affiliation: Department of Medical Oncology, Cancer Center, State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37 Guoxuexiang Street, Chengdu, 610041, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Nie
authors.forename: Xue-lei
authors.initials: XL
authors.lastname: Ma
authors.forename: Ya-xiong
authors.initials: YX
authors.lastname: Sang
authors.forename: Yu-li
authors.initials: YL
authors.lastname: Li
authors.forename: Xiang
authors.initials: X
authors.lastname: Gao
authors.forename: Guang-chao
authors.initials: GC
authors.lastname: Xu
authors.forename: Guo-bo
authors.initials: GB
authors.lastname: Shen
authors.forename: Hua-shan
authors.initials: HS
authors.lastname: Shi
authors.forename: Xiao-xiao
authors.initials: XX
authors.lastname: Liu
authors.forename: Feng-tian
authors.initials: FT
authors.lastname: Wang
authors.forename: Yu-quan
authors.initials: YQ
authors.lastname: Wei
mesh_terms: D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D006651:Histocytochemistry; D006979:Hyperthermia, Induced / Q000009:adverse effects / Q000379:methods*; D007150:Immunohistochemistry; D008807:Mice, Inbred BALB C; D009336:Necrosis; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use*; D013830:Thiadiazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D011799:Quinazolines; C586326:SKLB1002; D013830:Thiadiazoles