title: Combined effect of vascular-leakage-blocker Sac-1004 and antiangiogenic drug sunitinib on tumor angiogenesis.
abstract: Tumor blood vessels are often leaky because of poor covering by mural cells and loose cell-to-cell contacts. Leaky vessels result in hemorrhage and limited vascular perfusion, which lead to hypoxic tumor microenvironment. Antiangiogenic agents have been shown to normalize the tumor blood vessels, albeit temporarily. Continued administration has been found to be associated with increased tumor hypoxia, a major driving force behind chemoresistance and metastasis. Sac-1004 was recently demonstrated to prevent vascular leakage, normalize tumor vessels and prevent metastasis in sustained manner. Here, we sought that combining antiangiogenic agent, sunitinib with Sac-1004 could have better inhibitory effect upon tumor growth. We found that B16F10 tumor growth was significantly reduced and tumor-bearing mice survival was increased upon combining sunitinib therapy with Sac-1004. In concordance with this observation, tumor vascular perfusion was substantially improved in tumors receiving combination therapy. In addition, tumor vascular leakage was reduced to higher extent in combination treatment group as compared to either therapy alone, an effect attributed to improved vascular junction. Interestingly, hypoxia in tumor environment was significantly reduced, when sunitinib was combined with Sac-1004. Taken together, our data demonstrates that combining antiangiogenic therapy with vascular-leakage inhibiting agent might be a beneficial strategy to combat cancer.
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea.
authors.forename: Keunho
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea.
authors.forename: Vijayendra
authors.initials: V
authors.lastname: Agrawal
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Kyeojin
authors.initials: K
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea.
authors.forename: Hyojin
authors.initials: H
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea.
authors.forename: Sungwoon
authors.initials: S
authors.lastname: Lee
authors.affiliation: Vascular System Research Center, Kangwon National University, Chunchon 200-701, Republic of Korea.
authors.forename: Young-Myeong
authors.initials: YM
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, 599 Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Young-Ger
authors.initials: YG
authors.lastname: Suh
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 262 Seongsanno, Seodaemun-Gu, Seoul 120-749, Republic of Korea. Electronic address: ygkwon@yonsei.ac.kr.
authors.forename: Young-Guen
authors.initials: YG
authors.lastname: Kwon
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use*; D008546:Melanoma, Experimental / Q000098:blood supply*; D051379:Mice; D008810:Mice, Inbred C57BL; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D011758:Pyrroles / Q000008:administration & dosage / Q000627:therapeutic use*; D012503:Saponins / Q000008:administration & dosage / Q000627:therapeutic use*; D000077210:Sunitinib
chemical_list: D020533:Angiogenesis Inhibitors; C583002:CU06-1004; D007211:Indoles; D011758:Pyrroles; D012503:Saponins; D000077210:Sunitinib
keywords: Combination therapy; Endothelial junction; Hypoxia; Normalization; Sac-1004; Sunitinib