PMID- 25803180 OWN - NLM STAT- MEDLINE DCOM- 20160303 LR - 20191210 IS - 1660-3397 (Electronic) IS - 1660-3397 (Linking) VI - 13 IP - 3 DP - 2015 Mar 20 TI - Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells. PG - 1552-68 LID - 10.3390/md13031552 [doi] AB - The biologically active lipopeptide kalkitoxin was previously isolated from the marine cyanobacterium Moorea producens (Lyngbya majuscula). Kalkitoxin exhibited N-methyl-D-aspartate (NMDA)-mediated neurotoxicity and acted as an inhibitory ligand for voltage-sensitive sodium channels in cultured rat cerebellar granule neurons. Subsequent studies revealed that kalkitoxin generated a delayed form of colon tumor cell cytotoxicity in 7-day clonogenic cell survival assays. Cell line- and exposure time-dependent cytostatic/cytotoxic effects were previously observed with mitochondria-targeted inhibitors of hypoxia-inducible factor-1 (HIF-1). The transcription factor HIF-1 functions as a key regulator of oxygen homeostasis. Therefore, we investigated the ability of kalkitoxin to inhibit hypoxic signaling in human tumor cell lines. Kalkitoxin potently and selectively inhibited hypoxia-induced activation of HIF-1 in T47D breast tumor cells (IC50 5.6 nM). Mechanistic studies revealed that kalkitoxin inhibits HIF-1 activation by suppressing mitochondrial oxygen consumption at electron transport chain (ETC) complex I (NADH-ubiquinone oxidoreductase). Further studies indicate that kalkitoxin targets tumor angiogenesis by blocking the induction of angiogenic factors (i.e., VEGF) in tumor cells. FAU - Morgan, J Brian AU - Morgan JB AD - Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. jbmorga1@go.olemiss.edu. FAU - Liu, Yang AU - Liu Y AD - Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. 2007yl@gmail.com. FAU - Coothankandaswamy, Veena AU - Coothankandaswamy V AD - Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. ckveena@gmail.com. FAU - Mahdi, Fakhri AU - Mahdi F AD - Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. fmahdi@umc.edu. FAU - Jekabsons, Mika B AU - Jekabsons MB AD - Department of Biology, University of Mississippi, University, MS 38677, USA. jekabson@olemiss.edu. FAU - Gerwick, William H AU - Gerwick WH AD - Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography and Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 920933, USA. wgerwick@ucsd.edu. FAU - Valeriote, Frederick A AU - Valeriote FA AD - Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA. fvaleri1@hfhs.org. FAU - Zhou, Yu-Dong AU - Zhou YD AD - Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. ydzhou@olemiss.edu. FAU - Nagle, Dale G AU - Nagle DG AD - Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. dnagle@olemiss.edu. LA - eng GR - R01 CA100851/CA/NCI NIH HHS/United States GR - CA100851/CA/NCI NIH HHS/United States GR - R01 CA098787/CA/NCI NIH HHS/United States GR - R56 CA098787/CA/NCI NIH HHS/United States GR - C06 RR-14503/RR/NCRR NIH HHS/United States GR - NS053398/NS/NINDS NIH HHS/United States GR - C06 RR014503/RR/NCRR NIH HHS/United States GR - CA98787/CA/NCI NIH HHS/United States GR - P20RR021929/RR/NCRR NIH HHS/United States GR - P20 RR021929/RR/NCRR NIH HHS/United States GR - R01 NS053398/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20150320 PL - Switzerland TA - Mar Drugs JT - Marine drugs JID - 101213729 RN - 0 (Angiogenesis Inhibitors) RN - 0 (Hypoxia-Inducible Factor 1) RN - 0 (Lipids) RN - 0 (Thiazoles) RN - 0 (Vascular Endothelial Growth Factor A) RN - 79JC6ZX2R6 (kalkitoxin) RN - EC 7.1.1.2 (Electron Transport Complex I) SB - IM MH - Angiogenesis Inhibitors/administration & dosage/*pharmacology MH - Breast Neoplasms/*drug therapy/pathology MH - Cell Hypoxia/drug effects MH - Cell Line, Tumor MH - Electron Transport Complex I/drug effects/metabolism MH - Female MH - Humans MH - Hypoxia-Inducible Factor 1/metabolism MH - Inhibitory Concentration 50 MH - Lipids/administration & dosage/*pharmacology MH - Mitochondria/drug effects/metabolism MH - Neovascularization, Pathologic/*drug therapy MH - Signal Transduction/drug effects MH - Thiazoles/administration & dosage/*pharmacology MH - Vascular Endothelial Growth Factor A/metabolism PMC - PMC4377999 EDAT- 2015/03/25 06:00 MHDA- 2016/03/05 06:00 PMCR- 2015/03/01 CRDT- 2015/03/25 06:00 PHST- 2015/01/29 00:00 [received] PHST- 2015/03/07 00:00 [revised] PHST- 2015/03/11 00:00 [accepted] PHST- 2015/03/25 06:00 [entrez] PHST- 2015/03/25 06:00 [pubmed] PHST- 2016/03/05 06:00 [medline] PHST- 2015/03/01 00:00 [pmc-release] AID - md13031552 [pii] AID - marinedrugs-13-01552 [pii] AID - 10.3390/md13031552 [doi] PST - epublish SO - Mar Drugs. 2015 Mar 20;13(3):1552-68. doi: 10.3390/md13031552.