title: Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells.
abstract: 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.
authors: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. jbmorga1@go.olemiss.edu.
authors: J Brian
authors: JB
authors: Morgan
authors: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. 2007yl@gmail.com.
authors: Yang
authors: Y
authors: Liu
authors: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. ckveena@gmail.com.
authors: Veena
authors: V
authors: Coothankandaswamy
authors: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. fmahdi@umc.edu.
authors: Fakhri
authors: F
authors: Mahdi
authors: Department of Biology, University of Mississippi, University, MS 38677, USA. jekabson@olemiss.edu.
authors: Mika B
authors: MB
authors: Jekabsons
authors: 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.
authors: William H
authors: WH
authors: Gerwick
authors: Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA. fvaleri1@hfhs.org.
authors: Frederick A
authors: FA
authors: Valeriote
authors: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. ydzhou@olemiss.edu.
authors: Yu-Dong
authors: YD
authors: Zhou
authors: Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA. dnagle@olemiss.edu.
authors: Dale G
authors: DG
authors: Nagle
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D042967:Electron Transport Complex I / Q000187:drug effects / Q000378:metabolism; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008055:Lipids / Q000008:administration & dosage / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D020533:Angiogenesis Inhibitors; D051793:Hypoxia-Inducible Factor 1; D008055:Lipids; D013844:Thiazoles; D042461:Vascular Endothelial Growth Factor A; C121885:kalkitoxin; D042967:Electron Transport Complex I