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: J Brian Morgan, Yang Liu, Veena Coothankandaswamy, Fakhri Mahdi, Mika B Jekabsons, William H Gerwick, Frederick A Valeriote, Yu-Dong Zhou, Dale G Nagle
• Journal: Marine drugs (Mar Drugs) Vol. 13 Issue 3 Pg. 1552-68 (Mar 20 2015) ISSN: 1660-3397 [Electronic] Switzerland
• PMID: 25803180 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Angiogenesis Inhibitors
• Hypoxia-Inducible Factor 1
• Lipids
• Thiazoles
• Vascular Endothelial Growth Factor A
• kalkitoxin
• Electron Transport Complex I

Topics

• Angiogenesis Inhibitors (administration & dosage, pharmacology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Hypoxia (drug effects)
• Cell Line, Tumor
• Electron Transport Complex I (drug effects, metabolism)
• Female
• Humans
• Hypoxia-Inducible Factor 1 (metabolism)
• Inhibitory Concentration 50
• Lipids (administration & dosage, pharmacology)
• Mitochondria (drug effects, metabolism)
• Neovascularization, Pathologic (drug therapy)
• Signal Transduction (drug effects)
• Thiazoles (administration & dosage, pharmacology)
• Vascular Endothelial Growth Factor A (metabolism)