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Marine Drugs
Volume 13
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10.3390/md13031552
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Article

Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells

by
J. Brian Morgan
1,
Yang Liu
1,
Veena Coothankandaswamy
1,
Fakhri Mahdi
1,
Mika B. Jekabsons
2,
William H. Gerwick
3,
Frederick A. Valeriote
4,
Yu-Dong Zhou
1,* and
Dale G. Nagle
1,*
1
Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA
2
Department of Biology, University of Mississippi, University, MS 38677, USA
3
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
4
Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA
*
Authors to whom correspondence should be addressed.
Mar. Drugs 2015, 13(3), 1552-1568; https://doi.org/10.3390/md13031552
Submission received: 29 January 2015 / Revised: 7 March 2015 / Accepted: 11 March 2015 / Published: 20 March 2015
(This article belongs to the Collection Marine Compounds and Cancer)
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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.
Keywords: kalkitoxin; breast cancer; Moorea producens; mitochondria toxin; VEGF; angiogenesis inhibitor; hypoxia-inducible factor-1; HIF-1; Lyngbya majuscula kalkitoxin; breast cancer; Moorea producens; mitochondria toxin; VEGF; angiogenesis inhibitor; hypoxia-inducible factor-1; HIF-1; Lyngbya majuscula
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MDPI and ACS Style

Morgan, J.B.; Liu, Y.; Coothankandaswamy, V.; Mahdi, F.; Jekabsons, M.B.; Gerwick, W.H.; Valeriote, F.A.; Zhou, Y.-D.; Nagle, D.G. Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells. Mar. Drugs 2015, 13, 1552-1568. https://doi.org/10.3390/md13031552

AMA Style

Morgan JB, Liu Y, Coothankandaswamy V, Mahdi F, Jekabsons MB, Gerwick WH, Valeriote FA, Zhou Y-D, Nagle DG. Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells. Marine Drugs. 2015; 13(3):1552-1568. https://doi.org/10.3390/md13031552

Chicago/Turabian Style

Morgan, J. Brian, Yang Liu, Veena Coothankandaswamy, Fakhri Mahdi, Mika B. Jekabsons, William H. Gerwick, Frederick A. Valeriote, Yu-Dong Zhou, and Dale G. Nagle. 2015. "Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells" Marine Drugs 13, no. 3: 1552-1568. https://doi.org/10.3390/md13031552

APA Style

Morgan, J. B., Liu, Y., Coothankandaswamy, V., Mahdi, F., Jekabsons, M. B., Gerwick, W. H., Valeriote, F. A., Zhou, Y.-D., & Nagle, D. G. (2015). Kalkitoxin Inhibits Angiogenesis, Disrupts Cellular Hypoxic Signaling, and Blocks Mitochondrial Electron Transport in Tumor Cells. Marine Drugs, 13(3), 1552-1568. https://doi.org/10.3390/md13031552

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