Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells

TitleKalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells
Publication TypeJournal Article
Year of Publication2015
AuthorsMorgan J.B, Liu Y., Coothankandaswamy V., Mahdi F., Jekabsons M.B, Gerwick WH, Valeriote F.A, Zhou Y.D, Nagle D.G
JournalMarine Drugs
Volume13
Pagination1552-1568
Date Published2015/03
Type of ArticleArticle
ISBN Number1660-3397
Accession NumberWOS:000351930500026
Keywordsactivation; antitumor agents; breast-cancer; complex i; cyanobacterium lyngbya-majuscula; hif-1; inducible factor-i; respiration; sodium-channels; toxins
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.

DOI10.3390/md13031552
Short TitleMar. Drugs
Student Publication: 
No
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