|Title||Kalkitoxin inhibits angiogenesis, disrupts cellular hypoxic signaling, and blocks mitochondrial electron transport in tumor cells|
|Publication Type||Journal Article|
|Year of Publication||2015|
|Authors||Morgan J.B, Liu Y., Coothankandaswamy V., Mahdi F., Jekabsons M.B, Gerwick WH, Valeriote F.A, Zhou Y.D, Nagle D.G|
|Type of Article||Article|
|Keywords||activation; antitumor agents; breast-cancer; complex i; cyanobacterium lyngbya-majuscula; hif-1; inducible factor-i; respiration; sodium-channels; toxins|
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.
|Short Title||Mar. Drugs|