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

Marine Drugs

J. Brian Morgan¹  Yang Liu¹  Veena Coothankandaswamy¹  Fakhri Mahdi¹  Mika B. Jekabsons⁴  William H. Gerwick⁵  Frederick A. Valeriote³  Yu-Dong Zhou¹  Dale G. Nagle¹  Sergey A. Dyshlovoy² 

[1] Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA; E-Mails:Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, MS 38677, USA;;Department of Internal Medicine, Division of Hematology and Oncology, Henry Ford Hospital, Detroit, MI 48202, USA; E-Mail:;Department of Biology, University of Mississippi, University, MS 38677, USA; E-Mail:;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; E-Mail:

关键词: kalkitoxin;    breast cancer;    Moorea producens;    mitochondria toxin;    VEGF;    angiogenesis inhibitor;    hypoxia-inducible factor-1;    HIF-1;    Lyngbya majuscula;   

DOI  :  10.3390/md13031552

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.