Rakicidin A: a hypoxia-selective cytotoxin.
Hypoxia is a common feature of many solid tumors and contributes to their progression. Hypoxic cells in the tumor are not only involved in therapeutic resistance to chemotherapy and radiotherapy but are also relevant to tumor angiogenesis. To identify novel hypoxia-selective cytotoxins, we screened 20000 cultured broths of microorganisms and found that rakicidin A showed significant hypoxia-selective cytotoxicity. Rakicidin A was approximately 17.5-fold more cytotoxic under hypoxic than under normoxic conditions. CoCl2 and antioxidants had no effect on the rakicidin A cytotoxicity under normoxic conditions and rakicidin A did not show the inhibitory effects on HIF-1 transcriptional activity under hypoxic conditions. Thus, although the action mechanism of the hypoxia-selective cytotoxicity of rakicidin A was unknown, our screening study suggested that rakicidin A acts as an antitumor agent for selective therapy against solid tumors.
Yamazaki
Yohko
Y
Numazu Bio-Medical Research Institute, Microbial Chemistry Research Center, Shizuoka, Japan. yamako@bikaken.or.jp
Kunimoto
Setsuko
S
Ikeda
Daishiro
D
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D016466:CHO Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000860:Hypoxia; D055666:Lipopeptides; D010456:Peptides, Cyclic / Q000494:pharmacology; D047630:Depsipeptides
D000970:Antineoplastic Agents; D000975:Antioxidants; D055666:Lipopeptides; D010456:Peptides, Cyclic; C000723972:rakicidins; D047630:Depsipeptides