Ellipticines as DNA-targeted chemotherapeutics.
The anti-tumor therapeutic ellipticine and its derivatives act as potent anticancer agents via a combined mechanism involving cell cycle arrest and induction of apoptosis. Cell death induced by ellipticine has been shown to engage a p53-dependent pathway, cell cycle arrest, interaction with several kinases and induction of the mitochondrial pathway of apoptotic cell death. Cell cycle arrest was shown to result from DNA damage caused by a variety of tumor chemotherapeutic agents; this is also the case for ellipticines. The prevalent DNA-mediated mechanisms of anti-tumor, mutagenic and cytotoxic activities of ellipticine are (i) intercalation into DNA, (ii) inhibition of DNA topoisomerase II activity, and (iii) covalent binding to DNA in vitro and in vivo after enzymatic activation by cytochrome P450 and/or peroxidase enzymes The mechanism leading to apoptosis by ellipticine is thought to also be associated with DNA damage, by inhibition of topoisomerase II and the covalent modification of DNA. In addition, the formation of ellipticine-DNA adducts ultimately can mutate cancer cells or initiate cell death. The aim of this review is to summarize our knowledge on the molecular mechanisms with the aim to explain the effectiveness of ellipticines as DNA-targeted chemotherapeutics in cancer cells.
Marie
M
Stiborová
Department of Biochemistry, Charles University in Prague, Czech Republic. stiborov@natur.cuni.cz.
Eva
E
Frei
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D018736:DNA Adducts / Q000737:chemistry / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004611:Ellipticines / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy
D000970:Antineoplastic Agents; D018736:DNA Adducts; D004611:Ellipticines; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D004250:DNA Topoisomerases, Type II