{"refrec":{"BRefID":338231,"RR":"<b>Facompré, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Pérez, C.; Manzanares, I.; Cuevas, C.; Bailly, C.</b> (2003). Lamellarin D: A novel potent inhibitor of topoisomerase I. <i>Cancer Research 63(21)</i>: 7392-7399","BEntID":334857,"PublicFlag":1,"CheckedFlag":1,"wosflag":1,"vabbflag":1,"RefStringPartII":". <i>Cancer Research 63(21)</i>: 7392-7399","DocTypID":8,"DocType":"Journal article","MarineFlag":0,"FreshFlag":0,"BrackishFlag":0,"TerrestrialFlag":0,"Authorstring":"Facompré, M.; Tardy, C.; Bal-Mahieu, C.; Colson, P.; Pérez, C.; Manzanares, I.; Cuevas, C.; Bailly, C.","OrigTitleTranslFlag":0,"Authorstringtrunc":"Facompré, M. <i>et al.</i>","Englishabstract":"We report the identification and characterization of a novel potent inhibitor of DNA topoisomerase I: lamellarin D (LAM-D), initially isolated from a marine mollusk, Lamellaria sp., and subsequently identified from various ascidians. This alkaloid, which displays potent cytotoxic activities against multidrug-resistant tumor cell lines and is highly cytotoxic to prostate cancer cells, bears a 6H-[1]benzopyrano[4′,3′:4,5]pyrrolo[2,1-a]isoquinolin-one pentacyclic planar chromophore, whereas its synthetic 5,6-dehydro analogue, LAM-501, has a significantly tilted structure. DNA binding measurements by absorbance, fluorescence, and electric linear dichroism spectroscopy show that LAM-D is a weak DNA binder that intercalates between bp of the double helix. In contrast, the nonplanar analogue LAM-501 did not bind to DNA and failed to inhibit topoisomerase I. DNA intercalation may be required for the stabilization of topoisomerase I-DNA complexes by LAM-D. In the DNA relaxation assay, LAM-D strongly promoted the conversion of supercoiled DNA into nicked DNA in the presence of topoisomerase I. The marine product was ∼5 times less efficient than camptothecin (CPT) at stabilizing topoisomerase I-DNA complexes, but interestingly, the two drugs exhibited slightly distinct sequence specificity profiles. Topoisomerase I-mediated DNA cleavage in the presence of LAM-D occurred at some sites common to CPT, but a few specific sites identified with CPT but not with LAM-D or conversely unique sites cleaved by LAM-D but not by CPT were detected. The distinct specificity profiles suggest that LAM-D and CPT interact differently with the topoisomerase I-DNA interface. A molecular modeling analysis provided structural information on the orientation of LAM-D within the topoisomerase I-DNA covalent complex. The marine alkaloid did not induce DNA cleavage by topoisomerase II. Immunoblotting experiments revealed that endogenous topoisomerase I was efficiently trapped on DNA by LAM-D in P388 and CEM leukemia cells. P388/CPT5 and CEM/C2 cell lines, both resistant to CPT and expressing a mutated top1 gene, were cross-resistant to LAM-D. Collectively, the results identify LAM-D as a novel lead candidate for the development of topoisomerase I-targeted antitumor agents.","AbstractOtherLang":null,"BibLvlCode":"AS","StandardTitle":"Lamellarin D: A novel potent inhibitor of topoisomerase I","OrigTitleLangCode":"en","OrigTitleLangCodeExtended":"eng","OrigTitleLangID":15,"DateLastModified":{"date":"2024-12-10 01:33:17.368041","timezone_type":1,"timezone":"+01:00"},"UserAccessRight":null,"UserAccID":null,"AuthorKeywords":null,"OtherDescriptors":null,"Notes":null,"AnaPub":2003,"MonPub":null,"DateUpdate":"2021-06-01","DateCreate":"2021-05-17","SecASFANote":null,"ConfID":null,"PeerRev":1,"VlizCoreFlag":1,"WoScode":"WOS:000186535400050","VABBcode":null,"OpenAcc":1},"refs":null,"anarec":{"AnaID":338231,"PubliDate":2003,"Pagination":"7392-7399","XtraPublOfAnaID":null,"ISBN":null,"Volume":"63","Issue":"21","BRefMon":null,"BRefMonRR":null,"BRefXtra":null,"BRefXtraRR":null,"SerBRefID":265354,"SerRR":"Cancer Research: Philadelphia.  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