Cellular Sensitization to m-Diamminedichloroplatinum(II) by Novel Analogues of the Protein Kinase C Activator Lyngbyatoxin A

Alakananda Basu, Alan P. Kozikowski, Kazuo Sato, John S. Lazo

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Protein kinase C (PKC) has been implicated in enhancing cellularsensitivity to m-diamminedichloroplatinum(II) (CP). We have synthesized a series of novel analogues of lyngbyatoxin A (7-linalylindolactamV), a natural tumor promoter and a potent activator of PKC, andinvestigated the effects of these synthetic compounds on PKC activityand the antiproliferative activity of CP. Lyngbyatoxin A was as effectiveas phorbol esters, such as 12-0-tetradecanoylphorboM3-acetate, in enhancing the sensitivity of HeLa cells to CP. A 24-h pretreatment of HeLacells with 1 to 100 IIM lyngbyatoxin A caused an approximately 9-foldsensitization to CP. All analogues of lyngbyatoxin A that retained thelactam ring portion of the molecule but contained different hydrophobicsubstituents at C-7 including indolactam V (ILV), fert-butyl-ILV, or nhexyl-ILV increased cellular sensitivity to CP in a concentration-dependent manner. Maximum cellular sensitization to CP (9-fold) was seen with10 nM n-hexyl or ferr-butyl compounds, and ILV devoid of any C-7substitution required higher concentrations (1 n\\) for equivalent sensitization. The ability of lyngbyatoxin A analogues to sensitize cells to CPcorrelated directly with their ability to activate PKC in vitro. Syntheticanalogues that lacked the lactam ring structure neither activated PKCnor sensitized cells to CP. The C-9 epi analogue of n-hexyl-ILV was lesseffective than the corresponding natural stereoisomer in activating PKCas well as sensitizing cells to CP. Exposure of HeLa cells to 100 nMlyngbyatoxin A for 24 h caused a substantial decrease in cellular PKCactivity to 20% of the untreated control value, but a similar treatment of cells with n-hexyl- or fert-butyl-ILV led to only a 25% reduction in PKCactivity. Concentrations of ILV (e.g. 1 MM)that sensitized HeLa cells toCP caused no down-regulation of PKC. Thus, on the basis of results withthese novel lyngbyatoxin A analogues, we conclude that activation butnot down-regulation of PKC is necessary for sensitization of HeLa cellsto CP.

Original languageEnglish
Pages (from-to)2511-2514
Number of pages4
JournalCancer Research
Volume51
Issue number10
Publication statusPublished - 1 Jan 1991

    Fingerprint

Cite this