Polyamine analogs with xylene rings induce antizyme frameshifting, reduce ODC activity, and deplete cellular polyamines.
Numerous studies have correlated elevated polyamine levels with abnormal or rapid cell growth. One therapeutic strategy to treat diseases with increased cellular proliferation rates, most obviously cancer, has been to identify compounds which lower cellular polyamine levels. An ideal target for this strategy is the protein antizyme-a negative regulator of polyamine biosynthesis and import, and a positive regulator of polyamine export. In this study, we have optimized two tissue-culture assays in 96-well format, to allow the rapid screening of a 750-member polyamine analog library for compounds which induce antizyme frameshifting and fail to substitute for the natural polyamines in growth. Five analogs (MQTPA1-5) containing xylene (1,4-dimethyl benzene) were found to be equal to or better than spermidine at stimulating antizyme frameshifting and were inefficient at rescuing cell growth following polyamine depletion. These compounds were further characterized for effects on natural polyamine levels and enzymes involved in polyamine metabolism. Finally, direct measurements of antizyme induction in cells treated with two of the lead compounds revealed an 8- to 15-fold increase in antizyme protein over untreated cells. The impact of the xylene moiety and the distance between the positively charged amino groups on antizyme frameshifting and cell growth are discussed.
Petros
Lorin M
LM
Department of Human Genetics, University of Utah, 15 N 2030 E, Rm 7410, Salt Lake City, UT 84112-5330, USA. mhoward@genetics.utah.edu
Graminski
Gerard F
GF
Robinson
Susan
S
Burns
Mark R
MR
Kisiel
Nicholas
N
Gesteland
Raymond F
RF
Atkins
John F
JF
Kramer
Debora L
DL
Howard
Michael T
MT
Weeks
Reitha S
RS
D000123:Acetyltransferases / Q000378:metabolism; D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018965:Frameshifting, Ribosomal / Q000187:drug effects; D006801:Humans; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism* / Q000494:pharmacology*; D011506:Proteins / Q000235:genetics*; D014992:Xylenes / Q000494:pharmacology*; D000099228:Diamine N-Acetyltransferase
D000123:Acetyltransferases; D012437:Adenosylmethionine Decarboxylase; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D011506:Proteins; D014992:Xylenes; D000099228:Diamine N-Acetyltransferase; C031017:ornithine decarboxylase antizyme