TITLE: Antineoplastic Efficacy of Novel Polyamine Analogues in Human Breast Cancer. PRINCIPAL INVESTIGATOR:

Intracellular polyamines are absolutely required for cell proliferation and many tumorshave abnormal requirements for polyamines. Therefore, the polyamine metabolic pathwayrepresents a rational target for antineoplastic intervention. A number of polyamine analoguesact as potent modulators of cellular polyamine metabolism and exhibit encouragingeffects against tumor growth in both cell culture and animal studies. In this study wedemonstrate that specific polyamine analogues exhibit differential inhibitory actionagainst growth of human breast cancer MCF-7 cells. Treatment of MCF-7 cells witholigoamine analogues and the symmetrically substituted bis(alkyl)-substituted analogue,BENSpm, produced a G1 cell cycle arrest, while the unsymmetrically substituted bis(alkyl)-substituted analogue, CHENSpm, induced a G2/M cell cycle arrest. All four compoundssignificantly upregulated p53 and p21 expression in MCF-7 cells. Stable transfection ofsmall interfering RNA (siRNA) targeting p53 blocked the expression of p21 induced bythe polyamine analogues and significantly reduced polyamine analogue-induced growthinhibition and apoptosis, suggesting that polyamine analogue-induced p21 expressionoccurs through p53-dependent mechanisms. The effects of analogue exposure on cyclinsand cyclin dependent kinases varied with the specific agent used. Expression of p53siRNA reversed only BENSpm-modulated the cell cycle arrest, suggesting that regulationof cell cycle arrest by p53/p21 induced by polyamine analogues occurs through agent-specific mechanisms. Understanding the mechanism of p53-mediated cellular responsesto polyamine analogue may help to improve the therapeutic efficacy of polyamine analoguesin human breast cancer.