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A more recent version of this article appeared on February 4, 2005
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M409930200v1
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Papers In Press, published online ahead of print November 16, 2004
J. Biol. Chem, 10.1074/jbc.M409930200
Submitted on August 30, 2004
Revised on November 8, 2004
Accepted on November 16, 2004

Combination of 5-fluorouracil and N1, N11-diethylnorspermine markedly activates spermidine/spermine N1-acetyltransferase expression, depletes polyamines, and synergistically induces apoptosis in colon carcinoma cells

Woonyoung Choi, Eugene W. Gerner, Latha Ramdas, Jheri Dupart, Jennifer Carew, Lynsey Proctor, Peng Huang, Wei Zhang, and Stanley R. Hamilton

Pathology, Box 85, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030

Corresponding Author: wzhang{at}mdanderson.org

The thymidylate synthase inhibitor 5-fluorouracil (5-FU) is used widely for chemotherapy of colorectal carcinoma. Recent studies showed that 5-FU affects polyamine metabolism in colon carcinoma cells. We therefore examined whether combinations of 5-FU with drugs that specifically target polyamine metabolism, i.e. N1, N11-diethylnorspermine (DENSPM) or alpha-difluoromethylornithine (DFMO), have synergistic effects in killing HCT116 colon carcinoma cells with wild-type or absent p53. Our results showed that simultaneous 5-FU and DENSPM spermine analogue synergistically increased transcript levels of the polyamine catabolism enzyme spermidine/spermine N1-acetyltransferase (SSAT), depleted spermine and spermidine, increased acetylated spermidine, and produced synergistic tumor cell apoptosis in both p53 wild-type and p53-null variants. By contrast, simultaneous combination of 5-FU with DFMO, an inhibitor of the polyamine biosynthetic enzyme ornithine decarboxylase, depleted putrescine but did not produce synergistic cell killing. Some pre-treatment and post-treatment regimens of DENSPM and DFMO were antagonistic to 5FU depending on cellular p53 status. Protein and transcriptome expression analysis showed that combined 5-FU and DENSPM treatment activated caspase 9, but not caspase 3, and significantly suppressed NADH dehydrogenases and cytochrome c oxidases, consistent with the observed increase in hydrogen peroxide, loss of mitochondrial membrane potential, and release of cytochrome c. Our findings demonstrate the importance of the polyamine pathway in 5-FU effects and suggest that the combination of 5-FU with DENSPM has potential for development as therapy for colorectal carcinoma.


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