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J. Biol. Chem., Vol. 280, Issue 5, 3295-3304, February 4, 2005

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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**

From the Departments of Pathology and ^¶Molecular Pathology, Division of Pathology and Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 and the Department of Biochemistry and Biophysics, Arizona Cancer Center, University of Arizona, Tucson, Arizona 85724

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 -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, a spermine analogue, synergistically increased transcript levels of the polyamine catabolism enzyme spermidine/spermine N¹-acetyltransferase, 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 5-FU 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.

Received for publication, August 30, 2004 , and in revised form, November 8, 2004.

^* This work was supported in part by the Favrot Fund, NCI, National Institutes of Health Cancer Center Support Grant 5P30 CA016672–28, the Tobacco Settlement Fund to the M. D. Anderson Cancer Center as appropriated by the Texas Legislature, the Kadoorie Foundation, and the Wilson Foundation. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence may be addressed: Dept. of Pathology, Unit 85, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-745-1103; Fax: 713-792-5549; E-mail: wzhang{at}mdanderson.org. ** Recipient of the Frederick F. Becker Distinguished Chair in Cancer Research from The University of Texas. To whom correspondence may be addressed: Dept. of Pathology, Unit 85, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Tel.: 713-745-1103; Fax: 713-792-5549; E-mail: shamilto{at}mdanderson.org.

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