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Cancer Chemistry

Abstract #5366: The N2-deoxyguanosine adducts of mitomycins with mitosene-1-\#914; stereochemistry efficiently kill cells with compromised p53 through proteasome-mediated degradation of Chk1

Ernest Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria Figueredo-Pereira and Jill Bargonetti
Ernest Boamah
Hunter College and The Graduate Center CUNY, New York, NY
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Angelika Brekman
Hunter College and The Graduate Center CUNY, New York, NY
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Maria Tomasz
Hunter College and The Graduate Center CUNY, New York, NY
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Natura Myeku
Hunter College and The Graduate Center CUNY, New York, NY
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Maria Figueredo-Pereira
Hunter College and The Graduate Center CUNY, New York, NY
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Jill Bargonetti
Hunter College and The Graduate Center CUNY, New York, NY
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DOI:  Published May 2009
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AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

Abstract

Despite the importance of p53-independent cell death, little is known about the activation of such pathways. At least 50 percent of all cancers do not have a functional p53-pathway. We see that the mitomycin derivative 10-decarbamoyl mitomycin C (DMC), in contrast to mitomycin C (MC), can rapidly activate a p53-independent cell death pathway, which lacks markers for activation of an apoptotic death pathway. We recently reported that MC and DMC induce cellular cytotoxicity in human cells with wild-type p53, while only DMC shows significant cell death activity in the absence of wild-type p53. Nevertheless, it was unclear if the difference in cell death activity was due to the observed ability of DMC to form the alternative stereoisomeric 1-\#946; mono and 1-\#946; cross-link DNA adducts of guanine in human cell lines resulting in differential molecular signaling. In this study, we compared the DNA adducts and the cellular regulation of molecular targets upon treatment with MC and DMC in human cancer cell lines with or without wild-type p53. Compared to MC, DMC treatment produced substantially more 1-\#946; mono- and 1-\#946; cross-link DNA adducts, as measured by liquid chromatography/electrospray tandem mass spectrometry (Paz et al. Chem. Res.Toxicol., In Press). In addition, DMC-treatment resulted in abnormal nuclear morphology and increased cytotoxicity in human cancer cells with compromised p53 activity. We further established that DMC provoked a p53-independent cell death pathway that correlates with the formation of novel stereoisomeric DNA-adducts leading to down-regulation of Chk-1. Interestingly, Chk1 depletion was prevented by inhibition of the ubiquitin proteasome pathway, suggesting that DMC-DNA adducts may activate this proteolytic pathway. However, the observed decrease in the levels of ubiquitinated proteins upon DMC treatment was not caused by a direct change in proteasome activity suggesting that changed kinase signaling might be the cause of an activated pathway. Both MC and DMC have similar cytotoxicity upon depletion of Chk1 by siRNA, implicating loss of Chk1 as an important component in the DNA damage induced cell death pathway. In summary, we demonstrated that DMC generates significantly more mitosene-1-\#946; stereoisomeric DNA adducts than MC and causes down-regulation of Chk1 through the ubiquitin proteasome pathway. These studies suggest that mitosene-1-\#946; guanine adducts of DNA induce rapid and effective cell death of cancers with compromised p53, a cell type not rapidly killed by MC. This work was supported by a NIH SCORE Grant (1SC1CA137843-01), The Breast Cancer Research Foundation and was facilitated by a NIH Research Centers in Minority Institutions award from the Division of Research Resources (RR-03037) to Hunter College. EB is supported by the MBRS-RISE minority program at Hunter College.

Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 5366.

Footnotes

  • 100th AACR Annual Meeting-- Apr 18-22, 2009; Denver, CO

  • American Association for Cancer Research
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Cancer Research: 69 (9 Supplement)
May 2009
Volume 69, Issue 9 Supplement
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Abstract #5366: The N2-deoxyguanosine adducts of mitomycins with mitosene-1-\#914; stereochemistry efficiently kill cells with compromised p53 through proteasome-mediated degradation of Chk1
Ernest Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria Figueredo-Pereira and Jill Bargonetti
Cancer Res May 1 2009 (69) (9 Supplement) 5366;

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Abstract #5366: The N2-deoxyguanosine adducts of mitomycins with mitosene-1-\#914; stereochemistry efficiently kill cells with compromised p53 through proteasome-mediated degradation of Chk1
Ernest Boamah, Angelika Brekman, Maria Tomasz, Natura Myeku, Maria Figueredo-Pereira and Jill Bargonetti
Cancer Res May 1 2009 (69) (9 Supplement) 5366;
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