Differential toxicity of DNA adducts of mitomycin C.
The clinically used antitumor agent mitomycin C (MC) alkylates DNA upon reductive activation, forming six covalent DNA adducts in this process. This paper focuses on differential biological effects of individual adducts in various mammalian cell cultures, observed in the authors' laboratories. Evidence is reviewed that various adducts are capable of inducing different cell death pathways in cancer cells. This evidence is derived from a parallel study of MC and its derivatives 2,7-diaminomitosene (2,7-DAM) which is the main metabolite of MC and forms two monoadducts with DNA, and decarbamoyl mitomycin C (DMC), which alkylates and crosslinks DNA, predominantly with a chirality opposite to that of the DNA adducts of MC. Specifically, 2,7-DAM is not cytotoxic and does not activate the p53 pathway while MC and DMC are cytotoxic and able to activate the p53 pathway. DMC is more cytotoxic than MC and can also kill p53-deficient cells by inducing degradation of Checkpoint 1 protein, which is not seen with MC treatment of the p53-deficient cells. This difference in the cell death pathways activated by the MC and DMC is attributed to differential signaling by the DNA adducts of DMC. We hypothesize that the different chirality of the adduct-to-DNA linkage has a modulating influence on the choice of pathway. Future studies will be directed to elucidate mechanisms of MC- and DMC-DNA adduct signaling in a structure-dependent context.
Bargonetti
Jill
J
Department of Science, John Jay College, The City University of New York, New York, NY 10019, USA.
Champeil
Elise
E
Tomasz
Maria
M
Chem Res Toxicol. 2000 Jun;13(6):479-88
10858321
J Med Chem. 1971 Feb;14(2):109-12
4993458
Biochem Pharmacol. 2001 Jun 15;61(12):1517-29
11377381
J Biol Chem. 2002 Oct 25;277(43):40513-9
12183457
Cancer Biol Ther. 2003 Jul-Aug;2(4 Suppl 1):S16-22
14508077
Genes Dev. 2000 Jun 15;14(12):1448-59
10859164
Cell. 2009 May 1;137(3):413-31
19410540
Cell. 2008 May 30;133(5):864-77
18510930
Oncol Res. 1998;10(10):509-21
10338154
Cancer Cell. 2007 Feb;11(2):175-89
17292828
Biochemistry. 1993 May 11;32(18):4708-18
8490017
Biochemistry. 1981 Aug 18;20(17):5056-61
6794605
Mutat Res. 1979 Nov;63(1):175-88
522865
Mol Cell. 2009 Sep 11;35(5):716-23
19748364
Mol Cell. 2009 Sep 11;35(5):704-15
19748363
Oncol Res. 1995;7(1):39-47
7549043
Mol Cell. 2005 Sep 2;19(5):607-18
16137618
Chem Biol. 1995 Sep;2(9):575-9
9383461
Cancer Res. 1990 Aug 1;50(15):4692-7
2114946
Chem Res Toxicol. 2005 Feb;18(2):213-23
15720125
J Antibiot (Tokyo). 1956 Jul;9(4):141-6
13385186
Chem Res Toxicol. 2008 Dec;21(12):2370-8
19053323
ACS Chem Biol. 2007 Jun 15;2(6):399-407
17530733
Chem Res Toxicol. 2010 Jul 19;23(7):1151-62
20536192
Chem Res Toxicol. 2002 Nov;15(11):1398-406
12437330
Science. 2008 Mar 7;319(5868):1352-5
18323444
Proc Natl Acad Sci U S A. 1963 Aug;50:355-62
14060656
Chem Res Toxicol. 1998 Jan;11(1):64-9
9477227
Science. 1987 Mar 6;235(4793):1204-8
3103215
Eur J Cancer. 1995 Nov;31A(12):1928-33
8562144