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Review
. 2009;1(4):280-91.
doi: 10.1039/b907567d.

Inhibition of transcription by platinum antitumor compounds

Ryan C Todd  1 , Stephen J Lippard
Affiliations
Review

Inhibition of transcription by platinum antitumor compounds

Ryan C Todd et al. Metallomics. 2009.

Abstract

Cisplatin, carboplatin, and oxaliplatin are three FDA-approved members of the platinum anticancer drug family. These compounds induce apoptosis in tumor cells by binding to nuclear DNA, forming a variety of structural adducts and triggering cellular responses, one of which is the inhibition of transcription. In this report we present (i) a detailed review of the structural investigations of various Pt-DNA adducts and the effects of these lesions on global DNA geometry; (ii) research detailing inhibition of cellular transcription by Pt-DNA adducts; and (iii) a mechanistic analysis of how DNA structural distortions induced by platinum damage may inhibit RNA synthesis in vivo. A thorough understanding of the molecular mechanism of action of platinum antitumor agents will aid in the development of new compounds in the family.

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Figures

Figure 1
Figure 1
Chemical structures of platinum anticancer agents. Cisplatin, carboplatin, and oxaliplatin are FDA-approved for chemotherapy use in the United States. Satraplatin was the first Pt(IV) complex to reach Phase III clinical trials as an orally available platinum compound. cDPCP is a non-classical, monofunctional platinum complex with anti-tumor activity in colorectal cancer cells that inhibits transcription in vitro.
Figure 2
Figure 2
X-ray crystal and NMR structures of double stranded DNA containing adducts of various platinum anticancer agents. (a) Cisplatin 1,2-d(GpG) intrastrand cross-link (1AIO). (b) Cisplatin 1,3-d(GpTpG) intrastrand cross-link (1DA4). (c) Cisplatin inter-strand cross-link (1A2E). (d) Oxaliplatin 1,2-d(GpG) intrastrand cross-link (1PG9). (e) Satraplatin 1,2-d(GpG) intrastrand cross-link (1LU5). (f) cDPCP monofunctional adduct (3CO3). PDB accession codes are given in parentheses.
Figure 3
Figure 3
Protein recognition and binding to Pt-DNA adducts. (a) Overlay of X-ray crystal structures of TBP-bound DNA (1TGH, blue) and DNA containing a cisplatin 1,2-d(GpG) intrastrand cross-link (1AIO, burgundy). (b) X-ray crystal structure of HMGB1 domain A bound to a cisplatin 1,2-d(GpG) intrastrand cross-link (1CKT). An intercalated phenylalanine residue plays a key role in substrate recognition. PDB accession codes are given in parentheses.
Figure 4
Figure 4
Possible mechanisms of transcription inhibition by platinum antitumor agents. Platinum-modified DNA can recruit transcription factors to the damage site, preventing these proteins from binding promoter sites and blocking formation of transcriptional scomplexes. The Pt-DNA adduct can also serve as a physical block to RNA polymeras-es when the lesion is located on the transcribed DNA strand. Finally, Pt-DNA adducts can disrupt nucleosomal structure and/or mobility and block transcription by prohibiting access to DNA by transcriptional proteins.
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References

    1. Loehrer PJ, Einhorn LH. Ann Intern Med. 1984;100:704–713. - PubMed
    1. Keys HM, Bundy BN, Stehman FB, Muderspach LI, Chafe WE, Suggs CL, III, Walker JL, Gersell D. New Eng J Med. 1999;340:1154–1161. - PubMed
    1. Morris M, Eifel PJ, Lu J, Grigsby PW, Levenback C, Stevens RE, Rotman M, Gershenson DM, Mutch DG. New Eng J Med. 1999;340:1137–1143. - PubMed
    1. Bosl GJ, Bajorin DF, Sheinfeld J, Motzer RJ, Chaganti RSK. In: Cancer: Principles & practice of oncology. 6. DeVita VT Jr, Hellman S, Rosenberg SA, editors. Lippincott Williams & Wilkins; Philadelphia: 2001. pp. 1491–1518.
    1. Bosl GJ, Motzer RJ. New Eng J Med. 1997;337:242–253. - PubMed

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