Inhibition of transcription by platinum antitumor compounds

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.

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

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

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

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.