Center for Relativistic Laser Science

2019.07 Single-molecule biophysics conference 

Cisplatin is one of the most potent anti-cancer drugs, displaying clinical activity against various tumors. It is known that cisplatin binds to DNA and induces local kinks^[1], which can lead to cell death^[2]. The working mechanism of cisplatin has, however, not been fully understood yet. It is accepted that cisplatin delivery into a cell and its activity on DNA depends on local ionic states of cisplatin which is regulated by the ambient concentration of Cl⁻. In reality, other cellular anionic species also suppress cisplatin activity^[3,4]. Moreover, recent studies highlighted several intriguing roles of histones in cisplatin’s anti-cancer effect^[5-7]. Here we investigated these issues via magnetic tweezers. The reduced activity of cisplatin under physiological salt conditions is still sufficient to impair the integrity of a nucleosome by retaining its condensed structure firmly, even against severe mechanical and chemical disturbances. The cisplatin induced fastening of nucleosomal DNA can hamper DNA repair and inhibit nucleosome remodeling required for normal biological functions. Our direct physical measurements on cisplatin-nucleosome adducts suggest that formation of such adducts can be the key to the anti-cancer effect by cisplatin under physiological salt conditions and provide a new insight into understanding the mechanism of platinum-based anti-cancer drugs.

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Reference

[1] Rice et al., The major adduct of the antitumor drug cis-diamminedichloroplatinum(II) with DNA bends the duplex by ap-proximately equal to 40 degrees toward the major groove. Proc. Natl. Acad. Sci. U. S. A. 1988, 85, 4158-4161.
[2] Siddik et al., Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 2003, 22:7265-7279

[3] Binter et al., Formation of monofunctional cisplatin-DNA adducts in carbonate buffer.  Inorg. Biochem. 2006, 100, 1219-1224.

[4] Todd et al., Understanding the effect of carbonate ion on cisplatin binding to DNA.  J. Am. Chem. Soc. 2007, 129, 6370-6371.

[5] Mymryk et al., Cisplatin inhibits chromatin remodeling, transcription factor binding, and transcription from the mouse mammary tumor virus promoter in vivo. Proc. Natl. Acad. Sci. U. S. A. 1995, 92, 2076-2080

[6] Wang et al., Nucleotide excision repair from site-specifically platinum-modified nucleosomes. Biochemistry 2003, 42, 6747-6753.

[7] Kim et al., Inhibition of histone deacetylase increases cytotoxicity to anti-cancer drugs targeting DNA. Cancer Res. 2003, 63, 7291-7300.