Issue 7, 2023

DNA radiosensitization by terpyridine-platinum: damage induced by 5 and 10 eV transient anions

Abstract

Chemoradiation therapy (CRT), which combines a chemotherapeutic drug with ionizing radiation (IR), is the most common cancer treatment. At the molecular level, the binding of Pt-drugs to DNA sensitizes cancer cells to IR, mostly by increasing the damage induced by secondary low-energy (0–20 eV) electrons (LEEs). We investigate such enhancements by binding terpyridine-platinum (Tpy-Pt) to supercoiled plasmid DNA. Fifteen nanometer thick films of Tpy-Pt–DNA complexes in a molar ratio of 5 : 1 were irradiated with monoenergetic electrons of 5 and 10 eV, which principally attach to the DNA bases to form transient anions (TAs) decaying into a multitude of bond-breaking channels. At both energies, the effective yields of crosslinks (CLs), base damage (BD) related CLs, single and double strand breaks (SSBs and DSBs), non-DSB-cluster lesions, loss of supercoiled configuration and base lesions are 6.5 ± 1.5, 8.8± 3.0, 88 ± 11, 5.3 ± 1.3, 9.6 ± 2.2, 106 ± 17, 189 ± 31 × 10−15 per electron per molecule, and 11.9 ± 2.6, 19.9 ± 4.4, 128 ± 18, 7.7 ± 3.0, 13.4 ± 3.9, 144 ± 19, 229 ± 42 × 10−15 per electron per molecule, respectively. DNA damage increased 1.2–4.2-fold due to Tpy-Pt, the highest being for BD-related CLs. These enhancements are slightly higher than those obtained by the conventional Pt-drugs cisplatin, carboplatin and oxaliplatin, apart from BD-related CLs, which are about 3 times higher. Enhancements are related to the strong perturbation of the DNA helix by Tpy-Pt, its high dipole moment and its favorable binding to guanine (G), all of which increase bond-breaking via TA formation. In CRT, Tpy-Pt could considerably enhance crosslinking within genomic DNA and between DNA and other components of the nucleus, causing roadblocks to replication and transcription, particularly within telomeres, where it binds preferentially within G-quadruplexes.

Graphical abstract: DNA radiosensitization by terpyridine-platinum: damage induced by 5 and 10 eV transient anions

Supplementary files

Article information

Article type
Paper
Submitted
03 ربيع الأول 1444
Accepted
23 جمادى الثانية 1444
First published
23 جمادى الثانية 1444

Nanoscale, 2023,15, 3230-3242

DNA radiosensitization by terpyridine-platinum: damage induced by 5 and 10 eV transient anions

L. Ouyang, H. Lin, P. Zhuang, Y. Shao, M. Khosravifarsani, B. Guérin, Y. Zheng and L. Sanche, Nanoscale, 2023, 15, 3230 DOI: 10.1039/D2NR05403E

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