Platinum anti-cancer drugs: Free radical mechanism of Pt-DNA adduct formation and anti-neoplastic effect

Abstract

The literature on the anti-neoplastic effects of Pt drugs provides substantial evidence that free radical may be involved in the formation of Pt-DNA adducts and other cytotoxic effects. The conditions specific to cancerous tumours are more conducive to free radical mechanisms than the commonly accepted hydrolysis nucleophilic-electrophilic mechanism of Pt-DNA adduct formation. Molecular orbital studies of the adiabatic attachment of hydrated electrons to Pt drugs reveal that there is a significant lengthening of the Pt-X bond (where X is Cl, O in cisplatin, carboplatin and some pyrophosphate-Pt drugs but not oxaliplatin) in the anion radical species. This observation is consistent with a dissociative electron transfer (DET) mechanism for the formation of Pt-DNA adducts. A DET reaction mechanism is proposed for the reaction of Pt drugs with guanine which involves a quasi-inner sphere 2 electron transfer process involving a transient intermediate 5 co-ordinated activated anion radical species {R2Pt---Cl(G)(Cl)•}*(-) (where R is an ammine group, and G is guanine) and the complex has an elongated Pt---Cl (or Pt---O) bond. A DET mechanism is also proposed when Pt drugs are activated by reaction with free radicals such as HO•, CO3•(-), O2•(-) but do not react with DNA bases to form adducts, but form Pt-protein adducts with proteins such ezrin, FAS, DR5, TNFR1 etc. The DET mechanism may not occur with oxaliplatin.

Agrimonolide and Desmethylagrimonolide Induced HO-1 Expression in HepG2 Cells through Nrf2-Transduction and p38 Inactivation

“…Previously, numerous phenolic products have been found to exhibit SOD-like activity in vitro (Chen et al, 2012; Chen and Kang, 2013). ROS and radical species are able to induce DNA damages, which include strand breaks and DNA-protein cross-link (Fong, 2016) among others. In this study, genomic DNA was isolated from HepG2 cells in order to examine the protective effect of the AM and DM against DNA oxidative damage induced by H 2 O 2 stimulation.…”

Elevated exhalation of hydrogen peroxide in patients with non-small cell lung cancer is not affected by chemotherapy

“…Moreover, PR patients tended to have higher (albeit without statistical significance) EBC H 2 O 2 levels after the first and second CHT cycle. Free radicals may be involved in the formation of platinum (cisplatin, carboplatin) -DNA adducts and antineoplastic effects [32]. These drugs can also be activated by ROS to form adducts with proteins and subsequent cytostatic effects [32].…”

“…Free radicals may be involved in the formation of platinum (cisplatin, carboplatin) -DNA adducts and antineoplastic effects [32]. These drugs can also be activated by ROS to form adducts with proteins and subsequent cytostatic effects [32]. Therefore, one may suppose that in patients with PR these aforementioned processes had higher intensity and resulted in tumor suppression and increased H 2 O 2 exhalation in response to the fourth CHT cycle.…”

The Protective Effect of Naringenin on Oxaliplatin-Induced Genotoxicity in Mice

“…58) A clastogenic agent may act during cell division and result in chromosomal damage if administered during proliferation. 59) Oxaliplatin treatment in animals produced high MN frequency in bone-marrow cells suggesting increase in the rate of chro-mosomal loss or fragmentation during nuclear division. In the CA assay, oxaliplatin treatment produced a high frequency of aberrations, mostly stretching, chromatid break and gap.…”