<i>In Vitro</i> Investigation of DNA Damage Induced by the DNA Cross-Linking Agents Oxaliplatin and Satraplatin in Lymphocytes of Colorectal Cancer Patients

Abstract

Exposure to toxic chemicals, especially chemotherapeutic drugs, may induce several DNA lesions, including DNA interstrand crosslinks. These crosslinks are considered toxic lesions to the dividing cells since they can induce mutations, chromosomal rearrangements, and cell death. Many DNA interstrand crosslinks lesions can be generated by platinum-based chemotherapeutic agents. Satraplatin is a novel orally administered platinum-based chemotherapeutic agent. In the present study, we investigated DNA interstrand crosslinks lesions induced by oxaliplatin and satraplatin in lymphocytes obtained from colorectal cancer patients and healthy volunteers. Satraplatin demonstrated an increase in interstrand crosslinks in a dose-dependent manner in the Comet assay (p < 0.001). In addition, satraplatin and oxaliplatin increased significantly the number of sister chromatid exchanges up to 8.5-fold and 5.1-fold (p < 0.001) respectively, when treated with 2 µM concentration in comparison to untreated colorectal cancer cells. Further, the γH2AX foci formation was investigated by an immunofluorescence assay with oxaliplatin and satraplatin. The γH2AX foci formation rate was increased by approximately 9-fold when lymphocytes were treated with 2 μM oxaliplatin. Satraplatin was found to significantly induce the number of γH2AX foci by 8.5-fold and 11-fold with both 0.2 μM and 2.0 μM, respectively, compared to the control volunteers that may indicate the repair system in cancer cells experiences a loss of ability to cope with the repair of DSBs. In conclusion, oxaliplatin and satraplatin effectively induced DNA interstrand crosslinks in lymphocytes obtained from colorectal cancer patients and healthy volunteers in vitro. Here, to the best of our knowledge we report for the first time evidence of DNA double strand breaks formation as a possible molecular mechanism of action for satraplatin.

N-Heterocyclic Carbene–Polyethylenimine Platinum Complexes with Potent in Vitro and in Vivo Antitumor Efficacy

“…Indeed, in vitro DNA cross-link studies showed a significant and concentration-dependent increase in cross-linking activity for 2 PEI30 (up to 50% in relation with the untreated control). The effects were more pronounced than for oxaliplatin (33%, which agreed well with literature data). , …”

“…The effects were more pronounced than for oxaliplatin (33%, which agreed well with literature data). 47,48 We also performed experiments to correlate apoptosis with the production of Reactive Oxygen Species (ROS) in mitochondria, which is associated with a decrease of their normal respiratory activity. 49 We showed that apoptosis is correlated with the induction of a dose-dependent ROS production and an increased number of cells with inactive mitochondria (Figures 8, S4,5) similar to staurosporine, a compound known to affect ROS production and, thus, used as a reference.…”

Modification of cellular DNA by synthetic aziridinomitosenes

“…24–27 The assay investigates the extent of drug-induced DNA crosslinking in individual cells by visualizing and quantifying DNA migration following exposure to DNA damaging agents. 25 The study examined the electrophoretic mobility of DNA from individual cells first treated with MC , Me-AZM , or H-AZM and then subsequently treated with hydrogen peroxide.…”

“…This leads to a decreased tail length when compared to cells treated with hydrogen peroxide alone. 24,27 A smaller value for the “tail extent moment”, which is calculated by multiplying tail length by the measured amount of DNA in the tail, 24,25 is indicative of increased DNA interstrand, intrastrand, or DNA-protein crosslinks.…”

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

“…13) In addition, it is also associated with rare cases of ototoxicity 14,15) and hepatotoxicity. 16,17) It has also been reported that highly toxic DNA lesions are caused by oxaliplatin based therapy at the cellular level 18) and may result in DNA damage and therefore higher risk for development of secondary malignancies. 19) In fact, there have been a few cases of secondary acute leukemia reported with oxaliplatin-based therapy.…”