Structural study on the interactions of oxaliplatin and linear DNA

Zou, Yu; Biao, Linhai; Xu, Fengjie; Liu, Ruisi; Liu, Zhiguo; Fu, Yujie

doi:10.1002/sca.21337

Cited by 4 publications

(3 citation statements)

References 41 publications

(56 reference statements)

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“…Since it is known that the active fragment of oxaliplatin forms covalent adducts with DNA, the observed hyperchromism in DACHPtCl 2 and oxaliplatin should be due to a distortion in DNA conformation caused by adduct formation that exposes the DNA bases and results in higher absorbance values. These results are consistent with other studies regarding the interaction of oxaliplatin with linear DNA [ 35 ]. In the case of the G2.5COO(DACHPt) 16 metallodendrimer, one should not expect a full release of the coordinated metallic fragments from the dendrimer scaffold during the 5 min incubation period used in the assay, even in the presence of chloride ions.…”

Section: Resultssupporting

confidence: 93%

Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

2021

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The DACHPtCl2 compound (trans-(R,R)-1,2-diaminocyclohexanedichloroplatinum(II)) is a potent anticancer drug with a broad spectrum of activity and is less toxic than oxaliplatin (trans-l-diaminocyclohexane oxalate platinum II), with which it shares the active metal fragment DACHPt. Nevertheless, due to poor water solubility, its use as a chemotherapeutic drug is limited. Here, DACHPtCl2 was conjugated, in a bidentate form, with half-generation PAMAM dendrimers (G0.5–G3.5) with carboxylate end-groups, and the resulting conjugates were evaluated against various types of cancer cell lines. In this way, we aimed at increasing the solubility and availability at the target site of DACHPt while potentially reducing the adverse side effects. DNA binding assays showed a hyperchromic effect compatible with DNA helix’s disruption upon the interaction of the metallodendrimers and/or the released active metallic fragments with DNA. Furthermore, the prepared DACHPt metallodendrimers presented cytotoxicity in a wide set of cancer cell lines used (the relative potency regarding oxaliplatin was in general high) and were not hemotoxic. Importantly, their selectivity for A2780 and CACO-2 cancer cells with respect to non-cancer cells was particularly high. Subsequently, the anticancer drug 5-FU was loaded in a selected metallodendrimer (the G2.5COO(DACHPt)16) to investigate a possible synergistic effect between the two drugs carried by the same dendrimer scaffold and tested for cytotoxicity in A2780cisR and CACO-2 cancer cell lines. This combination resulted in IC50 values much lower than the IC50 for 5-FU but higher than those found for the metallodendrimers without 5-FU. It seems, thus, that the metallic fragment-induced cytotoxicity dominates over the cytotoxicity of 5-FU in the set of considered cell lines.

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Section: Resultssupporting

confidence: 93%

Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

2021

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“…Ox carries out its anti-cancer effect by causing cytotoxicity through the prevention of DNA replication (Alian et al, 2012) and the interruption of the base stacking of DNA in the platination process (Zou et al, 2016). This mechanism may affect organs with rapid cell divisions such as the testes.…”

Section: Introductionmentioning

confidence: 99%

Study on the effect of maternal administration of oxaliplatin on offspring testes using unbiased design-based stereology

Sadeghinezhad¹,

Dahmardeh²,

Tootian³

et al. 2021

J Exp Clin Med

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Oxaliplatin (Ox) is widely used for the treatment of various tumors. Since Ox prevents DNA replication and transcription, it may affect organs with rapid cell divisions such as the testes. Although its use during pregnancy has been reported, no information regarding its effects on the testes of the offspring is not available yet. Thirty-two mice were randomly divided into four groups. The control group (1) was administered intraperitoneally 0.2 ml of saline three times a week for the 21 days of pre-pregnancy, pregnancy and lactation. Experimental groups 2, 3 and 4 received 3 mg/kg of oxaliplatin three times a week for 21 days during pre-pregnancy, pregnancy and lactation, respectively. The left testis was removed from male offspring 30 and 60 days after birth. The volume of the testes, seminiferous tubules and interstitial tissue, the surface area and height of the seminiferous epithelium, as well as the length and diameter of seminiferous tubules, were analyzed by means of stereology. Results showed a decrease in the evaluated parameters in experimental groups, in comparison with the control group. Due to the ameliorating effect of Ox on offspring testes, cautiousness is needed during maternal administration in order to preserve the fertility of male offspring.

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“…6 b). When oxalate in oxaliplatin is replaced by chloride, an apparent blue-shift from 300 to 267 nm occurs [ 21 ], and then interactions with penicillin G or its degradants can occur more readily (Fig. 6 c).…”

Section: Resultsmentioning

confidence: 99%

Reactions of cisplatin and oxaliplatin with penicillin G: implications for drug inactivation and biological activity

et al. 2022

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Determination of the toxicity of compounds toward cancer cells is a frequent procedure in drug discovery. For metal complexes, which are often reactive prodrugs, care has to be taken to consider reactions with components of the cell culture medium that might change the speciation of the metal complex before it is taken up by the cells. Here, we consider possible reactions between the clinical platinum drugs cisplatin and oxaliplatin with penicillin G, an antibiotic added routinely to cell culture media to prevent bacterial contamination. Platinum has a high affinity for ligands with sulfur donors. Penicillin G is an unstable thioether that degrades in a range of pathways. Nuclear magnetic resonance (NMR) and UV–Vis absorption spectroscopic studies show that reactions with cisplatin can occur within minutes to hours at 310 K, but more slowly with oxaliplatin. The identities of the Pt- adducts were investigated by mass spectrometry. The marked effect on cytotoxicity of co-incubation of cisplatin with penicillin G was demonstrated for the HeLa human cervical cancer cell line. These studies highlight the possibility that reactions with penicillin G might influence the cytotoxic activity of metal complexes determined in culture media. Graphical abstract

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Structural study on the interactions of oxaliplatin and linear DNA

Cited by 4 publications

References 41 publications

Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

Use of Half-Generation PAMAM Dendrimers (G0.5–G3.5) with Carboxylate End-Groups to Improve the DACHPtCl2 and 5-FU Efficacy as Anticancer Drugs

Study on the effect of maternal administration of oxaliplatin on offspring testes using unbiased design-based stereology

Reactions of cisplatin and oxaliplatin with penicillin G: implications for drug inactivation and biological activity

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