Cisplatin: a review of toxicities and therapeutic applications

Barabas, Karri; Milner, Rowan J.; Lurie, D. M.; Adin, Christopher A.

doi:10.1111/j.1476-5829.2007.00142.x

Cited by 372 publications

(277 citation statements)

References 123 publications

(141 reference statements)

Supporting

Mentioning

273

Contrasting

Unclassified

Order By: Relevance

“…The anticancer action of these platinum drugs results from their capacity to form DNAplatinum covalent adducts, which ultimately lead to apoptosis of cancer cells [76]. However, tumour resistance and side effects such as nephrotoxicity are often consequences of their clinical applications [5,6,37,66]. The development of anticancer drugs with different mechanisms of action is urgently needed to overcome drug resistance and side Electronic supplementary material The online version of this article (doi:10.1007/s12154-011-0070-x) contains supplementary material, which is available to authorized users.…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

View full text Add to dashboard Cite

Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

View full text Add to dashboard Cite

show abstract

“…8 ). The molecular mechanism responsible for the nephrotoxicity is unknown at present but several theories have been postulated 5 . The kidneys play a major role in the homeostasis of body fluid compartments.…”

Section: Introductionmentioning

confidence: 99%

“…After this activation, cisplatin can form bifunctional adducts (the two sites are on the same DNA strand) with preference for the N 7 -positions of adenine and guanine (>90%), the cross-links (the binding sites are located on different DNA strands) are rather rare (<2%) (ref. 5 ). Formation of these adducts and cross-links inhibits the DNA replication, thus, interfering with the cell division by mitosis.…”

Section: Introductionmentioning

confidence: 99%

Na<sup>+</sup>/K<sup>+</sup>-ATPase inhibition by cisplatin and consequences for cisplatin nephrotoxicity

Kubala¹,

Geleticova²,

Huličiak³

et al. 2014

BIOMED PAP

View full text Add to dashboard Cite

Aims. Cisplatin is a widely used chemotherapeutic. However, it is associated with numerous adverse effects. The aim of our study was examination of cisplatin interaction with Na + /K + -ATPase (NKA, the sodium pump). This enzyme is of crucial importance for all animal cells and particularly for the kidney, which is frequently damaged during chemotherapy. Methods. The entire NKA was isolated from porcine kidney. Its large cytoplasmic segment connecting transmembrane helices 4 and 5 (C45), was heterologously expressed in E.coli (wild-type or C367S mutant). The ATPase activity was evaluated according to the inorganic phosphate production and the interaction of isolated C45 with cisplatin was studied using chronopotentiometry and mass spectrometry. Results. Our experiments revealed that cisplatin can inhibit NKA. The finding that other platinum-based drugs with a low nephrotoxicity, carboplatin and oxaliplatin, did not inhibit NKA, suggested that NKA/cisplatin interaction is an important factor in cisplatin adverse effects. The inhibitory effect of cisplatin could be prevented by preincubation of the enzyme with reduced glutathione or DTT. Using chronopotentiometry and mass spectrometry, we found that cisplatin is bound to C45. However, our mutagenesis experiment did not confirm that the suggested Cys367 could be the binding site for cisplatin. Conclusion. Unintended interactions of drugs present serious limitations to treatment success. Although a large number of membrane pumps have been identified as potential targets of cisplatin, vis-a-vis nephrotoxicity, NKA inhibition seems to be of crucial importance. Experiments with isolated large cytoplasmic segment C45 revealed that it is the main target of cisplatin on NKA and that the reaction with cysteine residues plays an important role in cisplatin/NKA interactions. However, further experiments must be performed to identify the interacting amino acid residues more precisely.

show abstract

“…Recent research has aimed at identifying protective molecules and/or mechanisms that could be used to prevent or alleviate CisPt insults and the onset of AKI (Barabas et al, 2008;dos Santos et al, 2012). These pharmacological approaches have mainly focused on discovering compounds of natural origin (Nagwani & Tripathi, 2010;Nitha & Janardhanan, 2008;Sohn et al, 2009), notably issuing from Traditional Chinese Medicine (TCM) remedies.…”

Section: Introductionmentioning

confidence: 99%

Potential nephroprotective effects of the Chinese herbAngelica sinensisagainst cisplatin tubulotoxicity

Bunel

Antoine

Nortier

et al. 2014

Pharmaceutical Biology

View full text Add to dashboard Cite

Context: Acute kidney injury (AKI) is often encountered in patients receiving cisplatin (CisPt), a chemotherapeutic drug that induces numerous toxic side effects. Techniques used to limit nephrotoxicity during CisPt treatment are not fully effective; about a third of patients experience AKI. New nephroprotective strategies, including pharmacological approaches, must be developed. Objective: The present study investigated the nephroprotective potential of Angelica sinensis (Oliv.) Diels (Apiaceae) root towards CisPt tubulotoxicity. Materials and methods: HK-2 cells were incubated with CisPt (10 mM) and/or with a methanolic extract of A. sinensis (AS). Nephroprotective capacity was evaluated by means of cellular viability (resazurin assay) and apoptosis (annexin-V/PI staining), oxidative stress generation (H 2 DCF-DA oxidation), Ki-67 index (immunofluorescence), cell cycle analysis (DNA staining), cell migration rate (scratch assay), extracellular matrix deposition (collagen determination), and b-catenin relocalization. Results: CisPt decreased cell viability [76% versus Ctrl], which was associated with an increased apoptosis. Simultaneous treatment with 50 mg/ml AS enhanced cell survival [84% versus Ctrl] and decreased the apoptosis rate. AS could not alleviate CisPt-induced oxidative stress; but doses of 5 and 50 mg/ml raised the Ki-67 index [135 and 244% versus Ctrl] and cell migration rates [1.2 and 1.3-fold versus Ctrl]. Finally, both doses of AS limited the amount of collagen deposition [121.6 and 119.6% for 5 and 50 mg/ml, respectively, versus 131.0% for CisPt-treated cells] and prevented the relocalization of b-catenin from the membrane to the nucleus. Conclusion: These results confirm the nephroprotective potential of A. sinensis and require further investigations aiming at identifying its active compounds.

show abstract

Cisplatin: a review of toxicities and therapeutic applications

Cited by 372 publications

References 123 publications

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Na<sup>+</sup>/K<sup>+</sup>-ATPase inhibition by cisplatin and consequences for cisplatin nephrotoxicity

Potential nephroprotective effects of the Chinese herbAngelica sinensisagainst cisplatin tubulotoxicity

Contact Info

Product

Resources

About