Effect of Cell Cycle Inhibition on Cisplatin-Induced Cytotoxicity

Fishel, Melissa L.; Newell, David R.; Griffin, Roger J.; Davison, Richard; Wang, Lan Zhen; Curtin, Nicola J.; Zuhowski, Eleanor G.; Kasza, Kristen; Egorin, Merrill J.; Moschel, Robert C.; Dolan, M. Eileen

doi:10.1124/jpet.104.073924

Cited by 20 publications

(17 citation statements)

References 35 publications

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“…As the effect of cell cycle inhibition on cisplatin cytotoxicity has been studied by our laboratory [33], we examined which genetic variants involved in cisplatininduced cytotoxicity are associated with cell death through an apoptotic pathway. Cisplatin is known to induce cell death through necrosis and apoptosis [6].…”

Section: Discussionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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Objectives-Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.Methods-Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.Results-Significant heritability, ranging from 0.32 to 0.43 (P < 10 −7 ), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 μmol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3−q35.2 (LOD = 2.65, P = 2.4 × 10 −4 ) for 5 μmol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191 973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P ≤ 1 × 10 −4 ). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatininduced apoptosis.Conclusions-Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

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Section: Discussionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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“…Interestingly, cisplatin has recently been shown to inhibit NAT1 at physiological concentrations (Ragunathan et al, 2008). Thus, cisplatin may modulate any increases in NAT1 after HDAC inhibitor treatment, which may be a basis for the observed synergy (Fishel et al, 2005). Further studies are needed to elucidate the effects of these drugs on NAT1 and the possible effects on tumor growth in vivo.…”

Section: Downloaded Frommentioning

confidence: 99%

Histone Deacetylase Inhibitors Increase Human Arylamine N-Acetyltransferase-1 Expression in Human Tumor Cells

Paterson

Sin²,

Tiang³

et al. 2010

Drug Metab Dispos

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ABSTRACT:Arylamine N-acetyltransferase-1 (NAT1) has been associated with disorders involving folate metabolism, such as spina bifida, as well as numerous human cancers. As a result, the transcriptional and post-transcriptional regulation of NAT1 activity has been extensively studied. However, little work has been reported on the epigenetic control of NAT1 expression. Here, we demonstrate that the histone deacetylase inhibitor trichostatin A (TSA) increases NAT1 activity in human cancer cells by increasing transcription from the proximal promoter NATb. A specific Sp1 binding site was identified as essential for optimal induction of NAT1 by TSA. However, TSA did not increase the expression of Sp1 in HeLa cells. Instead, TSA increased the acetylation of histones associated with the NATb promoter. This allowed recruitment of Sp1 to the promoter along with acetylated histones. We propose that NAT1 transcription is partially repressed by the local chromatin condensation in the vicinity of NATb and that histone deacetylase inhibition leads to up-regulation of NAT1 expression via a direct change in chromatin conformation.

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“…BG was originally developed as a potent inactivator of O 6 -alkylguanine DNA alkyltransferase (Dolan and Pegg, 1997); however, its enhancement of cisplatin cytotoxicity is independent of its ability to inactivate O 6 -alkylguanine DNA alkyltransferase (Fishel et al, 2003). Structural modifications to BG have resulted in more potent ( O 6 -cyclohexylmethyl guanine) and essentially inactive (9-methyl- O 6 -benzylguanine) compounds, indicating the importance of various structural features on the ability to enhance cisplatin-induced cytotoxicity (Fishel et al, 2005b). The mechanism by which BG enhances cisplatin-induced cytotoxicity is as yet unknown, but among the mechanisms ruled out are detoxification by GSH in the cytosol and increased DNA repair of platinum adducts through enzymes within nucleotide excision repair (Fishel et al, 2005a).…”

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Enhancement of Cisplatin [cis-Diammine Dichloroplatinum (II)] Cytotoxicity by O⁶-Benzylguanine Involves Endoplasmic Reticulum Stress

Rabik¹,

Fishel²,

Holleran³

et al. 2008

J Pharmacol Exp Ther

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O6-Benzylguanine (BG) enhances cisplatin [cis-diammine dichloroplatinum (II)]-induced cytotoxicity and apoptosis in head and neck cancer cell lines by an unknown mechanism. We investigated the effect of cisplatin with and without BG on two targets of damage: DNA and the endoplasmic reticulum (ER). We chose three cancer cell lines to ascertain the mechanism of BG-enhanced cytotoxicity: SQ20b head and neck and SKOV-3x ovarian cancer cell lines, where BG enhanced cisplatin cytotoxicity, and A549 nonsmall cell lung cancer line, where BG did not enhance cisplatin cytotoxicity. All three lines had an increase in DNA damage when BG was added to cisplatin treatment, as evidenced by increased platination and phosphorylated histone H2AX formation. The increase in cisplatin-induced DNA damage after treatment with BG plus cisplatin is not sufficient to increase cytotoxicity or apoptosis in A549 cells. We evaluated the effect of cisplatin on the ER and observed increased caspase 12 cleavage in SQ20b and SKOV-3x cells, but not in A549 cells, after treatment with BG plus cisplatin versus cisplatin alone. Growth arrest and DNA damage inducible (GADD) 153, an ER stress-response gene, is up-regulated after treatment with BG plus cisplatin compared with cisplatin alone in SQ20b and SKOV-3x cells, but not in A549 cells. ER stress-induced apoptosis is an integral part of the mechanism by which BG enhances cisplatin. Inhibition of ER stress in the SQ20b cell line by salubrinal, an inhibitor of eIF2α dephosphorylation, or GADD153 small interfering RNA, abrogated BG-enhancement of cisplatin cytotoxicity and apoptosis through caspase 3 and 12 cleavage. These data indicate GADD153 up-regulation plays an important role in BG-enhanced cisplatin cytotoxicity and apoptosis.

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Effect of Cell Cycle Inhibition on Cisplatin-Induced Cytotoxicity

Cited by 20 publications

References 35 publications

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Histone Deacetylase Inhibitors Increase Human Arylamine N-Acetyltransferase-1 Expression in Human Tumor Cells

Enhancement of Cisplatin [cis-Diammine Dichloroplatinum (II)] Cytotoxicity by O⁶-Benzylguanine Involves Endoplasmic Reticulum Stress

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Effect of Cell Cycle Inhibition on Cisplatin-Induced Cytotoxicity

Cited by 20 publications

References 35 publications

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Histone Deacetylase Inhibitors Increase Human Arylamine N-Acetyltransferase-1 Expression in Human Tumor Cells

Enhancement of Cisplatin [cis-Diammine Dichloroplatinum (II)] Cytotoxicity by O6-Benzylguanine Involves Endoplasmic Reticulum Stress

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Enhancement of Cisplatin [cis-Diammine Dichloroplatinum (II)] Cytotoxicity by O⁶-Benzylguanine Involves Endoplasmic Reticulum Stress