Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, -3 and -6 in osteosarcoma

Seki, Kazutake; Yoshikawa, Hideshi; Shiiki, Kazuhiko; Hamada, Y.; Akamatsu, Noriya; Tasaka, Kachio

doi:10.1007/s002800050030

Cited by 96 publications

(84 citation statements)

References 32 publications

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“…Additionally, SNPs used in our association analysis may not have been dense enough to capture all the genotypes in known genes contributing to apoptosis. For example, caspase-6 is involved in the signaling process that determines a cell's fate to live or die and has been shown to induce cisplatin-dependent apoptosis in human osteosarcoma lines [34,37]. This gene is located in the highest LOD score (2.65) region of the linkage scan (on chromosome 4) and may warrant more in-depth analyses.…”

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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“…Cisplatin is known to induce cell death by activating the apoptosis pathway (Zhang et al 2015;Seki et al 2000), and this constitutes the main mechanism of its antitumor action. In cells that express Hsp70, however, Hsp70 expression has been shown to exert a strongly anti-apoptotic effect (Terauchi et al 2003;Saleh et al 2000).…”

Section: Discussionmentioning

confidence: 99%

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells

Mori

Terauchi

Shirai

et al. 2017

Cell Stress and Chaperones

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Although advances in chemotherapy have improved the prognosis for osteosarcoma, some patients do not respond sufficiently to treatment. Heat shock protein 70 (Hsp70) is expressed at high levels in cancer cells and attenuates the therapeutic efficacy of anticancer agents, resulting in a poorer prognosis. This study investigated whether small interfering RNA (siRNA)-mediated inhibition of Hsp70 expression in an osteosarcoma cell line would enhance sensitivity to cisplatin. The expression of Hsp70 with cisplatin treatment was observed by using Western blotting and real-time reverse transcription polymerase chain reaction (RT-PCR). Changes in the IC 50 of cisplatin when Hsp70 was inhibited by siRNA were evaluated. Cisplatin's effectiveness in inducing apoptosis was assessed by assay of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), caspase-3 activity, and mitochondrial membrane potential. Up-regulation of Hsp70 expression was dependent on the concentration of cisplatin. Inhibition of Hsp70 expression significantly reduced the IC 50 of cisplatin. When cisplatin was added to osteosarcoma cells with Hsp70 expression inhibited, a significant increase in apoptosis was demonstrated in TUNEL, caspase-3, and mitochondrial membrane potential assays. Inhibition of Hsp70 expression induced apoptosis in cultured osteosarcoma cells, indicating that Hsp70 inhibition enhanced sensitivity to cisplatin. Inhibition of Hsp70 expression may provide a new adjuvant therapy for osteosarcoma.

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“…One mechanism by which CDDP has been proposed to induce apoptosis is through increased expression of the Fas-receptor, a member of the tumour necrosis receptor superfamily, via activation of p53 (Muller et al, 1997;Fulda et al, 1998;Seki et al, 2000). RNase protection analysis demonstrated that pxn65 and pxn100 tumours lacked detectable expression of the Fas-ligand and Fas-receptor and there was no evidence for induction of their expression following CDDP treatment (Figure 4).…”

Section: Analysis Of Apoptotic Gene Expression Following Cddp Treatmementioning

confidence: 99%

Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo

et al. 2004

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The detailed molecular basis and determinants of in vivo tumour sensitivity to conventional anticancer agents remain unclear. We examined the cellular and molecular consequences of cisplatin treatment using two ovarian tumour xenograft models that had not been previously adapted to culture in vitro. Both xenografts were curable with clinically relevant multiple doses of cisplatin. Following a single dose of cisplatin (6 mg kg À1 i.p.) growth delays of 25 and 75 days were obtained for pxn100 and pxn65, respectively. This difference in response was not due to differences in DNA damage. Pxn100 tumours had a functional p53 response and a wild-type p53 sequence, whereas pxn65 harboured a mutant p53 and lacked a functional p53 response. Microarray analysis revealed the induction of p53-regulated genes and regulators of checkpoint control and apoptosis in pxn100 tumours following cisplatintreatment. By contrast, there was no p53-dependent response and only limited changes in gene expression were detected in the pxn65 tumours. TUNEL analysis demonstrated high levels of apoptosis in the pxn100 tumours following cisplatin treatment, but there was no detectable apoptosis in the pxn65 tumours. Our observations show that a marked in vivo response to cisplatin can occur via p53-dependent apoptosis or independently of p53 status in human ovarian xenografts.

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Cisplatin (CDDP) specifically induces apoptosis via sequential activation of caspase-8, -3 and -6 in osteosarcoma

Cited by 96 publications

References 32 publications

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Suppression of heat shock protein 70 by siRNA enhances the antitumor effects of cisplatin in cultured human osteosarcoma cells

Characterisation of molecular events following cisplatin treatment of two curable ovarian cancer models: contrasting role for p53 induction and apoptosis in vivo

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