Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

Li, Q; Kawamura, Kiyoko; Yamanaka, Masamichi; Okamoto, Shinya; Yang, Shuyuan; Yamauchi, Satoshi; Fukamachi, Toshihiko; Kobayashi, Hiroshi; Tada, Yuji; Takiguchi, Yuichi; Tatsumi, Koichiro; Shimada, Hideaki; Hiroshima, Kenzo; Tagawa, Masatoshi

doi:10.1038/cgt.2011.86

Cited by 27 publications

(19 citation statements)

References 22 publications

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“…CDDP is one of such agents and augmented p53 levels in target tumors facilitate CDDP-induced cell death [19], [20]. In fact our previous study showed that Ad-p53-transduced MSTO-211H cells produced synergistic cytotoxicity with CDDP, and that the CI values were below 1 between 0.2 and 0.8 Fa points [21]. The present study demonstrated that combination of ZOL and CDDP produced synergistic or additive anti-tumor effects on mesothelioma with the wild-type p53 gene.…”

Section: Discussionmentioning

confidence: 98%

“…Intrapleural injections of Ad-p53 were in fact conducted safely in patients with pleural effusions [28]. Previous studies demonstrated that Ad-p53 activated the p53 pathways and achieved combinatory anti-tumor effects with an anti-cancer agent including CDDP [21], [29], [30]. The mechanism of ZOL-mediated p53 induction remains unclear but the p53-inducible p21 is a downstream target of Ras and RhoA, the major molecules of small G proteins [31].…”

Section: Discussionmentioning

confidence: 99%

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Zoledronic Acid Produces Combinatory Anti-Tumor Effects with Cisplatin on Mesothelioma by Increasing p53 Expression Levels

et al. 2013

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We examined anti-tumor effects of zoledronic acid (ZOL), one of the bisphosphonates agents clinically used for preventing loss of bone mass, on human mesothelioma cells bearing the wild-type p53 gene. ZOL-treated cells showed activation of caspase-3/7, -8 and -9, and increased sub-G1 phase fractions. A combinatory use of ZOL and cisplatin (CDDP), one of the first-line anti-cancer agents for mesothelioma, synergistically or additively produced the cytotoxicity on mesothelioma cells. Moreover, the combination achieved greater anti-tumor effects on mesothelioma developed in the pleural cavity than administration of either ZOL or CDDP alone. ZOL-treated cells as well as CDDP-treated cells induced p53 phosphorylation at Ser 15, a marker of p53 activation, and up-regulated p53 protein expression levels. Down-regulation of p53 levels with siRNA however did not influence the ZOL-mediated cytotoxicity but negated the combinatory effects by ZOL and CDDP. In addition, ZOL treatments augmented cytotoxicity of adenoviruses expressing the p53 gene on mesothelioma. These data demonstrated that ZOL-mediated augmentation of p53, which was not linked with ZOL-induced cytotoxicity, played a role in the combinatory effects with a p53 up-regulating agent, and suggests a possible clinical use of ZOL to mesothelioma with anti-cancer agents.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Zoledronic Acid Produces Combinatory Anti-Tumor Effects with Cisplatin on Mesothelioma by Increasing p53 Expression Levels

et al. 2013

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“…Recently, Li et al analyzed the effects of Ad-p53 transduction in p14 / p16 -defective mesothelioma [19], which is a direct way to reactivate the p53 pathways. Transduction with Ad-53 induced phosphorylation of p53 at serine 15 and 46 residues, a marker of the p53 activation, and augmented extrinsic apoptotic pathways through upregulating the death receptors.…”

Section: Gene Therapy Targeting Genetic and Signal Pathwaysmentioning

confidence: 99%

A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine

Tada

Shimada

Hiroshima

et al. 2013

BioMed Research International

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Malignant mesothelioma, closely linked with occupational asbestos exposure, is relatively rare in the frequency, but the patient numbers are going to increase in the next few decades all over the world. The current treatment modalities are not effective in terms of the overall survival and the quality of life. Mesothelioma mainly develops in the thoracic cavity and infrequently metastasizes to extrapleural organs. A local treatment can thereby be beneficial to the patients, and gene therapy with an intrapleural administration of vectors is one of the potential therapeutics. Preclinical studies demonstrated the efficacy of gene medicine for mesothelioma, and clinical trials with adenovirus vectors showed the safety of an intrapleural injection and a possible involvement of antitumor immune responses. Nevertheless, low transduction efficiency remains the main hurdle that hinders further clinical applications. Moreover, rapid generation of antivector antibody also inhibits transgene expressions. In this paper, we review the current status of preclinical and clinical gene therapy for malignant mesothelioma and discuss potential clinical directions of gene medicine in terms of a combinatory use with anticancer agents and with immunotherapy.

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“…In contrast, deficiency of p16 augmented phosphorylation of pRb and induced uninhibited cell growth. Increased p53 levels also inhibited the pRb phosphorylation through induction of p21, one of the p53 target molecules [16]. Consequently, up-regulation of p53 is a therapeutic strategy for mesothelioma by enhancing the downstream pathways and inhibiting cell cycle progression.…”

Section: Introductionmentioning

confidence: 99%

Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways

et al. 2017

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BackgroundMesothelioma is resistant to conventional treatments and is often defective in p53 pathways. We then examined anti-tumor effects of metformin, an agent for type 2 diabetes, and combinatory effects of metformin and nutlin-3a, an inhibitor for ubiquitin-mediated p53 degradation, on human mesothelioma.MethodsWe examined the effects with a colorimetric assay and cell cycle analyses, and investigated molecular events in cells treated with metformin and/or nutlin-3a with Western blot analyses. An involvement of p53 was tested with siRNA for p53.ResultsMetformin suppressed cell growth of 9 kinds of mesothelioma including immortalized cells of mesothelium origin irrespective of the p53 functional status, whereas susceptibility to nutlin-3a was partly dependent on the p53 genotype. We investigated combinatory effects of metformin and nutlin-3a on, nutlin-3a sensitive MSTO-211H and NCI-H28 cells and insensitive EHMES-10 cells, all of which had the wild-type p53 gene. Knockdown of p53 expression with the siRNA demonstrated that susceptibility of MSTO-211H and NCI-H28 cells to nutlin-3a was p53-dependent, whereas that of EHMES-10 cells was not. Nevertheless, all the cells treated with both agents produced additive or synergistic growth inhibitory effects. Cell cycle analyses also showed that the combination increased sub-G1 fractions greater than metformin or nutlin-3a alone in MSTO-211H and EHMES-10 cells. Western blot analyses showed that metformin inhibited downstream pathways of the mammalian target of rapamycin (mTOR) but did not activate the p53 pathways, whereas nutlin-3a phosphorylated p53 and suppressed mTOR pathways. Cleaved caspase-3 and conversion of LC3A/B were also detected but it was dependent on cells and treatments. The combination of both agents in MSTO-211H cells rather suppressed the p53 pathways that were activated by nutrin-3a treatments, whereas the combination rather augmented the p53 actions in NCI-H28 and EHMES-10 cells.ConclusionThese data collectively indicated a possible interactions between mTOR and p53 pathways, and the combinatory effects were attributable to differential mechanisms induced by a cross-talk between the pathways.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3300-y) contains supplementary material, which is available to authorized users.

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Upregulated p53 expression activates apoptotic pathways in wild-type p53-bearing mesothelioma and enhances cytotoxicity of cisplatin and pemetrexed

Cited by 27 publications

References 22 publications

Zoledronic Acid Produces Combinatory Anti-Tumor Effects with Cisplatin on Mesothelioma by Increasing p53 Expression Levels

Zoledronic Acid Produces Combinatory Anti-Tumor Effects with Cisplatin on Mesothelioma by Increasing p53 Expression Levels

A Potential Therapeutic Strategy for Malignant Mesothelioma with Gene Medicine

Metformin produces growth inhibitory effects in combination with nutlin-3a on malignant mesothelioma through a cross-talk between mTOR and p53 pathways

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