P53-independent thermosensitization by mitomycin c in human non–small-cell lung cancer cells

Jin, Zhao-Hui; Matsumoto, Hideki; Hayashi, Sachiko; Hatashita, Masanori; Ohtsubo, Toshio; Shioura, Hiroki; Kitai, Ryuhei; Kano, Eiichi

doi:10.1016/j.ijrobp.2004.01.033

Cited by 14 publications

(7 citation statements)

References 26 publications

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“…The enhancement ratio (ER) of TX-2004 was 1.54 at a dose of 50 mM on H1299/wtp53 cell (wild-type p53), while that of PFT-a was 1.06 at 50 mM. In addition, TX-2004 showed a protective effect for heat-induced apoptosis on H1299/wtp53 cell 67) to the same degree as PFT-a. From these results we demonstrated that TX-2004 is a bifunctional molecule with hypoxic cell radiosensitizing activity and p53 inhibitory activity.…”

Section: Design Of P53 Inhibiting Hypoxic Cell Ra-diosensitizersmentioning

confidence: 96%

Design of Hypoxia-Targeting Drugs as New Cancer Chemotherapeutics

Nagasawa

Uto

Kirk

et al. 2006

Biological & Pharmaceutical Bulletin

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The tumor microenvironment is now recognized as a major factor that influences not only the response to conventional anti-cancer therapies but also helps define the potential for malignant progression and metastasis. In particular, hypoxia is now considered a fundamentally important characteristic of the tumor microenvironment. Furthermore, discovery of the hypoxia inducible factor 1a a (HIF-1a a) has led to a rapidly increasing understanding of the molecular mechanisms involved in tumor hypoxia. This in turn has led to the current extensive interest in the signal molecules related to tumor hypoxia as potential molecular targets for cancer therapeutics. In this paper we give an overview of recent advances in hypoxia research, including cancer treatments that target tumor hypoxia. Progress in the development of hypoxia-targeting drugs will be discussed, including antiangiogenic hypoxic cell radiosensitizers and hypoxic cytotoxins, hypoxia targeting boron carriers and p53-inhibiting bifunctional radiosensitizers. We will also review our own recent research results in these areas. For example, we have found that certain of the 2-nitroimidazole radiosensitizers and heterocycle-N-oxide hypoxic cytotoxins we developed have antiangiogenic activity and antimetastatic activity. We propose that these activities are based on the inhibition of signal transduction mediated by HIF-1a a. The anti-tumor activities of hypoxia response are considered to be cytostatic (tumor dormancy-inducing) effects in contrast to cytotoxic DNA damaging effects. The combinaiton of these cytostatic effects that are related to radiosensitization with the cytotoxic effects of radiation should improve the prognosis and QOL of patients receiving radiation and lead to an overall response to treatment. Based on these considerations, we developed the antiangiogenic hypoxic cell radiosensitizers, TX-1877, TX-1898 and the hypoxic cytotoxin TX-402 that inhibits the HIF-1a a pathway We will also discuss our research involved with the development of other drugs to exploit tumor hypoxia, including a hypoxia-targeting boron carrier for boron neutron capture therapy (BNCT) and a p53 inhibiting radiosensitizer.Key words tumor hypoxia; angiogenic inhibitor; hypoxia inducible factor (HIF)-1a inhibitor; hypoxic cell radiosensitizer; boron neutron capture therapy; p53 inhibitor Review

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Section: Design Of P53 Inhibiting Hypoxic Cell Ra-diosensitizersmentioning

confidence: 96%

Design of Hypoxia-Targeting Drugs as New Cancer Chemotherapeutics

Nagasawa

Uto

Kirk

et al. 2006

Biological & Pharmaceutical Bulletin

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“…In addition, molecular mechanisms underlying radiosensitization by mTOR inhibition were also to be investigated. (34). These resulting H1299/wtp53 and H1299/mp53 cell lines were kindly provided by Dr Hideki Matsumoto (Fukui University).…”

Section: Introductionmentioning

confidence: 99%

Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status

Nagata

Takahashi²,

Ohnishi³

et al. 2010

Int J Oncol

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Abstract. Activation to a large extent of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway and mutations in the p53 gene are involved in lung cancer therapeutic resistance. The mammalian target of rapamycin (mTOR) acts as a downstream effector for Akt. Activation of the Akt/mTOR signal is a contributing factor to decreased radiation sensitivity. The purpose of this study was to examine whether the effect of rapamycin on radiation sensitivity is affected by cellular p53 gene status. Cellular radiation sensitivity was evaluated by using two human non-small cell lung cancer (NSCLC) cell lines with the same genetic background except for their p53 gene status (H1299/wtp53 and H1299/mp53). The cells were treated with rapamycin and/or radiation. Cell viability, cell proliferation, apoptosis, cell cycle and Akt/mTOR signaling activity were explored. Rapamycin synergistically enhanced the cytotoxicity of radiation, promoting the induction of apoptosis. Moreover, the combined treatment augmented the cytostatic effects of radiation regardless of cellular p53 gene status. Rapamycin in combination with radiation increased G 1 arrest and suppressed progression to S phase in both cell lines. Furthermore, the combined treatment conduced to a prominent p53-independent down-regulation of the mTOR signal and pro-survival molecule, cyclin D1. Rapamycin can enhance the effect of radiation through the repression of prosurvival signals and the reduction in the apoptotic threshold. Taken together, inhibition of the mTOR signal may be a promising strategy for radiosensitization with no relevance to p53 gene status from the aspects of cell lethality and cell growth depression.

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“…Several randomized clinical trials showed hyperthermia to be effective for the treatment of human cancer, particularly when combined with radiotherapy (Overgaard et al, 1995;Sneed et al, 1998). The combined use of hyperthermia and chemotherapeutic drugs (cisplatin (CDDP), irinotecan (CPT-11), and mitomycin C (MMC)) has had a synergistic effect in both cultured cancer cells in vitro (Matsumoto et al, 1998a, b;Jin et al, 2004) and human advanced cancer in vivo (Dahl and Mella, 2002;Takahashi et al, 2002). Human head and neck cancer is the most suitable for hyperthermia because it is easy to elevate the temperature of the tumor without injuring normal tissue (Engin et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer

et al. 2005

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To elucidate the molecular mechanisms for the enhancement of heat-induced apoptosis on exposure to acidic conditions, human maxillary carcinoma IMC-3 cells were heat-shocked at 441C for 30 min at either pH 7.4 or 6.7. Analyses with cDNA arrays, the reverse transcriptionpolymerase chain reaction (RT-PCR), and Western blotting were performed. We found that histone deacetylase 3 (HDAC3) was specifically induced after hyperthermia at 441C for 30 min at pH 6.7. Although the cytotoxicity of heating at 441C for 30 min was enhanced by decreasing the pH from 7.4 to 6.7, it was enhanced even more by antisense RNA oligonucleotides for HDAC3. The induction of G 2 /M arrest after heating occurred earlier at pH 6.7 than at pH 7.4. The inhibition of HDAC3 by the antisense RNA oligonucleotides suppressed partially the induction of G 2 /M arrest, resulting in an enhancement of the apoptosis caused by the heating under acidic conditions. Antisense RNA oligonucleotides for HDAC3 enhanced apoptosis 48 h after hyperthermia at 431C for 30 min in vivo. Analyses of p65 activity suggested that NF-jB is involved in this enhancement of hyperthermia. HDAC3 may be a novel target enhancing hyperthermia and combined treatment with hyperthermia and HDAC inhibitors is a possible modality for cancer therapy.

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P53-independent thermosensitization by mitomycin c in human non–small-cell lung cancer cells

Cited by 14 publications

References 26 publications

Design of Hypoxia-Targeting Drugs as New Cancer Chemotherapeutics

Design of Hypoxia-Targeting Drugs as New Cancer Chemotherapeutics

Effect of rapamycin, an mTOR inhibitor, on radiation sensitivity of lung cancer cells having different p53 gene status

Inhibition of histone deacetylase 3 stimulates apoptosis induced by heat shock under acidic conditions in human maxillary cancer

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