p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

Lee, E J; Gerhold, M; Palmer, Mykayla; Christen, Randolph D.

doi:10.1038/sj.bjc.6600779

Cited by 28 publications

(20 citation statements)

References 30 publications

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“…The effect of WR1065 on apoptosis is minimal, as demonstrated by the absence of any significant subdiploid population of cells (Figure 4), the absence of morphologically detectable cell death, and the lack of caspase-mediated PARP degradation (Figure 3). Our results contrast with the results of Lee EJ et al (2003) in which amifostine increases apoptosis in p53-negative HCT116 cells, whereas the presence of p53 protein actually confers resistance to this amifostine-induced apoptosis. However, the high concentration (3.8 mM) of amifostine used in the study of Lee et al could, on conversion of the prodrug to the aminothiol, result in a concentration of WR1065 greater than the 1.5 mM dosage, which we have shown to be cytotoxic.…”

Section: Discussioncontrasting

confidence: 56%

“…In a number of experimental systems, WR1065 exerts antimutagenic and cytoprotective effects at concentrations ranging between 100 mM and 1 mM and can even induce p53 accumulation at concentrations as low as 50 mM (North et al, 2000). Also, the absence of AG in the culture medium in the experiments by Lee EJ et al (2003) may result in the generation of toxic products from amifostine breakdown. Previously, transcription of several genes has been reported to be altered by treatment with WR1065: p21 is upregulated by treatment of cells containing wild-type p53 (North et al, 2000), as are fas, gadd45, and mdm2 (Shen et al, 2001), whereas MnSOD is upregulated in response to WR1065 activation of NF-kB (Kataoka et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

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Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53

Mann

Hainaut

2005

Oncogene

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The aminothiol WR1065 exerts selective cytoprotective effects in normal cells compared to cancer cells and has clinical applications for the protection of normal cells in cancer patients undergoing radio-or chemotherapy. There is evidence that p53 is activated in response to WR1065. To examine the effects of WR1065 on the signalling pathways controlled by p53, isogeneic human colon carcinoma cell lines (HCT116) differing only in the presence or absence of wild-type p53 were used. Treatment with WR1065 resulted in G1 cell cycle arrest in the p53-positive cell line but not in the p53-negative cell line. Long-term exposure resulted in minimal apoptosis of either cell line. Changes in gene expression in p53-positive or -negative cells treated with WR1065 were examined using commercial human stress and cancer gene arrays (Clontech Atlas arrays). Genes found to be specifically upregulated in a p53-dependent manner included coproporphyrinogen oxidase, ICErel-II cysteine protease, macrophage inhibitory cytokine-1 (also known as placental transforming growth factor beta), S100A4, and Waf1/ p21. However, most proapoptotic genes typically upregulated by p53 in response to DNA damage were not activated. These studies show that WR1065 specifically modulates a subset of p53 target genes in a colon carcinoma cell line, consistent with the observation that this agent elicits essentially p53-dependent, cell cycle arrest responses.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53

Mann

Hainaut

2005

Oncogene

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“…In colon cancer cells amifostine caused p53-proficient cells to arrest in G1 and provided protection against the cytotoxic effects of paclitaxel, but these effects of amifostine were not seen in p53-deficient cells. 22 However, yet another study investigated amifostine's cytoprotection of human glioma cells during radiation therapy and found that it was independent of p53 status. 23 We suggest that amifostine-mediated cell death may result from two different mechanisms.…”

Section: Induction Of Apoptosis In Human Lung Cancer Cells a Pataer Ementioning

confidence: 99%

Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53

et al. 2006

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Adenoviral delivery of the p53 gene is a potential therapeutic approach for the treatment of lung cancer. Furthermore, amifostine is a cytoprotective agent and recent reports have described its potentiation of chemotherapy's antitumor activity in lung cancer. Therefore, we wished to investigate the ability of amifostine both alone and in combination with p53-based therapy to induce apoptosis, and to understand the mechanisms by which this apoptosis occurs. Using p53 null and wild-type p53 human lung cancer cells and normal human bronchial epithelial cells, we evaluated the effects of amifostine on proliferation and apoptosis. We then analyzed Adp53 in combination with amifostine and performed isobologram analysis. Expression of p53, p21 WAF1 , Bax, Bak, bcl-2, as well as total and phosphorylated Cdc2 in the absence and presence of olomoucine, a phosphorylated Cdc2 kinase inhibitor, was then determined. Amifostine-induced apoptosis in human lung cancer cells in a dose-dependent fashion. The combination of amifostine and Adp53 significantly enhanced, with a supra-additive effect, the inhibition of proliferation of lung cancer cells. This enhancement of apoptosis by amifostine was associated with activation of p53 and dephosphorylation of Cdc2 proteins. Notably, olomoucine effectively prevented amifostine and/or Adp53-induced Cdc2 kinase activation and subsequent apoptosis. Our data shows that amifostine alone can induce apoptosis of human lung cancer cells, and that the combination of Adp53 with amifostine resulted in significantly higher levels of apoptosis. In addition, it appears that Cdc2 kinase plays an important role in the induction of apoptosis by amifostine and Adp53.

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“…Amifostine induced a G 1 arrest and protected against paclitaxel toxicity in cells with functional p53 (32). In contrast, amifostine enhanced the cytotoxicity of paclitaxel in the absence of p53.…”

Section: Discussionmentioning

confidence: 94%

A Potential Synergistic Anticancer Effect of Paclitaxel and Amifostine on Endometrial Cancer

Dai¹,

Holmes²,

Tan³

et al. 2005

Cancer Research

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Although paclitaxel is one of the most effective chemotherapeutic agents, its usefulness is still limited in advanced and recurrent endometrial cancer. Amifostine protection of normal tissues against the side effects of chemotherapeutic agents has been clinically proven in cancer patients; however, its application in endometrial cancer has not been fully evaluated. We have investigated the use of paclitaxel and amifostine in controlling the growth of poorly differentiated endometrial cancer cells, Hec50co, in vitro and in vivo. Our studies show that amifostine had direct anticancer effects on endometrial cancer cells in vitro by arresting the cell cycle at the G 1 phase and inducing apoptosis. Amifostine also inhibited s.c. tumor growth in athymic mice. Paclitaxel IC 50 value was reduced from 14 to 2 nmol/L with pretreatment of a single dose of 178 Mmol/L of amifostine for 72 hours. Amifostine also synergized with paclitaxel in the arrest of the cell cycle at the G 2 -M phase and in the induction of apoptosis. This two-drug regimen inhibited s.c. tumor growth as well as improved mouse survival significantly more than paclitaxel alone. Amifostine also significantly improved paclitaxel-induced cytotoxic effects on peripheral blood profiles. Our studies show that amifostine has direct anticancer effects on endometrial cancer. Our data have also shown a potential anticancer synergy between amifostine and paclitaxel in vitro and in vivo, whereas amifostine maintained a protective role in peripheral blood profiles. The dual specificity of amifostine action should be further investigated. (Cancer Res 2005; 65(20): 9517-24)

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p53 protein regulates the effects of amifostine on apoptosis, cell cycle progression, and cytoprotection

Cited by 28 publications

References 30 publications

Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53

Aminothiol WR1065 induces differential gene expression in the presence of wild-type p53

Induction of apoptosis in human lung cancer cells following treatment with amifostine and an adenoviral vector containing wild-type p53

A Potential Synergistic Anticancer Effect of Paclitaxel and Amifostine on Endometrial Cancer

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