Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy.

Dominique Kranz, Matthias Dobbelstein

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

Udgivelsesdato: 1 november 2006
OriginalsprogEngelsk
TidsskriftCancer Research
Vol/bind66
Udgave nummer21
Sider (fra-til)10274-10280
Antal sider6
ISSN0008-5472
StatusUdgivet - 1. nov. 2006

Fingeraftryk

gemcitabine
Cell Cycle Checkpoints
HCT116 Cells
Keratinocytes
Cisplatin
Neoplasms
nutlin 3
Mutation
Pharmaceutical Preparations

Citer dette

Kranz, Dominique ; Dobbelstein, Matthias. / Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. I: Cancer Research. 2006 ; Bind 66, Nr. 21. s. 10274-10280.
@article{267cd0b0d7b811dbae98000ea68e967b,
title = "Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy.",
abstract = "Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS and HCT116 cells to induce cell cycle arrest. These arrested cells were found to be resistant to subsequent transient treatment with the nucleoside analogue gemcitabine, as revealed by clonogenic assays following drug removal. In contrast, isogenic cells lacking functional p53 continued to enter S phase regardless of nutlin-3 pretreatment and remained highly susceptible to gemcitabine-mediated cytotoxicity. The sequential treatment with nutlin-3 alone, followed by transient exposure to nutlin-3 plus gemcitabine, efficiently compromised the clonogenicity of tumor cells with deletions or mutations of p53 but largely spared the proliferation of nontransformed human keratinocytes. Nutlin-3 pretreatment also conferred protection of p53-proficient cells against cytosine arabinoside but not against doxorubicin or cisplatin. We propose that the cell cycle arrest function of p53 can be used to convert p53 from a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy.",
author = "Dominique Kranz and Matthias Dobbelstein",
note = "Paper id:: PMID: 17079445 [PubMed - indexed for MEDLINE]",
year = "2006",
month = "11",
day = "1",
language = "English",
volume = "66",
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Kranz, D & Dobbelstein, M 2006, 'Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy.', Cancer Research, bind 66, nr. 21, s. 10274-10280.

Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy. / Kranz, Dominique; Dobbelstein, Matthias.

I: Cancer Research, Bind 66, Nr. 21, 01.11.2006, s. 10274-10280.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Nongenotoxic p53 activation protects cells against S-phase-specific chemotherapy.

AU - Kranz, Dominique

AU - Dobbelstein, Matthias

N1 - Paper id:: PMID: 17079445 [PubMed - indexed for MEDLINE]

PY - 2006/11/1

Y1 - 2006/11/1

N2 - Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS and HCT116 cells to induce cell cycle arrest. These arrested cells were found to be resistant to subsequent transient treatment with the nucleoside analogue gemcitabine, as revealed by clonogenic assays following drug removal. In contrast, isogenic cells lacking functional p53 continued to enter S phase regardless of nutlin-3 pretreatment and remained highly susceptible to gemcitabine-mediated cytotoxicity. The sequential treatment with nutlin-3 alone, followed by transient exposure to nutlin-3 plus gemcitabine, efficiently compromised the clonogenicity of tumor cells with deletions or mutations of p53 but largely spared the proliferation of nontransformed human keratinocytes. Nutlin-3 pretreatment also conferred protection of p53-proficient cells against cytosine arabinoside but not against doxorubicin or cisplatin. We propose that the cell cycle arrest function of p53 can be used to convert p53 from a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy.

AB - Mutations in the tumor suppressor gene TP53 represent the most frequent genetic difference between tumor cells and normal cells. Here, we have attempted to turn this difference into an advantage for normal cells during therapy. Using the Mdm2 antagonist nutlin-3, we first activated p53 in U2OS and HCT116 cells to induce cell cycle arrest. These arrested cells were found to be resistant to subsequent transient treatment with the nucleoside analogue gemcitabine, as revealed by clonogenic assays following drug removal. In contrast, isogenic cells lacking functional p53 continued to enter S phase regardless of nutlin-3 pretreatment and remained highly susceptible to gemcitabine-mediated cytotoxicity. The sequential treatment with nutlin-3 alone, followed by transient exposure to nutlin-3 plus gemcitabine, efficiently compromised the clonogenicity of tumor cells with deletions or mutations of p53 but largely spared the proliferation of nontransformed human keratinocytes. Nutlin-3 pretreatment also conferred protection of p53-proficient cells against cytosine arabinoside but not against doxorubicin or cisplatin. We propose that the cell cycle arrest function of p53 can be used to convert p53 from a killer to a protector of cells, with the potential to reduce unwanted side effects of chemotherapy.

M3 - Journal article

VL - 66

SP - 10274

EP - 10280

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 21

ER -