Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent

Wentao Luo; Fan Wu; Ruba Elmaoued; Brandon B Beck; Edgar Fischer; Xiangbing Meng; Kimberly K Leslie; Donghai Dai

doi:10.3892/ijo_00000770

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Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent

Journal article

Open access

Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent

Wentao Luo, Fan Wu, Ruba Elmaoued, Brandon B Beck, Edgar Fischer, Xiangbing Meng, Kimberly K Leslie and Donghai Dai

International journal of oncology, Vol.37(5), pp.1187-1194

11/2010

DOI: 10.3892/ijo_00000770

PMID: 20878066

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Abstract

Endometrial cancer (ECa) is the fourth most common malignancy in women. Currently, there is no effective therapy for advanced and recurrent cancer. Among the poor-outcome endometrial cancers, there is a high frequency of TP53 mutations. We have previously reported that amifostine has a direct anti-cancer effect and has a significant synergistic effect with paclitaxel when used in endometrial cancer cell and xenograft models. In this report, using a cell line with knock-down p53 expression through siRNA, we found that amifostine enhancement of paclitaxel's anticancer effect is p53 status-dependent. Amifostine promotes entry into the G2-M phase through regulation of cyclin-dependent kinase-1 activity in cells with dysfunctional p53, thereby enhancing cancer cell sensitivity to paclitaxel. The synergistic effect between amifostine and paclitaxel was further confirmed in vivo using xenografts created with primary patient tumor tissue. Sensitivity to the therapeutic effect of paclitaxel in combination with amifostine was dependent upon the status of p53. A tumor with a nonsense TP53 mutation showed increased therapeutic response to paclitaxel and amifostine as measured by tumor weight compared to a tumor with wild- type TP53. Our study provides a rationale for a clinical trial of combined paclitaxel and amifostine in endometrial cancer patients whose tumors harbor TP53 mutations.

Flow Cytometry

Mutation

Amifostine - pharmacology

Apoptosis - drug effects

Cell Separation

Humans

Blotting, Western

Tumor Suppressor Protein p53 - genetics

Antineoplastic Combined Chemotherapy Protocols - pharmacology

Drug Synergism

Xenograft Model Antitumor Assays

Animals

Endometrial Neoplasms - genetics

Mice, Nude

Cell Line, Tumor

Endometrial Neoplasms - drug therapy

Female

Mice

Paclitaxel - administration & dosage

Details

Title: Subtitle: Amifostine enhancement of the anti-cancer effects of paclitaxel in endometrial cancer is TP53-dependent
Creators: Wentao Luo - Department of Internal Medicine, University of New Mexico, Albuquerque, NM 87131, USA
Fan Wu
Ruba Elmaoued
Brandon B Beck
Edgar Fischer
Xiangbing Meng
Kimberly K Leslie
Donghai Dai
Resource Type: Journal article
Publication Details: International journal of oncology, Vol.37(5), pp.1187-1194
Publisher: Greece
DOI: 10.3892/ijo_00000770
PMID: 20878066
eISSN: 1791-2423
Language: English
Date published: 11/2010
Academic Unit: Pathology; Obstetrics and Gynecology
Record Identifier: 9983931191602771

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