Carboplatin and oxaliplatin in sequenced combination with bortezomib in ovarian tumour models

Zaynab Al-Eisawi,Philip Beale,Charles Chan,Jun Q Yu,Fazlul Huq

doi:10.1186/1757-2215-6-78

Abstract

BackgroundOvarian cancer remains an on-going challenge mainly due to the development of drug resistance and also because the cancer is likely to have metastasized at the time of diagnosis. Currently, chemotherapy based on platinum drugs such as cisplatin is the primary treatment for the disease. Copper transporter 1 is involved in the transport of cisplatin into the cell, but is also down-regulated by the drug. Bortezomib, a proteasome inhibitor, has been reported to block this platinum-induced down-regulation of CTR1, so that in the presence of bortezomib, the cellular uptake of platinum drugs may be increased. Increased platinum accumulation may result in increased platinum − DNA binding so that the platinum drug in combination with bortezomib may produce enhanced cell kill.MethodsIn this study the efficacy of the sequential combinations of carboplatin, oxaliplatin and a trans-platinum compound coded as CH1 with BORT on the human ovarian A2780, A2780cisR, A2780ZD0473R and SKOV-3 cancer cell lines was evaluated. The levels of cellular platinum accumulation and platinum-DNA binding were determined following the treatment with these combinations. In order to investigate the effect of the combinations of the formation of ROS, the total and oxidized glutathione levels were also determined.ResultsPrevention of copper transporter 1 degradation by bortezomib is found to enhance the cellular accumulation of platinum, the level of Platinum − DNA binding and increases oxidative stress especially in the resistant cell lines.ConclusionsThe results suggest that the prevention of CTR1 degradation by bortezomib may be playing a major role in increasing the cellular uptake of platinum drugs and platinum-DNA binding level. Furthermore, the generation of oxidative stress appears to be a major contributor to the enhanced cell kill.

Highlights

Ovarian cancer remains an on-going challenge mainly due to the development of drug resistance and because the cancer is likely to have metastasized at the time of diagnosis
The CS-resistant variant of ovarian A2780 cancer cell line has been found to have a reduced expression of hCTR1 mRNA. These results strongly suggest that efficacy due to platinum-based chemotherapy may be significantly improved through the modulation of copper transporter 1 (CTR1) expression
Howell and co-workers have demonstrated that CS is transported into the cell by CTR1, the drug triggers the proteasomal degradation of the carrier thereby limiting its own uptake [15], a process that can be prevented by pretreatment of cells with proteasomal inhibitors such as MG-132, lactacystin and bortezomib (BORT) [15,16]

Summary

Introduction

Ovarian cancer remains an on-going challenge mainly due to the development of drug resistance and because the cancer is likely to have metastasized at the time of diagnosis. In line with the idea that copper transporter 1 (CTR1) is a carrier for CS into the cell [6,7,8,9,10], it has been found that platinum accumulation in CTR1 knockout mice is markedly reduced [11] and its over-expression enhances the uptake [12,13]. The CS-resistant variant of ovarian A2780 cancer cell line has been found to have a reduced expression of hCTR1 mRNA. These results strongly suggest that efficacy due to platinum-based chemotherapy may be significantly improved through the modulation of CTR1 expression. Our recent studies have confirmed that an increase in cell kill resulting from the combination of CS with BORT in ovarian tumour models is associated with an increase in cellular accumulation of CS and the level of Pt − DNA binding [18]

Methods

Results

Conclusion