Changes in the in vitro activity of platinum drugs when administered in two aliquots.

Zaynab Al-Eisawi,Charles Chan,Mark Molloy,Nicholas Proschogo,Fazlul Huq,Philip Beale,Jun Qing Yu

doi:10.1186/s12885-016-2731-1

Abstract

BackgroundThe management of ovarian cancer remains a challenge. Because of the lack of early symptoms, it is often diagnosed at a late stage when it is likely to have metastasized beyond ovaries. Currently, platinum based chemotherapy is the primary treatment for the disease. However acquired drug resistance remains an on-going problem. As cisplatin brings about apoptosis by intrinsic and extrinsic pathways, this study aimed to determine changes in activity of platinum drugs when administered in two aliquots as against a bolus and sought to determine association with changes in GSH, speciation of platinum drugs and changes in protein expression.MethodsThe efficacy of administering cisplatin, carboplatin and oxaliplatin in two aliquots with a time gap was investigated in ovarian A2780, A2780cisR, A2780ZD0473R and SKOV-3 cell lines. The cellular accumulation of platinum, level of platinum − DNA binding and cellular glutathione level were determined, and proteomic studies were carried out to identify key proteins associated with platinum resistance in ovarian A2780cisR cancer cell line.ResultsMuch greater cell kill was observed with solutions left standing at room temperature than with freshly prepared solutions, indicating that the increase in activity on ageing was related to speciation of the drug in solution. Proteomic studies identified 72 proteins that were differentially expressed in A2780 and A2780cisR cell lines; 22 of them were restored back to normal levels as a result of synergistic treatments, indicating their relevance in enhanced drug action.ConclusionsThe proteins identified are relevant to several different cellular functions including invasion and metastasis, cell cycle regulation and proliferation, metabolic and biosynthesis processes, stress-related proteins and molecular chaperones, mRNA processing, cellular organization/cytoskeleton, cellular communication and signal transduction. This highlights the multifactorial nature of platinum resistance in which many different proteins with diverse functions play key roles. This means multiple strategies can be harnessed to overcome platinum resistance in ovarian cancer. The results of the studies can be significant both from fundamental and clinical view points.

Highlights

The management of ovarian cancer remains a challenge
We proposed that the administration of first aliquot of CS would place cancer cells under increased oxidative stress caused by depletion of cellular thiols due to their binding with the drug [5] and if so when the second aliquot was administered after a brief time period (2 to 4 h), depleted glutathione level would allow more of the drug to bind with DNA resulting into increased apoptosis
The values were higher in the resistant A2780cisR, A2780ZD0473R and SKOV-3 cell lines with OX having the largest value in SKOV-3

Summary

Introduction

The management of ovarian cancer remains a challenge. Because of the lack of early symptoms, it is often diagnosed at a late stage when it is likely to have metastasized beyond ovaries. As cisplatin brings about apoptosis by intrinsic and extrinsic pathways, this study aimed to determine changes in activity of platinum drugs when administered in two aliquots as against a bolus and sought to determine association with changes in GSH, speciation of platinum drugs and changes in protein expression. We proposed that the administration of first aliquot of CS would place cancer cells under increased oxidative stress caused by depletion of cellular thiols due to their binding with the drug [5] and if so when the second aliquot was administered after a brief time period (2 to 4 h), depleted glutathione level would allow more of the drug to bind with DNA resulting into increased apoptosis. The sequenced administration of CS in two aliquots with a small time gap could be looked upon as being the combination of two drugs with somewhat different mechanisms of action [5]

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