Synergism between cisplatin and Bortezomib in ovarian cancer cells
Zaynab Al-Eisawi
School of Biomedical Sciences,faculty of medicine,University of Sydney,Lidcombe,NSW,Australia
Abstract:
Cisplatin is a widely used antitumour drug that is highly effective against various cancers, including testicular, ovarian and lung cancer. However, the drug has two major drawbacks: (1) limited spectrum of activity due to intrinsic and/or acquired resistance and (2) the toxic side-effects including nausea, vomiting, nephrotoxicity, ototoxicity, neurotoxicity, and peripheral neuropathy. Thus, many cisplatin analogues have been prepared by altering the nature of the leaving groups and carrier ligands with the aim of reducing the effects and altering the spectrum of activity. However, besides cisplatin only two of its analogues carboplatin and oxaliplatin are widely used in the clinic.
Being neutral cisplatin can cross the cell membrane by passive diffusion. Recent studies have shown that cisplatin actually enters the cell by both passive diffusion and carrier-mediated transport e.g. using copper transporter CTR1. However, cisplatin is found to trigger the down-regulation of CTR1 in the human ovarian cancer cells and also the proteasomal degradation of the transporter. Bortezomib, a proteasome inhibitor, has been reported to block cisplatin-induced down-regulation of CTR1. This means that in presence of bortezomib, the cellular uptake of cisplatin and consequently the level of platinum-DNA binding can be increased so that cisplatin and bortezomib in combination may act synergistically. In this project we are investigating synergism in activity from sequenced combination of cisplatin with bortezomib in the human ovarian tumour models. The results of the study including drug potency, synergism from sequenced combination of cisplatin and bortezomib will be presented in the poster.
