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

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.

Proteomics Analysis of Ovarian Cancer Cell Lines and Tissues Reveals Drug Resistance-associated Proteins

“…Al-Eisawi et al showed that bortezomib prevented the degradation of the copper transporter 1, essential for cellular uptake of platinum (40). This effect was associated with enhanced accumulation of platinum, DNA adduct formation and oxidative stress in a panel of drug-resistant ovarian cancer cell lines, lending support to our findings.…”

Synergistic effects of cisplatin and proteasome inhibitor bortezomib on human bladder cancer cells

“…The proteasome inhibitor bortezomib is a promising novel agent in the treatment of bladder cancer; however, inducible cytoprotective mechanisms may limit its potential efficacy (15). In previous studies, bortezomib has been observed to enhance the activity of cisplatin, particularly in cisplatin-resistant cells (6,8,(16)(17)(18). The present study demonstrated for the first time that cisplatin and bortezomib combined treatment induced inhibition of cell proliferation by intrinsic and extrinsic apoptotic signaling pathways in the T24 human bladder cancer cell line.…”

“…Various studies have demonstrated that proteasome inhibition is the key regulator of intracellular protein degradation (8,9). This inhibition promotes the degradation of anti-apoptotic proteins while preventing the degradation of pro-apoptotic proteins, resulting in increased accumulation of pro-apoptotic proteins within the cells, and subsequent cell growth inhibition and programmed cell death in numerous malignant cell types (8,9).…”

Mifepristone increases mRNA translation rate, triggers the unfolded protein response, increases autophagic flux, and kills ovarian cancer cells in combination with proteasome or lysosome inhibitors

“…For instance, the toxicity of bortezomib was enhanced by ER stressors and dysregulators of the UPR such as TNF in colon cancer cells (Nowis et al., 2007), the multi‐kinase inhibitor sorafenib in hepatic cancer cells (Honma and Harada, 2013), eayarestatin—an inhibitor of the ER associated ATPase p97 that retro‐translocates proteins from the ER to the proteasome—in cervical cancer cells (Brem et al., 2013), Bcl‐2 antagonists in diffuse lymphocytic B‐cell lymphoma (Dasmahapatra et al., 2009), tunicamycin and thapsigargin in pancreatic cancer cells (Nawrocki et al., 2005), and photodynamic therapy in cervical cancer cells (Szokalska et al., 2009). In ovarian cancer cells, bortezomib increased the toxicity of TRAIL (Saulle et al., 2007), histone deacetylase inhibitors (Bazzaro et al., 2008; Fang et al., 2011), carboplatin (Al‐Eisawi et al., 2013), and the natural compound indole‐3‐carbinol (Taylor‐Harding et al., 2012). Here we show that mifepristone‐induced ER stress aggravation, combined with proteasome inhibition, provides preclinical therapeutic advantage towards ovarian cancer cells—i.e.…”