Abstract
BackgroundOvarian carcinoma is the leading cause of mortality among gynecological cancers in the world. The high mortality rate is associated with lack of early diagnosis and development of drug resistance. The antitumor efficacy and mechanism of NCX-4040, a nitric oxide-releasing aspirin derivative, against ovarian cancer is studied.MethodsNCX-4040, alone or in combination with cisplatin (cis-diamminedichloroplatinum, cDDP), was studied in cisplatin-sensitive (A2780 WT) and cisplatin-resistant (A2780 cDDP) cell lines as well as xenograft tumors grown in nude mice. Electron paramagnetic resonance (EPR) was used for measurements of nitric oxide and redox state. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice was used for mechanistic studies.ResultsCells treated with NCX-4040 (25 μM) showed a significant reduction of cell viability (A2780 WT, 34.9 ± 8.7%; A2780 cDDP, 41.7 ± 7.6%; p < 0.05). Further, NCX-4040 significantly enhanced the sensitivity of A2780 cDDP cells (cisplatin alone, 80.6 ± 11.8% versus NCX-4040+cisplatin, 26.4 ± 7.6%; p < 0.01) and xenograft tumors (cisplatin alone, 74.0 ± 4.4% versus NCX-4040+cisplatin, 56.4 ± 7.8%; p < 0.05), to cisplatin treatment. EPR imaging of tissue redox and thiol measurements showed a 5.5-fold reduction (p < 0.01) of glutathione in NCX-4040-treated A2780 cDDP tumors when compared to untreated controls. Immunoblotting analysis of A2780 cDDP tumor xenografts from mice treated with NCX-4040 and cisplatin revealed significant downregulation of pEGFR (Tyr845 and Tyr992) and pSTAT3 (Tyr705 and Ser727) expression.ConclusionThe results suggested that NCX-4040 could resensitize drug-resistant ovarian cancer cells to cisplatin possibly by depletion of cellular thiols. Thus NCX-4040 appears to be a potential therapeutic agent for the treatment of human ovarian carcinoma and cisplatin-resistant malignancies.
Highlights
Ovarian carcinoma is the leading cause of mortality among gynecological cancers in the world
NCX-4040 enhances cisplatin cytotoxicity in ovarian cancer cell lines NCX-4040 is a positional isomer of NCX-4016 (Figure 1A), which we have previously reported to be cytotoxic to human ovarian cancer cell lines [18]
The results suggested that administration of NCX-4040, in combination with cisplatin, inhibited tumor growth by inducing apoptosis through downregulation of Epidermal growth factor receptor (EGFR) and STAT3 signaling in the cisplatin-resistant ovarian cancer xenograft in mice
Summary
Ovarian carcinoma is the leading cause of mortality among gynecological cancers in the world. The high mortality rate is associated with lack of early diagnosis and development of drug resistance. The high mortality rate is attributed to the lack of early diagnosis of the malignancy and difficulties associated with treatment. Ovarian cancer is treated using cisplatin drugs; relapse of the disease involving a substantial population of cisplatin-resistant cells is commonly observed [1]. The development of drug resistance is a major impediment toward successful treatment of the recurrent cancer [2]. Higher doses of cisplatin and paclitaxel are required to treat the recurrent disease. There have been a number of studies aimed at understanding the causes of drug resistance, so as to develop strategies to overcome or avoid this complication [7,8,9]. Several mechanisms of cisplatin resistance in ovarian cancer cells have been proposed, including decreased cellular uptake and increased cellular efflux of cisplatin [8], inactivation of intracellular cisplatin by glutathione [10,11,12], and increased levels of DNA repair and DNA tolerance [12,13]
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