Abstract
Melittin, the main peptide present in bee venom, has been proposed as having potential for anticancer therapy; the addition of melittin to cisplatin, a first line treatment for ovarian cancer, may increase the therapeutic response in cancer treatment via synergy, resulting in improved tolerability, reduced relapse, and decreased drug resistance. Thus, this study was designed to compare the metabolomic effects of melittin in combination with cisplatin in cisplatin-sensitive (A2780) and resistant (A2780CR) ovarian cancer cells. Liquid chromatography (LC) coupled with mass spectrometry (MS) was applied to identify metabolic changes in A2780 (combination treatment 5 μg/mL melittin + 2 μg/mL cisplatin) and A2780CR (combination treatment 2 μg/mL melittin + 10 μg/mL cisplatin) cells. Principal components analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) multivariate data analysis models were produced using SIMCA-P software. All models displayed good separation between experimental groups and high-quality goodness of fit (R2) and goodness of prediction (Q2), respectively. The combination treatment induced significant changes in both cell lines involving reduction in the levels of metabolites in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, purine and pyrimidine metabolism, and the arginine/proline pathway. The combination of melittin with cisplatin that targets these pathways had a synergistic effect. The melittin-cisplatin combination had a stronger effect on the A2780 cell line in comparison with the A2780CR cell line. The metabolic effects of melittin and cisplatin in combination were very different from those of each agent alone.
Highlights
IntroductionCombination therapy has long been studied in the treatment of cancer, including ovarian cancer [1]
Combination therapy has long been studied in the treatment of cancer, including ovarian cancer [1].It is a logical approach, focusing on increasing the response and tolerability to treatment, while decreasing resistance [2]
Our study demonstrated profound metabolic changes in the cells after melittin monotherapy, there has been no metabolomics study to date that has comparatively profiled the metabolite composition of ovarian cancer cells (OCCs) treated with a combination of melittin and cisplatin
Summary
Combination therapy has long been studied in the treatment of cancer, including ovarian cancer [1]. It is a logical approach, focusing on increasing the response and tolerability to treatment, while decreasing resistance [2]. Several cancers, including ovarian cancer, have demonstrated resistance or reduced sensitivity to cisplatin treatment, leading to decreased time to disease progression, increased likelihood of relapse, and reduced efficacy upon re-treatment during relapse [3,4]; cisplatin itself causes significant health problems, such as nephrotoxicity [5]. Cisplatin (or another platinum agent) in combination with taxanes (e.g., paclitaxel) is regarded as standard chemotherapy in ovarian cancer, where the taxane enhances the tumour’s radiosensitivity. Cisplatin and the adenovirus OBP-301 have been shown to work synergistically [1]
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