Resistance to cis- and carboplatin initiated by epigenetic changes in ovarian cancer patients

Abstract

Initially, most ovarian tumors respond to the treatment with platinum components, but frequently recurrence occurs within the following two years in advanced ovarian cancer patients. In this regard, previous studies have shown changes in the epigenetic patterns in ovarian cancer that are linked with resistance to cis- and carboplatin therapy. Thus, epigenetic changes mediated by a treatment with cis- or carboplatin could identify such patients who do or do not respond to this therapy. Therefore, an understanding of the impact of platinum on epigenetics in ovarian cancer is important in overcoming platinum resistance. In this review, we delineate epigenetic abnormalities in cis- and carboplatin-resistant ovarian tumors, such as changes in DNA methylation, histone modifications and deregulation of microRNAs, and discuss the potential of epigenetic therapies in combination with platinum.

Keywords: DNA methylation; Ovarian cancer; carboplatin; cisplatin; histone modifications; microRNAs; resistance.

Figure 1

Chemical structures of cis- and carboplatin (A). Action of platinium. Cisplatin [Cis-diamminedichloroplatinum (II)] forms intracellular electrophilic water complexes based on the commonly predominant lower chloride concentrations. Due to its high affinity to the bases guanine and adenine, it forms chelates and inhibits DNA expression. Crosslinks of the DNA single and double strands are formed by platination with a disorder of template function and cell division. Carboplatin [Cis-Diamin (1,1cyclobutandicarboxylo)-platinium] has an equivalent mechanism of action. Chelation and cross-linking of the single and double-stranded DNA inhibit DNA synthesis and transcription triggering apoptosis (B)

Figure 2

Chemical structures of azacitidine and decitabine. Azacitidine is metabolized intracellularly into decitabine