Page 77 - Read Online

Page 276 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

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)

e.g., changes in drug efflux through the modulation of diverse transporter systems, deregulated levels of
intracellular glutathione and metallothioneine able to bind and sequester platinum, altered DNA repair
pathways and reduced expression of pro-apoptotic proteins. These modulations are associated with epigenetic
changes in DNA methylation, histone modifications and microRNA levels, but also with genetic alterations,
such as mutations or deletion [52,54] . In this section, we present a short overview of the main mechanisms of
cis- and carboplatin resistance to better illustrate the impact of these drugs on epigenetics in the following
sections.

Cis- and carboplatin enter the cells and are exported from cells via transporters that e.g., manage copper
homeostasis. The major copper influx transporter, copper transporter 1 (CTR1), controls the tumor cell
accumulation and cytotoxic effect of cisplatin and carboplatin. Both copper and cisplatin may trigger the
down-regulation of CTR1 via a process that involves ubiquitination and proteosomal degradation. In this
regard, the majority of cells with acquired resistance to platinum drugs exhibit reduced drug accumulation.
Thus, the cytotoxicity of these drugs correlates with the amounts of drugs entering the cell [55,56] .

Furthermore, oxidative stress is the one of most important mechanisms involved in cisplatin toxicity. Under
normal physiological conditions, cells control reactive oxygen species levels by balancing the generation of
reactive oxygen species with their elimination by e.g., GSH. Hence, glutathione acts as an antioxidant in
the cell and supports the redox environment while conserving reduced sulfhydryl groups. Elevated levels
of glutathione and glutathione-S-transferase, an enzyme mediating cisplatin coupling to GSH, induce
resistance to cisplatin . In this regard, cisplatin is detoxified by glutathione through adduct formation,
[57]
and these platinum/glutathione conjugates are readily secreted out of the cells by e.g., multidrug resistance
proteins of the ABC family .
[58]
Finally, platinum damage is repaired primarily by the nucleotide excision repair system and the homologous
recombination pathway. The nucleotide excision repair system recognizes platinum-induced inter- and intra-strand
crosslinks and induces a process of DNA unwinding, incision, excision and synthesis. Induced DNA double-strand
breaks are recognized by homologous recombination repair which initiates a process of single strand DNA
formation, coating, filament formation, strand invasion and DNA synthesis. In particular, excision repair
cross complementation group-1 and the related genes XPA and BRCA1 are involved in DNA repair. For
example, 50% of high-grade serous ovarian cancers (HGSOC) exhibit defective DNA repair by inactivation
of the homologous recombination due to germline and somatic mutations in BRCA1 (11%), BRCA2 (9%) and