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Page 282 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

Finally, Glasspool et al. also tested the hypothesis whether a DNA hypomethylating agent can reverse
[83]
resistance to carboplatin in women with relapsed ovarian cancer. Surprisingly, and in contrast to SGI-110,
the administration of decitabine appeared to reduce rather than increase the efficacy of carboplatin in
partially platinum-sensitive ovarian cancer patients. These findings provoked the authors to suggest that
other demethylating agents should be considered in future combination studies.

Cis- and carboplatin resistance
To date, there are some studies that have compared the resistance to both, cis- and carboplatin. Using
a comprehensive DNA methylation microarray platform, Nogales et al. investigated the relationship of
[40]
resistance to both platinum compounds with the DNA methylation of the putative DNA/RNA helicase
Schlafen-11 (SLFN11). They identified hypermethylation of promoter CpG sites associated with the silencing
of this gene that correlated with increased resistance to cis- and carboplatin. Notably, their clinical findings
showed that those ovarian cancer patients harboring epigenetic inactivation of SLFN11 had a poor response
to both drugs.

In the biosynthesis of arginine, argininosuccinate synthetase (ASS1) is the rate-limiting enzyme . Down-
[84]
regulation of its expression was associated with the development of platinum resistance in ovarian cancer .
[85]
Nicholson et al. showed that ASS1 expression correlated with the ability of ovarian cancer cells to grow
[41]
in media supplemented with cisplatin, carboplatin or taxol or in arginine-depleted media. Aberrant
methylation of the ASS1 promoter correlated with transcriptional silencing in ovarian cancer cell lines
leading to selective resistance to platinum-based drugs and conferred arginine auxotrophy and sensitivity
to arginine deprivation. In ovarian cancer patients at diagnosis, ASS1 methylation was associated with
significantly reduced overall survival and relapse-free survival. In patients who relapsed, ASS1 methylation
was significantly more frequent compared to patients who did not relapse, suggesting that hypermethylated
ASS1 contributes to treatment failure in ovarian cancer.

Metalloestrogens are metals that activate the estrogen receptor in the absence of estradiol. They encompass
two subclasses: metal/metalloid anions and bivalent cationic metals. Arsenite and selenite belong to the
subclass of metal/metalloid anions . Aebi et al. demonstrated that selection of cells for resistance to
[87]
[86]
platinum resulted in resistance to arsenite and selenite. Since mammalian cells detoxify arsenite and
selenite by S-adenosylmethionine dependent methylation, they examined whether the latter is involved in
the cellular metabolism of cisplatin. Treatment of ovarian cancer cells and their cisplatin-resistant subline
with the S-adenosylhomocysteine hydrolase inhibitor adenosine-dialdehyde, an indirect inhibitor of
transmethylation, led to a significant increase in the cellular content of S-adenosylhomocysteine without
changing S-adenosylmethionine. Adenosine dialdehyde synergistically enhanced the cytotoxicity of both,
cisplatin and carboplatin. These findings indicate that inhibition of S-adenosylmethionine dependent
transmethylation enhanced the toxicity of cisplatin and carboplatin in ovarian cancer cells in vitro without
directly affecting the metabolism of either platinum drug.

HISTONE MODIFICATIONS
Epigenetic modifications of histones include methylation, acetylation, phosphorylation, sumoylation,
glycosylation, ubiquitination, carbonylation and ADP-ribosylation of individual histone components . Such
[88]
histone modifications have a direct effect upon DNA through nucleohistone repositioning. Histone changes
are heritable and can result in modification of gene expression. Furthermore, the epigenetic modifications
of histones lead to the deregulation of miRNAs in tumor cells . The effect of epigenetic changes in ovarian
[89]
cancer is well-reviewed by Yang et al. [5]

The combination of DNA methylation inhibitors and HDAC inhibitors synergistically activates gene
expression [90,91] . Thus, not only DNA methylation but also histone deacetylation has a central role in the
transcriptional repression of tumor suppressor genes and genes involved in sensitivity to chemotherapy .
[91]