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Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010 Page 279

but not in cisplatin-sensitive cells. Notably, overexpression of OXCT1 conferred sensitivity to cisplatin in the
ovarian cancer cells .
[18]

The gene encoding for myelin and lymphocyte protein (MAL) has been reported to be among the most
highly expressed genes in serous ovarian cancers from short-term survivors (< 3 years) compared with those
of long-term survivors (> 7 years) . Lee et al. showed that this difference in MAL expression is due to
[71]
[70]
differences in DNA methylation at specific sites within the MAL promoter. MAL was largely unmethylated
at the transcriptional start site in serous ovarian cancers. Methylation of the region 200-400 bp upstream of
the promoter could be reduced by the treatment of an ovarian cancer cell line with 5-azacytidine, resulting
in a 10-fold increase in MAL expression. MAL transcript levels were also higher in cisplatin resistant ovarian
cell lines suggesting that MAL methylation status serves as a marker of platinum sensitivity.

α-N-acetylgalactosaminidase (NAGA) is responsible for deglycosylating the group-specific component
(Gc), a precursor of Gc protein-derived macrophage activating factor (GcMAF). The deglycosylated form
of Gc protein cannot be converted into GcMAF and subsequently, decreased GcMAF levels can promote
immunosuppression . Ha et al. identified NAGA as one of the key candidate genes for cisplatin drug
[25]
[72]
response. In cisplatin-resistant cell lines, NAGA was significantly downregulated and hypermethylated at
its promoter. Restoration and overexpression of NAGA in cisplatin-resistant lines induced cytotoxicity in
response to cisplatin, whereas depletion of NAGA increased cisplatin resistance .
[25]
In their study, Cui et al. investigated coiled coil domain containing protein 69 (CCDC69), and found that its
[32]
inhibition may interfere with the effectiveness of a combination therapy with platinum drugs. The expression
levels of CCDC69 were 3-4 fold higher in cisplatin-resistant cells than its parental cisplatin-sensitive cells.
Treatment of CCDC69 knockout, cisplatin-resistant cells with cisplatin was accompanied with increasing
sensitivity to cisplatin, abrogation of G1 and G2/M arrest, increasing caspase activity, p53 acetylation and
higher levels, as well as mitochondrial redistribution of the apoptosis modulator Bax.

Ubiquitin carboxyl terminal hydrolase 1 (UCHL1) catalyzes the hydrolysis of COOH-terminal ubiquityl
esters and amides . Jin et al. detected UCHL1 promoter methylation in ovarian cancer cell lines and a
[73]
[26]
negative correlation of UCHL1 with their cisplatin resistance. Microarray data revealed that after UCHL1
knockdown several apoptosis related genes, including apoptosis regulators BCL2, BCL11A, AEN and XIAP,
and the phosphorylated serine/threonine protein kinase AKT were up-regulated, whereas the pro-apoptotic
Bax was down-regulated.

FANCF (Fanconi anemia, complementation group M) is a gene associated with Fanconi anemia, the protein
products of which were reported to interact with proteins involved in DNA repair pathways, e.g., with
BRCA1 . More than 15 years ago, Olopade and Wei described a model of ovarian cancer tumor progression
[74]
[28]
that implicated aberrant FANCF promoter methylation and correlated with gene silencing and disruption of
the Fanconi-anemia-BRCA pathway. Disruption of this pathway occurred de novo in ovarian cancer and
might contribute to selective sensitivity to platinum components. The laboratory of D’Andrea investigated
[29]
the relationship of chromosome instability with cisplatin hypersensitivity, and showed that the phenotype
of ovarian cancer cells was caused by methylation and silencing of the signaling Fanconi-anemia-BRCA
pathway. Restoration of this pathway was associated with demethylation of FANCF, leading to acquired
cisplatin resistance. The laboratory proposed a model for ovarian tumor progression in which the initial
methylation of FANCF was followed by FANCF demethylation, ultimately resulting in cisplatin resistance .
[30]
AT-101 is a natural compound from cotton seeds and inhibits the anti-apoptotic Bcl-2 family of proteins .
[75]
Karaca et al. investigated the effects of AT-101 in combination with cisplatin on the expression of pro-apoptotic
[76]
proteins and epigenetic events in ovarian cancer cells. Combined administration of both agents led to a strong