**9. Chemotherapy and the acquisition of chemoresistance in EOC cells**

Resistance to taxanes and platinums, chemotherapy drugs in current use for ovarian cancer treatment, remains a major obstacle to a successful treatment of ovarian cancer patients [6]. Resistance to chemotherapy not only limits the use of the initial drug but also limits the use of other agents, even those with different mechanisms of action [129]. Chemotherapy drugs exert their actions by the initiation of cell death either directly through the generation of oxidative stress or as an indirect effect of exposure, as observed with several chemotherapeutic agents [130]. The development of chemoresistance to drugs is dependent on several factors that include: influx/efflux of drugs that decrease platinum accumulation in tumor cells, enhanced GSH and GST levels, upregulation of anti-apoptotic proteins such as Bcl-2, loss of tumor necrosis factor receptor ligand which induces apoptosis, increased DNA repair through up-regulation of repair

between common SNPs in oxidative DNA repair genes and redox genes with human cancer susceptibility has been established [28]. Common SNPs in the redox enzymes are known to be strongly associated with an altered enzymatic activity in these enzymes, and may explain the enhanced redox state that has been linked to several malignancies, including ovarian cancer [40, 52]. Additionally, it may further explain the observation of significantly decreased apoptosis and increased survival of EOC cells [53]. It is therefore critical to determine the exact effect of common SNPs in various redox enzymes on all process involved in the development of the oncogenic phenotype [21, 46, 133, 134]. Such studies can be linked to other studies focusing on determining the effects of genes involved in carcinogen metabolism (detoxification and/or activation), redox enzymes, and DNA repair pathways [133]. Numerous SNPs associated with change of function have been identified in antioxidant enzymes including *CAT*, *GPX1*, *GSR*, and *SOD2* [21, 134]. Additionally, the association between genetic polymorphisms in genes with anti-tumor activity and those involved in the cell cycle has been reported in ovarian cancer [135, 136]. Recently, several genetic variations have been identified in genome-wide association studies (GWAS), and were found to act as low to moderate penetrant alleles, which contribute to ovarian cancer risk, as well as other diseases [23, 137]. There is now an association of specific SNPs in key oxidant and anti-oxidant enzymes with increased risk and overall survival of ovarian cancer [21, 46]. A common SNP that reduced CAT activity (rs1001179) was utilized as a significant predictor of death when present in ovarian cancer patients and was also associated with increased risk for breast cancer [21, 46, 134, 138]. This SNP is also linked to increased risk, survival, and response to adjuvant treatment of cancer patients, including ovarian [46, 139]. Another common SNP that reduced CYBA activity (rs4673) was also reported to be associated with an increased risk for ovarian cancer [21, 46]. The mutant genotype of the *CYBA* gene has been shown to both decrease and increase

New Insights into the Pathogenesis of Ovarian Cancer: Oxidative Stress

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ally distinct *MPO* polymorphisms, such as (rs2333227) have been linked to relative increased risk for development of ovarian cancer as well as other cancers [21, 44, 46]. Additional SNPs that influenced the risk of EOC have been successfully identified from the GWAS studies including rs3814113 (located at 9p22, near BNC2), rs2072590 (located at 2q31, which contains a family of HOX genes), rs2665390 (located at 3q25, intronic to TIPARP), rs10088218 (located at 8q24, 700 kb downstream of MYC), rs8170 (located at 19p13, near MERIT40), and rs9303542 (located at 17q21, intronic to SKAP1) [21, 46]. Thus, the genetic component of increased ovarian cancer risk may be attributed to SNPs that result in point mutations in the redox genes and

**11. Chemoresistance is associated with point mutations in key redox** 

To date, the acquisition of chemoresistance in ovarian cancer is not fully understood. The enhanced oxidant state reported in chemoresistant EOC cells may be linked to point mutations in key redox enzymes [21]. Chemoresistant EOC cells manifested increased levels of CAT, GPX, and iNOS and decreased levels of GSR, SOD, and NAD(P)H oxidase as compared to their sensitive counterparts [21]. Interestingly, chemoresistant EOC cells, and not their sensitive counterparts,

●– [21, 46]. Moreover, function-

activity of the protein, thereby altering the generation of O2

potentially other genes [140].

**enzymes in EOC cells**

**Figure 2.** Summary of the role of oxidative stress in the development of sensitive and chemoresistant ovarian cancer [1].

genes, and loss of functional p53 that augments NF-κB activation [13, 131]. We have previously shown that chemoresistant EOC cells manifested increased iNOS and nitrate/nitrite levels as well as a decrease in GSR expression as compared to sensitive EOC cells, suggesting a further enhancement of the redox state in chemoresistant cells [1, 45]. Additionally, CAT, GPX, and iNOS were shown to be significantly increased while, GSR, SOD, and the NAD(P)H oxidase subunit (p22phox) were decreased in chemoresistant EOC cells as compared to their sensitive counterparts [21]. These finding supports a key role for oxidative stress, not only in the development of the oncogenic phenotype, but also in the development of chemoresistance (**Figure 2**).
