Cancer Research Journal
Volume 4, Issue 6, November 2016, Pages: 106-114
Received: Nov. 30, 2016;
Accepted: Dec. 10, 2016;
Published: Jan. 9, 2017
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Shakeria Cohen, Department of Internal Medicine, Morehouse School of Medicine, Atlanta, USA
Sharifeh Mehrabi, Department of Internal Medicine, Morehouse School of Medicine, Atlanta, USA
Xuebiao Yao, Department of Physiology, Morehouse School of Medicine, Atlanta, USA
Stephanie Millingen, Department of Internal Medicine, Morehouse School of Medicine, Atlanta, USA
Felix O. Aikhionbare, Department of Internal Medicine, Morehouse School of Medicine, Atlanta, USA
Serous ovarian cancer (SOC) is usually diagnosed at late stage and stage-adjusted five year survival rate is low. Mortality is relatively heavy on African-Americans/Black (AA) affected with SOC compared to their Caucasian counterparts, though the cause for the disparity remains unclear. DNA damage induced by oxidative stress has been linked to ovarian cancer, but the role of oxidative stress in distinguishing differences in aggressive SOC tumors among patients is yet to be determined. This study aims to determine the levels of reactive oxygen species (ROS), malondialdehyde (MDA), reactive carbonyl groups and antioxidants in primary SOC normal, precancerous (cystadenoma, borderline) and invasive (III/IV) tissue samples obtained from AA and Caucasian subgroups. Additionally, the study seeks to investigate significant changes in the level of ROS between AA and Caucasian SOC samples. A fluorogenic probe, dichlorodihydrofluorescein (DCFH-DiOxyQ), was used to scavenge reactive oxygen species in SOC normal, precancerous and malignant stages III/IV tissue samples. Malondialdehyde (MDA), a lipid peroxidation marker, and reactive carbonyl groups were measured as indicators of oxidative injury. Moreover, antioxidant status was assessed by estimating glutathione peroxidase 3 (GPX3) enzyme levels. Results indicate ROS concentration was approximately 96% higher in the malignant tissues in comparative to the normal non-diseased controls. In addition, ROS concentration among AA women was approximately 9% higher than Caucasian women. MDA levels increased exponentially from non-disease control and precancerous tissues relative to malignant tissues. Furthermore, malignant serous ovarian samples showed significantly higher reactive carbonyl content compared to the non-disease controls (p=0.009), while GPX3 levels decreased considerably in serous cystadenoma and malignant tissue samples, and non-diseased control compared to borderline disease. The results suggest accumulation of ROS and MDA levels may be a causative factor for SOC. Elevated levels of MDA and reactive carbonyl proteins could override the GPX3 enzyme capacity therefore, initiating serous ovarian neoplasm.
Felix O. Aikhionbare,
Reactive Oxygen Species and Serous Epithelial Ovarian Adenocarcinoma, Cancer Research Journal.
Vol. 4, No. 6,
2016, pp. 106-114.
Mehrabi S, Partridge EE, Seffens W, Yao X, Aikhionbare FO. Oxidatively modified proteins in the serous subtype of ovarian carcinoma. Biomed Res Int 2014; 2014: 585083.
Gupta D, Lis CG. Role of CA125 in predicting ovarian cancer survival - a review of the epidemiological literature. J Ovarian Res 2009; 2: 13.
Aikhionbare FO, Mehrabi S, Kumaresan K, Zavareh M, Olatinwo M, Odunsi K, Partridge EE. Mitochondrial DNA sequence variants in epithelial ovarian tumor subtypes and stages. J Carcinog 2007; 6: 1.
Collins Y, Holcomb K, Chapman-Davis E, Khabele D, Farley JH. Gynecologic cancer disparities: a report from the Health Disparities Taskforce of the Society of Gynecologic Oncology. Gynecologic Oncology 2014; 133 (2): 353-361.
Jasen, P. From the "Silent Killer" to the "Whispering Disease": Ovarian Cancer and the Uses of Metaphor. Med Hist 2009; 53 (4): 489-512.
Toyokuni S, Okamoto K, Yodoi J, Hiai H. Persistent oxidative stress in cancer. FEBS Letters 1995; 358 (1): 1-3.
Kang D, Hamasaki N. Mitochondrial oxidative stress and mitochondrial DNA. Clin Chem Lab Med 2003; 41 (10): 1281-1288.
Behrend L, Henderson G, Zwacka RM. Reactive oxygen species in oncogenic transformation. Biochemical Society Transactions 2003; 31 (6): 1441-1444.
Marrs KA. The Functions and Regulations of Glutathione S-Transferases in Plants. Annu Rev Plant Physiol Plant Mol Biol 1996; 47: 127-158.
Schafer FQ, Buettner GR. Redox environment of the cell as viewed through the redox state of the glutathione disulfide/glutathione couple. Free Radic Biol Med 2001; 30 (11): 1191-1212.
Agnani D, Camacho-Vanegas O, Camacho C, Lele S, Odunsi K, Cohen S, Dottino P, Martignetti. Decreased levels of serum glutathione peroxidase 3 are associated with papillary serous ovarian cancer and disease progression. J Ovarian Res 2011; 4:18.
Adami HO, Hsieh CC, Lambe M, Trichopoulos D, Leon D, Persson I, Ekborn A, Janson PO. Parity, age at first childbirth, and risk of ovarian cancer. a population-based study in Sweden Lancet 1994; 344 (8932): 1250-1254.
Kurman RJ, Trimble CL. The behavior of serous tumors of low malignant potential: are they ever malignant? Int J Gynecol Pathol 1993; 12 (2): 120-127.
Evans P, Lyras L, Halliwell B. Measurement of protein carbonyls in human brain tissue. Methods Enzymol 1999; 300: 145-156.
Kalghatgi S, Spina CS, Costello JC, Liesa M, Morones-Ramirez JR, Slomovic S, Molina A, Shirihai OS, Collins JJ. Bactericidal antibiotics induce mitochondrial dysfunction and oxidative damage in Mammalian cells. Sci Transl Med 2013; 5 (192): 192ra85.
Mesquita CS, Oliveira R, Bento F, Geraldo D, Rodrigues JV, Marcos JC. Simplified 2,4-dinitrophenylhydrazine spectrophotometric assay for quantification of carbonyls in oxidized proteins. Anal Biochem 2014; 458: 69-71.
Chevion M, Berenshtein E, Stadtman ER. Human studies related to protein oxidation: protein carbonyl content as a marker of damage. Free Radical Research 2000; 33: S99-108.
Kurman RJ, Shih I. The origin and pathogenesis of epithelial ovarian cancer: a proposed unifying theory. Am J Surg Pathol 2010; 34 (3): 433-443.
Waris G, Ahsan H. Reactive oxygen species: role in the development of cancer and various chronic conditions. J Carcinog 2006; 5: 14.
Apel K, Hirt H. Reactive oxygen species: metabolism, oxidative stress, and signal transduction. Annu Rev Plant Biol 2004; 55: 373-399.
Costa A, Scholer-Dahirel A, Mechta-Grigoriou F. The role of reactive oxygen species and metabolism on cancer cells and their microenvironment. Sem in Cancer Biol 2014; 25: 23-32.
Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11 (2): 85-95.
Berlett BS, Stadtman ER. Protein oxidation in aging, disease, and oxidative stress. J Biol Chem 1997; 272 (33): 20313-20316.
Takahashi R, Goto S. Alteration of aminoacyl-tRNA synthetase with age: heat-labilization of the enzyme by oxidative damage. Arch Biochem Biophys 1990; 277 (2): 228-233.
Fathalla MF. Incessant ovulation--a factor in ovarian neoplasia? Lancet 1971; 2 (7716): 163.
Nathan FM, Singh VA, Dhanoa A, Palanisamy UD. Oxidative stress and antioxidant status in primary bone and soft tissue sarcoma. BMC Cancer 2011; 11: 382.
Harman D. Free radical theory of aging. Triangle 1973; 12 (4): 153-158.
Chole RH, Patil RN, Basak A, Palandurkar K, Bhowate R. Estimation of serum malondialdehyde in oral cancer and precancer and its association with healthy individuals, gender, alcohol, and tobacco abuse. J Cancer Res Ther 2010; 6 (4): 487-491.
Gönenç A, Özkan Y, Torun M, Şimşek B. Plasma malondialdehyde (MDA) levels in breast and lung cancer patients. J Clin Pharm Ther 2001; 26 (2): 141-144.
Burkholz KJ, Wood BP, Zuppan C. Best cases from the AFIP: Borderline papillary serous tumor of the right ovary. Radiographics 2005; 25 (6): 1689-1692.
Moorman PG, Palmieri RT, Akushevich L, Berchuck A, Schildkraut JM. Ovarian cancer risk factors in African-American and white women. Am J Epidemiol 2009; 170 (5): 598-606.