Effect of chemotherapy on serum nitric oxide levels in advanced stage breast cancer patients

Charushila Y. Kadam, Subodhini A. Abhang


Background: The role of nitric oxide is still unclear in advanced breast cancer patients undergoing adjuvant chemotherapy. This study was undertaken to investigate the effect of chemotherapy on serum nitric oxide levels in advanced stage breast cancer patients.

Methods: In this observational study, clinically and histopathologically proven sixty female patients with advanced stage breast cancer were included. According to Tumor-Node-Metastasis (TNM) classification, patients were further grouped as stage III and stage IV. Thirty healthy and age-matched female controls were selected for comparison. Blood was collected from healthy controls and from breast cancer patients after surgery prior to chemotherapy and after three weeks of administration of first adjuvant chemotherapy cycle. Serum nitric oxide levels were measured by spectrophotometric method.

Results: Significantly higher concentrations of serum nitric oxide were observed in breast cancer patients before chemotherapy in stage III (p<0.0001) and stage IV (p<0.0001) of the disease as compare to concentrations in healthy controls. The serum levels of nitric oxide were significantly decreased in stage III as well as stage IV of breast cancer patients after three weeks of receiving first adjuvant chemotherapy cycle as compare to levels before chemotherapy (p<0.0001), however serum nitric oxide levels were higher in stage III (p=0.0036) and stage IV (p<0.0001) of the disease as compare to healthy controls.

Conclusions: Chemotherapy drug administration causes decrease in serum nitric oxide levels in advanced stages of breast cancer patients. Monitoring serum nitric oxide levels could be used to predict patients’ response to chemotherapy treatment in breast cancer.


Breast cancer, Chemotherapy, Nitric oxide, Oxidative stress

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Sparano J, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008; 358(16):1663-71.

Elmore S. Apoptosis: a review of programmed cell death. Toxicologic pathology. 2007;35(4):495-516.

Lowe SW. Lin, a W. Apoptosis in cancer. Carcinogenesis. 2000;21(3):485-95.

Panis C, Herrera AC, Victorino VJ, Campos FC, Freitas LF, De Rossi T, et al. Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. Breast Cancer Res Treat. 2012;133(1):89-97.

Mates JM, Sanchez-Jimenez FM. Role of reactive oxygen species in apoptosis: implications for cancer therapy. Int J Biochem Cell Biol. 2000;32(2):157-70.

Kim YM, Bombeck CA, Billiar TR. Nitric oxide as a bifunctional regulator of apoptosis. Circulat Res. 1999;84(3):253-6.

Kim YM, Kim TH, Seol DW, Talanian RV, Billiar TR. Nitric Oxide Suppression of Apoptosis Occurs in Association with an Inhibition of Bcl-2 Cleavage and Cytochrome Release. J Biol Chem. 1998;273(47):31437-41.

Glynn SA, Boersma BJ, Dorsey TH, Yi M, Yfantis HG, Ridnour LA, et al. Increased NOS2 predicts poor survival in estrogen receptor-negative breast cancer patients. J Clin Invest. 2010;120(11):3843-54.

Öktem G, Bilir A, Selvi N, Yurtseven ME, Vatansever S, Ates U, et al. Chemotherapy influences inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) activity on 3D breast cancer cell line. Oncology Res Featuring Preclin Clin Cancer Therap. 2006;16(4):195-203.

Jin Z, Wang W, Jiang N, Zhang L, Li Y, Xu X, et al. Clinical implications of iNOS levels in triple-negative breast cancer responding to neoadjuvant chemotherapy. PloS One. 2015;10(7):0130286.

Cortas NK, Wakid NW. Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem. 1990 Aug 1;36(8):1440-3.

Konukoglu D, Turhan MS, Celik V, Turna H. Relation of serum vascular endothelial growth factor as an angiogenesis biomarker with nitric oxide and urokinase-type plasminogen activator in breast cancer patients. Ind J Med Res. 2007;125(6):747-51.

Günel N, Coskun U, Sancak B, Hasdemir O, Sare M, Bayram O, et al. Prognostic value of serum IL-18 and nitric oxide activity in breast cancer patients at operable stage. Am J Clin Oncol. 2003;26(4):416-21.

Kilic S, Bayraktar N, Beytur A, Ergin H, Bayraktar M, EǦRI M. Can the levels of nitric oxide in the urine, serum and tumor tissue be putative markers for bladder cancer?. Int J Urol. 2006;13(8):1079-85.

Abdel-Salam OM, Youness ER, Hafez HF. The antioxidant status of the plasma in patients with breast cancer undergoing chemotherapy. Open J Mol Integrat Physiol. 2011;1(03):29.

Amin KA, Mohamed BM, El-Wakil MA, Ibrahem SO. Impact of breast cancer and combination chemotherapy on oxidative stress, hepatic and cardiac markers. J Breast Cancer. 2012;15(3):306-12.

Sim SH, Ahn YO, Yoon J, Kim TM, Lee SH, Kim DW, et al. Influence of chemotherapy on nitric oxide synthase, indole‐amine‐2, 3‐dioxygenase and CD124 expression in granulocytes and monocytes of non‐small cell lung cancer. Cancer Sci. 2012;103(2):155-60.

Garner AP, Paine MJ, Rodriguez-Crespo I, Chinje EC, De Montellano PO, Stratford IJ, et al. Nitric oxide synthases catalyze the activation of redox cycling and bioreductive anticancer agents. Cancer Res. 1999;59(8):1929-34.

Vásquez-Vivar J, Martasek P, Hogg N, Masters BS, Pritchard KA, Kalyanaraman B. Endothelial nitric oxide synthase-dependent superoxide generation from adriamycin. Biochem. 1997;36(38):11293-7.

Luo D, Vincent SR. Inhibition of nitric oxide synthase by antineoplastic anthracyclines. Biochem Pharmacol. 1994;47(11):2111-2.

Jung ID, Yang SY, Park CG, Lee KB, Kim JS, Lee SY, et al. 5-Fluorouracil inhibits nitric oxide production through the inactivation of IκB kinase in stomach cancer cells. Biochem Pharmacol. 2002;64(10):1439-45.

Loeffler M, Krüger JA, Reisfeld RA. Immunostimulatory effects of low-dose cyclophosphamide are controlled by inducible nitric oxide synthase. Cancer Res. 2005;65(12):5027-30.

Miljkovic D, Cvetkovic I, Sajic M, Vuckovic O, Harhaji L, Markovic M, et al. 5-Aza-2′-deoxycytidine and paclitaxel inhibit inducible nitric oxide synthase activation in fibrosarcoma cells. Europ J Pharmacol. 2004;485(1-3):81-8.