Nitric Oxide Synthase Potentiates the Resistance of Cancer Cell Lines to Anticancer Chemotherapeutics

Author(s):

Ibrahim Barnawi, Yousef M. Hawsawi, Philip Dash, Atif Abdulwahab A. Oyouni, Syed Khalid Mustafa, Nahed A. Hussien, Osama Al-Amer, Suliman Alomar* and Lamjed Mansour*   Pages 1397 - 1406 ( 10 )

Abstract:

Background: Despite the advancement in the fields of medical science and molecular biology, cancer is still the leading cause of death worldwide. Chemotherapy is a choice for treatment; however, the acquisition of chemoresistance is a major impediment for cancer management. Many mechanisms have been postulated regarding the acquisition of chemo-resistance in breast cancer and the impact on cellular signalling and the induction of apoptosis in tumour cells. The mechanism of the apoptotic mutation ofp53 and bcl-2 proteins is commonly associated with increased resistance to apoptosis and, therein, to chemotherapy. <P> Objectives: The current study was aimed to investigate A172 and MDA-MB-231 cancer cells’sensitivity against chemotherapeutic drugs, including cisplatin, doxorubicin, and paclitaxel with different doses. Moreover, it estimates resistance of cancer cells by evaluating Nitric Oxide Synthase (NOS) expression and evaluate its correlation with the expression profile proteins of the apoptosis regulating Bcl-2 family. <P> Methods: Dose-dependent sensitivity to cisplatin, doxorubicin or paclitaxel was evaluated on spheroid cultured A172 and MDA-MB-231 cells lines, was measured by time-lapse microscopy over a 72h period. Expressions of two Nitric Oxide (NO) synthases isoforms (iNOS, eNOS), anti-apoptotic (Bcl-2, phospho-Bcl-2, Mcl-1, and Bcl-xL) and proapoptotic (BID, Bim, Bok, Bad, Puma, and Bax) were evaluated by Western blot. The effect of NO modulation on antiand pro-apoptotic molecule expression was also studied using Western blot. <P> Results: A172 cells show more resistance to chemotherapy drugs than MDA-MB-231 cancer cells, therefore, they need higher doses for apoptosis. Resistance of gliomas might be returned to higher significant expression of endothelial eNOS expression. It was clear that there is not a significant effect of NO modulation on the expression of pro- andantiapoptotic proteins on both cell lines. <P> Conclusion: The present work provides a putative mechanism for the acquisition of drug resistance in breast cancer and glioma, which might be significant for clinical outcomes.

Keywords:

Nitric oxide, anti-apoptotic proteins, pro-apoptotic proteins, breast cancer, glioblastoma, chemotherapy.

Affiliation:

Department of Biology, Faculty of Sciences, University of Taiba, Madina, Research Center, King Faisal Specialist Hospital and Research Center, Jeddah 21499, P.O. Box 40047, University of Reading Faculty of Life Sciences, school of science, Reading, Reading, Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Department of Biology, Faculty of Sciences, University of Tabuk, Tabuk, Department of Zoology, Faculty of Science, Cairo University, Giza 12613, Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk, Doping Research Chair, Department of Zoology, College of Science, King Saud University PO. Box: 2455, Riyadh, 11451, Doping Research Chair, Department of Zoology, College of Science, King Saud University PO. Box: 2455, Riyadh, 11451

Graphical Abstract:

Read Full-Text article