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Anti-Cancer Agents in Medicinal Chemistry

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ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

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Research Article

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*

Volume 22, Issue 7, 2022

Published on: 23 June, 2021

Page: [1397 - 1406] Pages: 10

DOI: 10.2174/1871520621666210623094526

Price: $65

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.

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.

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.

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.

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.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2018. CA Cancer J. Clin., 2018, 68(1), 7-30.
[http://dx.doi.org/10.3322/caac.21442] [PMID: 29313949]
[2]
Hawsawi, Y.M.; Al-Zahrani, F.; Mavromatis, C.H.; Baghdadi, M.A.; Saggu, S.; Oyouni, A.A.A. Stem cell applications for treatment of cancer and autoimmune diseases: Its promises, obstacles, and future perspectives. Technol. Cancer Res. Treat., 2018, 17, 1533033818806910.
[http://dx.doi.org/10.1177/1533033818806910] [PMID: 30343639]
[3]
Baquiran, D.C. Lippincott’s cancer chemotherapy handbook, 2nd; Lippincott: Philadelphia, 2001.
[4]
Lee, S.H.; Kang, W.K.; Park, J.; Kim, H.Y.; Kim, J.H.; Lee, S.I.; Park, J.O.; Kim, K.; Jung, C.W.; Park, Y.S.; Im, Y.H.; Lee, M.H.; Park, K. Combination chemotherapy with epirubicin, docetaxel and cisplatin (EDP) in metastatic or recurrent, unresectable gastric cancer. Br. J. Cancer, 2004, 91(1), 18-22.
[http://dx.doi.org/10.1038/sj.bjc.6601891] [PMID: 15188010]
[5]
Komarova, N.L.; Wodarz, D. Drug resistance in cancer: Principles of emergence and prevention. Proc. Natl. Acad. Sci. USA, 2005, 102(27), 9714-9719.
[http://dx.doi.org/10.1073/pnas.0501870102] [PMID: 15980154]
[6]
Igney, F.H.; Krammer, P.H. Death and anti-death: Tumour resistance to apoptosis. Nat. Rev. Cancer, 2002, 2(4), 277-288.
[http://dx.doi.org/10.1038/nrc776] [PMID: 12001989]
[7]
Kotb, A.; El Fakih, R.; Hanbali, A.; Hawsawi, Y.; Alfraih, F.; Hashmi, S.; Aljurf, M. Philadelphia-like acute lymphoblastic leukemia: Diagnostic dilemma and management perspectives. Exp. Hematol., 2018, 67, 1-9.
[http://dx.doi.org/10.1016/j.exphem.2018.07.007] [PMID: 30075295]
[8]
Luqmani, Y.A. Mechanisms of drug resistance in cancer chemotherapy. Med. Princ. Pract., 2005, 14(Suppl. 1), 35-48.
[http://dx.doi.org/10.1159/000086183] [PMID: 16103712]
[9]
Hawsawi, Y.; Humphries, M.P.; Wright, A.; Berwick, A.; Shires, M.; Al-Kharobi, H.; El-Gendy, R.; Jove, M.; Twelves, C.; Speirs, V.; Beattie, J. Deregulation of IGF-binding proteins -2 and -5 contributes to the development of endocrine resistant breast cancer in vitro. Oncotarget, 2016, 7(22), 32129-32143.
[http://dx.doi.org/10.18632/oncotarget.8534] [PMID: 27050076]
[10]
Jordan, V.C.; Fan, P.; Abderrahman, B.; Maximov, P.Y.; Hawsawi, Y.M.; Bhattacharya, P.; Pokharel, N. Sex steroid induced apoptosis as a rational strategy to treat anti-hormone resistant breast and prostate cancer. Discov. Med., 2016, 21(117), 411-427.
[PMID: 27355337]
[11]
Maximov, P.Y.; Abderrahman, B.; Curpan, R.F.; Hawsawi, Y.M.; Fan, P.; Jordan, V.C. A unifying biology of sex steroid-induced apoptosis in prostate and breast cancers. Endocr. Relat. Cancer, 2018, 25(2), R83-R113.
[http://dx.doi.org/10.1530/ERC-17-0416] [PMID: 29162647]
[12]
Maximov, P.Y.; Abderrahman, B.; Hawsawi, Y.M.; Chen, Y.; Foulds, C.E.; Jain, A.; Malovannaya, A.; Fan, P.; Curpan, R.F.; Han, R.; Fanning, S.W.; Broom, B.M.; Quintana Rincon, D.M.; Greenland, J.A.; Greene, G.L.; Jordan, V.C. The structure-function relationship of angular estrogens and estrogen receptor alpha to initiate estrogen-induced apoptosis in breast cancer cells. Mol. Pharmacol., 2020, 98(1), 24-37.
[http://dx.doi.org/10.1124/mol.120.119776] [PMID: 32362585]
[13]
Nitta, A.; Chung, Y.S.; Nakata, B.; Yashiro, M.; Onoda, N.; Maeda, K.; Sawada, T.; Sowa, M. Establishment of a cisplatin-resistant gastric carcinoma cell line OCUM-2M/DDP. Cancer Chemother. Pharmacol., 1997, 40(1), 94-97.
[http://dx.doi.org/10.1007/s002800050632] [PMID: 9137537]
[14]
Pabla, N.; Dong, Z. Cisplatin nephrotoxicity: Mechanisms and renoprotective strategies. Kidney Int., 2008, 73(9), 994-1007.
[http://dx.doi.org/10.1038/sj.ki.5002786] [PMID: 18272962]
[15]
Li, J.; Feng, Q.; Kim, J.M.; Schneiderman, D.; Liston, P.; Li, M.; Vanderhyden, B.; Faught, W.; Fung, M.F.; Senterman, M.; Korneluk, R.G.; Tsang, B.K. Human ovarian cancer and cisplatin resistance: Possible role of inhibitor of apoptosis proteins. Endocrinology, 2001, 142(1), 370-380.
[http://dx.doi.org/10.1210/endo.142.1.7897] [PMID: 11145600]
[16]
Sledge, G.W., Jr Cisplatin and platinum analogues in breast cancer. Semin. Oncol., 1992, 19(1)(Suppl. 2), 78-82.
[PMID: 1411630]
[17]
Wang, D.; Lippard, S.J. Cellular processing of platinum anticancer drugs. Nat. Rev. Drug Discov., 2005, 4(4), 307-320.
[http://dx.doi.org/10.1038/nrd1691] [PMID: 15789122]
[18]
Kelland, L. The resurgence of platinum-based cancer chemotherapy. Nat. Rev. Cancer, 2007, 7(8), 573-584.
[http://dx.doi.org/10.1038/nrc2167] [PMID: 17625587]
[19]
Mellor, H.R.; Callaghan, R. Resistance to chemotherapy in cancer: A complex and integrated cellular response. Pharmacology, 2008, 81(4), 275-300.
[http://dx.doi.org/10.1159/000115967] [PMID: 18259091]
[20]
Negoro, K.; Yamano, Y.; Fushimi, K.; Saito, K.; Nakatani, K.; Shiiba, M.; Yokoe, H.; Bukawa, H.; Uzawa, K.; Wada, T.; Tanzawa, H.; Fujita, S. Establishment and characterization of a cisplatin-resistant cell line, KB-R, derived from oral carcinoma cell line, KB. Int. J. Oncol., 2007, 30(6), 1325-1332.
[http://dx.doi.org/10.3892/ijo.30.6.1325] [PMID: 17487352]
[21]
Jekunen, A.P.; Christen, R.D.; Shalinsky, D.R.; Howell, S.B. Synergistic interaction between cisplatin and taxol in human ovarian carcinoma cells in vitro. Br. J. Cancer, 1994, 69(2), 299-306.
[http://dx.doi.org/10.1038/bjc.1994.55] [PMID: 7905279]
[22]
Judson, P.L.; Watson, J.M.; Gehrig, P.A.; Fowler, W.C., Jr; Haskill, J.S. Cisplatin inhibits paclitaxel-induced apoptosis in cisplatin-resistant ovarian cancer cell lines: Possible explanation for failure of combination therapy. Cancer Res., 1999, 59(10), 2425-2432.
[PMID: 10344753]
[23]
Mikhailov, V.; Mikhailova, M.; Pulkrabek, D.J.; Dong, Z.; Venkatachalam, M.A.; Saikumar, P. Bcl-2 prevents Bax oligomerization in the mitochondrial outer membrane. J. Biol. Chem., 2001, 276(21), 18361-18374.
[http://dx.doi.org/10.1074/jbc.M100655200] [PMID: 11279112]
[24]
Hersey, P.; Zhang, X.D. Overcoming resistance of cancer cells to apoptosis. J. Cell. Physiol., 2003, 196(1), 9-18.
[http://dx.doi.org/10.1002/jcp.10256] [PMID: 12767037]
[25]
Alzahrani, F.A.; Ahmed, F.; Sharma, M.; Rehan, M.; Mahfuz, M.; Baeshen, M.N.; Hawsawi, Y.; Almatrafi, A.; Alsagaby, S.A.; Kamal, M.A.; Warsi, M.K.; Choudhry, H.; Jamal, M.S. Investigating the pathogenic SNPs in BLM helicase and their biological consequences by computational approach. Sci. Rep., 2020, 10(1), 12377.
[http://dx.doi.org/10.1038/s41598-020-69033-8] [PMID: 32704157]
[26]
Pecorino, L. Molecular biology of cancer: Mechanisms, targets, and therapeutics; Oxford University Press: Oxford, New York, 2008, p. 243.
[27]
Schulz, W.A. Molecular biology of human cancers: An advanced student’s textbook; Springer: Dordrecht, The Netherlands; Norwell, MA, 2007, p. 508.
[28]
Lowe, S.W.; Lin, A.W. Apoptosis in cancer. Carcinogenesis, 2000, 21(3), 485-495.
[http://dx.doi.org/10.1093/carcin/21.3.485] [PMID: 10688869]
[29]
Singh, N. Apoptosis in health and disease and modulation of apoptosis for therapy: An overview. Indian J. Clin. Biochem., 2007, 22(2), 6-16.
[http://dx.doi.org/10.1007/BF02913307] [PMID: 23105676]
[30]
Kim, E.H.; Kim, S.U.; Choi, K.S. Rottlerin sensitizes glioma cells to TRAIL-induced apoptosis by inhibition of Cdc2 and the subsequent downregulation of survivin and XIAP. Oncogene, 2005, 24(5), 838-849.
[http://dx.doi.org/10.1038/sj.onc.1208241] [PMID: 15531913]
[31]
Schmalz, P.G.; Shen, M.J.; Park, J.K. Treatment resistance mechanisms of malignant glioma tumor stem cells. Cancers (Basel), 2011, 3(1), 621-635.
[http://dx.doi.org/10.3390/cancers3010621] [PMID: 24212632]
[32]
Bruckdorfer, R. The basics about nitric oxide. Mol. Aspects Med., 2005, 26(1-2), 3-31.
[http://dx.doi.org/10.1016/j.mam.2004.09.002] [PMID: 15722113]
[33]
Olson, S.Y.; Garbán, H.J. Regulation of apoptosis-related genes by nitric oxide in cancer. Nitric Oxide, 2008, 19(2), 170-176.
[http://dx.doi.org/10.1016/j.niox.2008.04.005] [PMID: 18460349]
[34]
Ichinose, F.; Roberts, J.D., Jr; Zapol, W.M. Inhaled nitric oxide: A selective pulmonary vasodilator: Current uses and therapeutic potential. Circulation, 2004, 109(25), 3106-3111.
[http://dx.doi.org/10.1161/01.CIR.0000134595.80170.62] [PMID: 15226227]
[35]
Lala, P.K.; Chakraborty, C. Role of nitric oxide in carcinogenesis and tumour progression. Lancet Oncol., 2001, 2(3), 149-156.
[http://dx.doi.org/10.1016/S1470-2045(00)00256-4] [PMID: 11902565]
[36]
Cailleau, R.; Young, R.; Olivé, M.; Reeves, W.J., Jr Breast tumor cell lines from pleural effusions. J. Natl. Cancer Inst., 1974, 53(3), 661-674.
[http://dx.doi.org/10.1093/jnci/53.3.661] [PMID: 4412247]
[37]
Giard, D.J.; Aaronson, S.A.; Todaro, G.J.; Arnstein, P.; Kersey, J.H.; Dosik, H.; Parks, W.P. In vitro cultivation of human tumors: Establishment of cell lines derived from a series of solid tumors. J. Natl. Cancer Inst., 1973, 51(5), 1417-1423.
[http://dx.doi.org/10.1093/jnci/51.5.1417] [PMID: 4357758]
[38]
Barbone, D.; Ryan, J.A.; Kolhatkar, N.; Chacko, A.D.; Jablons, D.M.; Sugarbaker, D.J.; Bueno, R.; Letai, A.G.; Coussens, L.M.; Fennell, D.A.; Broaddus, V.C. The Bcl-2 repertoire of mesothelioma spheroids underlies acquired apoptotic multicellular resistance. Cell Death Dis., 2011, 2, e174.
[http://dx.doi.org/10.1038/cddis.2011.58] [PMID: 21697949]
[39]
Shi, L.; Chen, J.; Yang, J.; Pan, T.; Zhang, S.; Wang, Z. MiR-21 protected human glioblastoma U87MG cells from chemotherapeutic drug temozolomide induced apoptosis by decreasing Bax/Bcl-2 ratio and caspase-3 activity. Brain Res., 2010, 1352, 255-264.
[http://dx.doi.org/10.1016/j.brainres.2010.07.009] [PMID: 20633539]
[40]
Xu, W.; Liu, L.Z.; Loizidou, M.; Ahmed, M.; Charles, I.G. The role of nitric oxide in cancer. Cell Res., 2002, 12(5-6), 311-320.
[http://dx.doi.org/10.1038/sj.cr.7290133] [PMID: 12528889]
[41]
Koh, E.; Noh, S.H.; Lee, Y.D.; Lee, H.Y.; Han, J.W.; Lee, H.W.; Hong, S. Differential expression of nitric oxide synthase in human stomach cancer. Cancer Lett., 1999, 146(2), 173-180.
[http://dx.doi.org/10.1016/S0304-3835(99)00265-7] [PMID: 10656623]
[42]
Vannini, F.; Kashfi, K.; Nath, N. The dual role of iNOS in cancer. Redox Biol., 2015, 6, 334-343.
[http://dx.doi.org/10.1016/j.redox.2015.08.009] [PMID: 26335399]
[43]
Li, C.Q.; Wogan, G.N. Nitric oxide as a modulator of apoptosis. Cancer Lett., 2005, 226(1), 1-15.
[http://dx.doi.org/10.1016/j.canlet.2004.10.021] [PMID: 16004928]
[44]
Brüne, B. Nitric oxide: NO apoptosis or turning it ON? Cell Death Differ., 2003, 10(8), 864-869.
[http://dx.doi.org/10.1038/sj.cdd.4401261] [PMID: 12867993]
[45]
Choi, B.M.; Pae, H.O.; Jang, S.I.; Kim, Y.M.; Chung, H.T. Nitric oxide as a pro-apoptotic as well as anti-apoptotic modulator. J. Biochem. Mol. Biol., 2002, 35(1), 116-126.
[PMID: 16248976]
[46]
Kolb, J.P. Mechanisms involved in the pro- and anti-apoptotic role of NO in human leukemia. Leukemia, 2000, 14(9), 1685-1694.
[http://dx.doi.org/10.1038/sj.leu.2401896] [PMID: 10995017]
[47]
Blaise, G.A.; Gauvin, D.; Gangal, M.; Authier, S. Nitric oxide, cell signaling and cell death. Toxicology, 2005, 208(2), 177-192.
[http://dx.doi.org/10.1016/j.tox.2004.11.032] [PMID: 15691583]
[48]
Rudkowski, J.C.; Barreiro, E.; Harfouche, R.; Goldberg, P.; Kishta, O.; D’Orleans-Juste, P.; Labonte, J.; Lesur, O.; Hussain, S.N. Roles of iNOS and nNOS in sepsis-induced pulmonary apoptosis. Am. J. Physiol. Lung Cell. Mol. Physiol., 2004, 286(4), L793-L800.
[http://dx.doi.org/10.1152/ajplung.00266.2003] [PMID: 14660484]
[49]
Fukumura, D.; Kashiwagi, S.; Jain, R.K. The role of nitric oxide in tumour progression. Nat. Rev. Cancer, 2006, 6(7), 521-534.
[http://dx.doi.org/10.1038/nrc1910] [PMID: 16794635]
[50]
Hwang, S.Y.; Yoo, B.C.; Jung, J.W.; Oh, E.S.; Hwang, J.S.; Shin, J.A.; Kim, S.Y.; Cha, S.H.; Han, I.O. Induction of glioma apoptosis by microglia-secreted molecules: The role of nitric oxide and cathepsin B. Biochim. Biophys. Acta, 2009, 1793(11), 1656-1668.
[http://dx.doi.org/10.1016/j.bbamcr.2009.08.011] [PMID: 19748528]
[51]
Broholm, H.; Rubin, I.; Kruse, A.; Braendstrup, O.; Schmidt, K.; Skriver, E.B.; Lauritzen, M. Nitric oxide synthase expression and enzymatic activity in human brain tumors. Clin. Neuropathol., 2003, 22(6), 273-281.
[PMID: 14672505]
[52]
Loibl, S.; Buck, A.; Strank, C.; von Minckwitz, G.; Roller, M.; Sinn, H.P.; Schini-Kerth, V.; Solbach, C.; Strebhardt, K.; Kaufmann, M. The role of early expression of inducible nitric oxide synthase in human breast cancer. Eur. J. Cancer, 2005, 41(2), 265-271.
[http://dx.doi.org/10.1016/j.ejca.2004.07.010] [PMID: 15661552]
[53]
Tschugguel, W.; Schneeberger, C.; Unfried, G.; Czerwenka, K.; Weninger, W.; Mildner, M.; Gruber, D.M.; Sator, M.O.; Waldhör, T.; Huber, J.C. Expression of inducible nitric oxide synthase in human breast cancer depends on tumor grade. Breast Cancer Res. Treat., 1999, 56(2), 145-151.
[http://dx.doi.org/10.1023/A:1006288526311] [PMID: 10573107]
[54]
Vakkala, M.; Paakko, P.; Soini, Y. eNOS expression is associated with the estrogen and progesterone receptor status in invasive breast carcinoma. Int. J. Oncol., 2000, 17(4), 667-671.
[http://dx.doi.org/10.3892/ijo.17.4.667] [PMID: 10995876]
[55]
Ying, L.; Hofseth, L.J. An emerging role for endothelial nitric oxide synthase in chronic inflammation and cancer. Cancer Res., 2007, 67(4), 1407-1410.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2149] [PMID: 17308075]

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