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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Dian Dayer*, Mohammad R. Tabandeh and Majid Kazemi

DOI: 10.2174/1871520620666200612144124

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The Radio-Sensitizing Effect of Pharmacological Concentration of Ascorbic Acid on Human Pancreatic Cancer Cells

Page: [1927 - 1932] Pages: 6

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Abstract

Background: Previous studies reported the inevitable destructive effects of radiotherapy on normal adjacent cells. Ascorbic Acid (AA) has been proposed as an effective anti-cancer agent with no obvious effects on normal cells.

Objective: The effects of Ascorbic acid in combination with radiotherapy on human pancreatic carcinoma cell line were studied.

Methods: The human pancreatic cancer cells were cultured and divided into four groups: control group (A) without any treatment, group B that received 2Gy radiotherapy alone, group C that was treated with 4mM AA alone, and group D that was co-treated with AA and radiotherapy. Cell viability, DNA fragmentation, expression of apoptotic genes, and Reactive Oxygen Species (ROS) production were determined in treated cells.

Results: There was a noticeable decrease in cell viability after treatment with AA (and/or) radiotherapy. All treated groups showed elevated ROS production, Bax/Bcl2 expression, DNA fragmentation, and cytotoxycity compared with the control group. Cells under combination therapy showed the most cytotoxicity.

Conclusion: The results suggest that AA at a dose of 4mmol/l may be used as an effective radio-sensitizing agent in pancreatic cancer cell line.

Keywords: Ascorbic acid, radiotherapy, pancreatic cancer, reactive oxygen species, Bax expression, Bcl2 expression, DNA fragmentation.

Graphical Abstract

[1]
Ilic, M.; Ilic, I. Epidemiology of pancreatic cancer. World J. Gastroenterol., 2016, 22(44), 9694-9705.
[http://dx.doi.org/10.3748/wjg.v22.i44.9694 ] [PMID: 27956793]
[2]
Farhood, B.; Geraily, G.; Alizadeh, A. Incidence and mortality of various cancers in Iran and compare to other countries: A review article. Iran. J. Public Health, 2018, 47(3), 309-316.
[PMID: 29845017]
[3]
Lee, S.H.; Kang, C.M.; Kim, H.; Hwang, H.K.; Song, S.Y.; Seong, J.; Kim, M.J.; Lee, W.J. Pathological complete remission of pancreatic cancer following neoadjuvant chemoradiation therapy; not the end of battles. Medicine (Baltimore), 2015, 94(52),e2168.
[http://dx.doi.org/10.1097/MD.0000000000002168] [PMID: 26717359]
[4]
Hubenak, J.R.; Zhang, Q.; Branch, C.D.; Kronowitz, S.J.; Kronowitz, S.J. Mechanisms of injury to normal tissue after radiotherapy: A review. Plast. Reconstr. Surg., 2014, 133(1), 49e-56e.
[http://dx.doi.org/10.1097/01.prs.0000440818.23647.0b ] [PMID: 24374687]
[5]
Matsui, H.; Hazama, S.; Shindo, Y.; Nagano, H. Combination treatment of advanced pancreatic cancer using novel vaccine and traditional therapies. Expert Rev. Anticancer Ther., 2018, 18(12), 1205-1217.
[http://dx.doi.org/10.1080/14737140.2018.1531707] [PMID: 30295097]
[6]
Carr, A.C.; Cook, J. Intravenous vitamin C for cancer therapy - identifying the current gaps in our knowledge. Front. Physiol., 2018, 9, 1182-1198.
[http://dx.doi.org/10.3389/fphys.2018.01182 ] [PMID: 30190680]
[7]
Singh, K.; Bhori, M.; Kasu, Y.A.; Bhat, G.; Marar, T. Antioxidants as precision weapons in war against cancer chemotherapy induced toxicity - Exploring the armoury of obscurity. Saudi Pharm. J., 2018, 26(2), 177-190.
[http://dx.doi.org/10.1016/j.jsps.2017.12.013 ] [PMID: 30166914]
[8]
Khan, F.M.; Gibbons, J.P. The physics of radiation therapy, 3rd Ed.;; Lippincott Williams & Wilkins: USA, 2003.
[9]
Du, J.; Martin, S.M.; Levine, M.; Wagner, B.A.; Buettner, G.R.; Wang, S.H.; Taghiyev, A.F.; Du, C.; Knudson, C.M.; Cullen, J.J. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin. Cancer Res., 2010, 16(2), 509-520.
[http://dx.doi.org/10.1158/1078-0432.CCR-09-1713 ] [PMID: 20068072]
[10]
Cieslak, J.A.; Sibenaller, Z.A.; Susan, A.; Walsh, S.A. Boles, Ponto, L.L.; Du, J. Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an index of cell proliferation after pharmacological ascorbate-based therapy. Radiat. Res., 2016, 185, 31-38.
[11]
Grasso, C.; Fabre, M.S.; Collis, S.V.; Castro, M.L.; Field, C.S.; Schleich, N.; McConnell, M.J.; Herst, P.M. Pharmacological doses of daily ascorbate protect tumors from radiation damage after a single dose of radiation in an intracranial mouse glioma model. Front. Oncol., 2014, 4, 356.
[http://dx.doi.org/10.3389/fonc.2014.00356 ] [PMID: 25566497]
[12]
Dayer, D.; Tabar, M.H.; Moghimipour, E.; Tabandeh, M.R.; Ghadiri, A.A.; Bakhshi, E.A.; Orazizadeh, M.; Ghafari, M.A. Sonic hedgehog pathway suppression and reactivation accelerates differentiation of rat adipose-derived mesenchymal stromal cells toward insulin-producing cells. Cytotherapy, 2017, 19(8), 937-946.
[http://dx.doi.org/10.1016/j.jcyt.2017.05.003 ] [PMID: 28647274]
[13]
Chen, Q.; Espey, M.G.; Krishna, M.C.; Mitchell, J.B.; Corpe, C.P.; Buettner, G.R.; Shacter, E.; Levine, M. Pharmacologic ascorbic acid concentrations selectively kill cancer cells: Action as a pro-drug to deliver hydrogen peroxide to tissues. Proc. Natl. Acad. Sci. USA, 2005, 102(38), 13604-13609.
[http://dx.doi.org/10.1073/pnas.0506390102 ] [PMID: 16157892]
[14]
Azimian, H.; Dayyani, M.; Toossi, M.T.B.; Mahmoudi, M. Bax/Bcl-2 expression ratio in prediction of response to breast cancer radiotherapy. Iran. J. Basic Med. Sci., 2018, 21(3), 325-332.
[PMID: 29511500]
[15]
Sant, D.W.; Mustafi, S.; Gustafson, C.B.; Chen, J.; Slingerland, J.M.; Wang, G. Vitamin C promotes apoptosis in breast cancer cells by increasing TRAIL expression. Sci. Rep., 2018, 8(1), 5306-5317.
[http://dx.doi.org/10.1038/s41598-018-23714-7 ] [PMID: 29593282]
[16]
Matassov, D.; Kagan, T.; Leblanc, J.; Sikorska, M.; Zakeri, Z. Measurement of apoptosis by DNA fragmentation. Methods Mol. Biol., 2004, 282, 1-17.
[PMID: 15105553]
[17]
Tabandeh, M.R.; Golestani, N.; Kafi, M.; Hosseini, A.; Saeb, M.; Sarkoohi, P. Gene expression pattern of adiponectin and adiponectin receptors in dominant and atretic follicles and oocytes screened based on brilliant cresyl blue staining. Anim. Reprod. Sci., 2012, 131(1-2), 30-40.
[http://dx.doi.org/10.1016/j.anireprosci.2012.02.006 ] [PMID: 22391295]
[18]
Jambunathan, N. Determination and detection of Reactive Oxygen Species (ROS), lipid peroxidation, and electrolyte leakage in plants. Methods Mol. Biol., 2010, 639, 292-298.
[http://dx.doi.org/10.1007/978-1-60761-702-0_18 ] [PMID: 20387054]
[19]
Mikirova, N.A.; Ichim, T.E.; Riordan, N.H. Anti-angiogenic effect of high doses of ascorbic acid. J. Transl. Med., 2008, 6, 50.
[http://dx.doi.org/10.1186/1479-5876-6-50 ] [PMID: 18789157]
[20]
Padayatty, S.J.; Riordan, H.D.; Hewitt, S.M.; Katz, A.; Hoffer, L.J.; Levine, M. Intravenously administered vitamin C as cancer therapy: Three cases. CMAJ, 2006, 174(7), 937-942.
[http://dx.doi.org/10.1503/cmaj.050346 ] [PMID: 16567755]
[21]
Luo, J.; Shen, L.; Zheng, D. Association between vitamin C intake and lung cancer: A dose-response meta-analysis. Sci. Rep., 2014, 4, 6161.
[http://dx.doi.org/10.1038/srep06161 ] [PMID: 25145261]
[22]
Chen, Q.; Espey, M.G.; Sun, A.Y.; Lee, J.H.; Krishna, M.C.; Shacter, E.; Choyke, P.L.; Pooput, C.; Kirk, K.L.; Buettner, G.R.; Levine, M. Ascorbate in pharmacologic concentrations selectively generates ascorbate radical and hydrogen peroxide in extracellular fluid in vivo. Proc. Natl. Acad. Sci. USA, 2007, 104(21), 8749-8754.
[http://dx.doi.org/10.1073/pnas.0702854104 ] [PMID: 17502596]
[23]
Yeom, C.H.; Lee, G.; Park, J.H.; Yu, J.; Park, S.; Yi, S.Y.; Lee, H.R.; Hong, Y.S.; Yang, J.; Lee, S. High dose concentration administration of ascorbic acid inhibits tumor growth in BALB/C mice implanted with sarcoma 180 cancer cells via the restriction of angiogenesis. J. Transl. Med., 2009, 7, 70-79.
[http://dx.doi.org/10.1186/1479-5876-7-70 ] [PMID: 19671184]
[24]
Riordan, H.D.; Jackson, J.A.; Riordan, N.H.; Mavis Schultz, M. High-dose intravenous vitamin C in the treatment of a patient with renal cell carcinoma of the kidney., https://riordanclinic.org/wp-content/uploads/2014/12/89023775_jom.pdf
[25]
Park, S.; Han, S.S.; Park, C.H.; Hahm, E.R.; Lee, S.J.; Park, H.K.; Lee, S.H.; Kim, W.S.; Jung, C.W.; Park, K.; Riordan, H.D.; Kimler, B.F.; Kim, K.; Lee, J.H. L-Ascorbic acid induces apoptosis in acute myeloid leukemia cells via hydrogen peroxide-mediated mechanisms. Int. J. Biochem. Cell Biol., 2004, 36(11), 2180-2195.
[http://dx.doi.org/10.1016/j.biocel.2004.04.005 ] [PMID: 15313465]
[26]
Nagappan, A.; Park, K.I.; Park, H.S.; Kim, J.A.; Hong, G.E.; Kang, S.R.; Lee, D.H.; Kim, E.H.; Lee, W.S.; Won, C.K.; Kim, G.S. Vitamin C induces apoptosis in AGS cells by down-regulation of 14-3-3σ via a mitochondrial dependent pathway. Food Chem., 2012, 135(3), 1920-1928.
[http://dx.doi.org/10.1016/j.foodchem.2012.06.050 ] [PMID: 22953941]
[27]
Jackson, J.A.; Riordan, H.D.; Hunninghake, R.E.; Riordan, N. High dose intravenous vitamin C and long time survival of a patient with cancer of head of the pancreas. J. Orthomol. Med., 1995, 10(2), 87-88.
[28]
Padayatty, S.J.; Sun, A.Y.; Chen, Q.; Espey, M.G.; Drisko, J.; Levine, M.; Vitamin, C. Intravenous use by complementary and alternative medicine practitioners and adverse effects. PLoS One, 2010, 5(7),e11414.
[http://dx.doi.org/10.1371/journal.pone.0011414] [PMID: 20628650]
[29]
Zhao, H.; Zhu, H.; Huang, J.; Zhu, Y.; Hong, M.; Zhu, H.; Zhang, J.; Li, S.; Yang, L.; Lian, Y.; Wang, S.; Mao, J.; Chen, Y.; Li, J.; Qian, S. The synergy of Vitamin C with decitabine activates TET2 in leukemic cells and significantly improves overall survival in elderly patients with acute myeloid leukemia. Leuk. Res., 2018, 66, 1-7.
[http://dx.doi.org/10.1016/j.leukres.2017.12.009 ] [PMID: 29331774]
[30]
Verrax, J.; Calderon, P.B. Pharmacologic concentrations of ascorbate are achieved by parenteral administration and exhibit antitumoral effects. Free Radic. Biol. Med., 2009, 47(1), 32-40.
[http://dx.doi.org/10.1016/j.freeradbiomed.2009.02.016 ] [PMID: 19254759]
[31]
Herst, P.M.; Broadley, K.W.R.; Harper, J.L.; McConnell, M.J. Pharmacological concentrations of ascorbate radiosensitize glioblastoma multiforme primary cells by increasing oxidative DNA damage and inhibiting G2/M arrest. Free Radic. Biol. Med., 2012, 52(8), 1486-1493.
[http://dx.doi.org/10.1016/j.freeradbiomed.2012.01.021 ] [PMID: 22342518]