Skip to main content
SpringerLink
Log in
Book cover

Nitric Oxide (NO) and Cancer pp 479–488Cite as

Role of Inducible Nitric Oxide Synthase (iNOS) in Regulation of Nitric Oxide (NO) Production and Stabilization of HIF-1α: Potential Role of Se-Methylselenocysteine (MSC), an Antioxidant Multi-targeted Small Molecule

  • Chapter
  • First Online:

  • 1038 Accesses

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

The authors of chapters presented in Part VII dealt with the therapeutic application of nitric oxide (NO). The authors extensively reviewed the field demonstrating the potential therapeutic value of NO donors alone and in combination with cytotoxic therapy in the treatment of various solid tumor types. The authors indicate that while the mechanisms of activity of these agents may vary according to tumor type and treatment conditions, the fact that these agents have minimal toxicity profile and therefore potentially selective in their effects provide the scientific rationale for their continued development at the basic level and more importantly, the need to validate the clinical potential of this interesting class of relatively non-toxic agents with significant biological and therapeutic potential. This opinion is offered relevant to the data presented in Part VII and offers new and novel approaches on the potential role of Se-methylselenocysteine (MSC) on the expression levels of hypoxia-inducible factor 1α (HIF-1α) and its transcriptionally regulated genes, including vascular endothelial growth factor (VEGF), in therapy of squamous cell carcinoma of the head and neck. The use of MSC as a multi-targeted, non-toxic inhibitor of iNOS and other biomarkers such as COX-2, HIF-1α, and VEGF as therapeutic modulators of anticancer drugs against established tumors in xenografts is discussed.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Adamski, J.K., Estlin, E.J., Makin, G.W. (2008). The cellular adaptations to hypoxia as novel therapeutic targets in childhood cancer. Cancer Treat. Rev. 34(3), 231–246.

    Article  PubMed  CAS  Google Scholar 

  • Bernstein, B.J., Grasso, T. (2001). Prevalence of complementary and alternative medicine use in cancer patients. Oncology 15(10), 1267–1272.

    PubMed  CAS  Google Scholar 

  • Berra, E., Ginouves, A., Pouyssegur, J. (2006). The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signaling. EMBO Rep. 7(1), 41–45.

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharya, A., Toth, K., Mazurchuk, R., et al. (2004). Lack of microvessels in well-differentiated regions of human head and neck squamous cell carcinoma A253 associated with functional magnetic resonance imaging detectable hypoxia, limited drug delivery, and resistance to irinotecan therapy. Clin. Cancer Res. 10(23), 8005–8017.

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharya, A., Seshadri, M., Oven, S., Toth, K., Vaughan, M., Rustum, Y.M. (2008). Tumor vascular maturation and improved drug delivery induced by Methylselenocysteine leads to therapeutic synergy with anticancer drugs. Clin. Cancer Res. 14(12), 3926–3932.

    Article  PubMed  CAS  Google Scholar 

  • Bhattacharya, A., Toth, K., Durrani, F.A., Cao, S., Slocum, H.K., Chintala, S., Rustum, Y.M. (2008). Hypoxia specific drug tirapazamine does not abrogate hypoxic tumor cells in combination therapy with irinotecan and Methylselenocysteine in well-differentiated human head and neck squamous cell carcinoma A253 xenografts. Neoplasia 10(8), 857–865.

    PubMed  CAS  Google Scholar 

  • Bhattacharya, A., Toth, K., Sen, A., et al. (2009). Inhibition of colon cancer growth by methylselenocysteine-induced angiogenic chemomodulation is influenced by histologic characteristics of the tumor. Clin. Colorectal Cancer. 8(3), 155–162.

    Google Scholar 

  • Brunelle, J.K., Bell, E.L., Quesada, N.M., et al. (2005). Oxygen sensing requires mitochondrial ROS but not oxidative phosphorylation. Cell Metab. 1(6), 409–414.

    Article  PubMed  CAS  Google Scholar 

  • Cao, S., Durrani, F.A., and Rustum, Y.M. (2004). Selective modulation of the therapeutic efficacy of anticancer drugs by selenium containing compounds against human tumor xenografts. Clin. Cancer Res. 10, 2561–2569.

    Article  PubMed  CAS  Google Scholar 

  • Chandel, N.S., McClintock, D.S., Feliciano, C.E., et al. (2000). Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J. Biol. Chem. 275(33), 25130–25138.

    Article  PubMed  CAS  Google Scholar 

  • Chintala, S., Toth, K., Cao, S., et al. (2010). Se-methylselenocysteine sensitizes hypoxic tumor cells to irinotecan by targeting hypoxia-inducible factor 1alpha. Cancer Chemother. Pharmacol. [Epub ahead of print] DOI 10.1007/s00280-009-1238-8.

    Google Scholar 

  • Clark, L.C., Cantor, K.P., Allaway, W.H. (1991). Selenium in forage crops and cancer mortality in U.S. counties. Arch. Environ. Health 46(1), 37–42.

    Article  PubMed  CAS  Google Scholar 

  • Clark, L.C., Combs, G.F. Jr., Turnbull, B.W., et al. (1996). Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin. A randomized controlled trial. Nutritional Prevention of Cancer Study Group. JAMA 276(24), 1957–1963.

    Article  PubMed  CAS  Google Scholar 

  • Combs, G.F. Jr., Clark, L.C., Turnbull, B.W. (1997). Reduction of cancer mortality and incidence by selenium supplementation. Med. Klin. (Munich) 92 (Suppl 3), 42–45.

    Article  CAS  Google Scholar 

  • Combs, G.F. Jr., Gray, W.P. (1998). Chemopreventive agents: selenium. Pharmacol. Ther. 79(3), 179–192.

    Article  PubMed  CAS  Google Scholar 

  • Demidenko, Z.N., Rapisarda, A., Garayoa, M., Giannakakou, P., Melillo, G., Blagosklonny, M.V. (2005). Accumulation of hypoxia-inducible factor-1alpha is limited by transcription-dependent depletion. Oncogene 24(30), 4829–4838.

    Article  PubMed  CAS  Google Scholar 

  • De Schutter, H., Landuyt, W., Verbeken, E., Goethals, L., Hermans, R., Nuyts, S. (2005). The prognostic value of the hypoxia markers CA IX and GLUT 1 and the cytokines VEGF and IL 6 in head and neck squamous cell carcinoma treated by radiotherapy +/– chemotherapy. BMC Cancer 5, 42, doi:10.1186/1471-2407-5-42.

    Article  PubMed  Google Scholar 

  • Dias, S., Shmelkov, S.V., Lam, G., Rafii, S. (2002). VEGF(165) promotes survival of leukemic cells by Hsp90-mediated induction of Bcl-2 expression and apoptosis inhibition. Blood 99(7), 2532–2540.

    Article  PubMed  CAS  Google Scholar 

  • Dias, S., Choy, M., Alitalo, K., Rafii, S. (2002). Vascular endothelial growth factor (VEGF)-C signaling through FLT-4 (VEGFR-3) mediates leukemic cell proliferation, survival, and resistance to chemotherapy. Blood 99(6), 2179–2184.

    Article  PubMed  CAS  Google Scholar 

  • Elango, N., Samuel, S., Chinnakkannu, P. (2006). Enzymatic and non-enzymatic antioxidant status in stage (III) human oral squamous cell carcinoma and treated with radical radio therapy: influence of selenium supplementation. Clin. Chim. Acta 373(1–2), 92–98.

    Article  PubMed  CAS  Google Scholar 

  • Fakih, M.G., Pendyala, L., Brady, W., et al. (2008). A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors. Cancer Chemother. Pharmacol. 62(3), 499–508.

    Article  PubMed  CAS  Google Scholar 

  • Fakih, M.G., Rustum, Y. M. (2009). Does celecoxib have a role in the treatment of patients with colorectal cancer? Clinical Colorectal Cancer 8(1), 11–14.

    Article  PubMed  CAS  Google Scholar 

  • Fleet, J.C. (1997). Dietary selenium repletion may reduce cancer incidence in people at high risk who live in areas with low soil selenium. Nutr. Rev. 55(7), 277–279.

    Article  PubMed  CAS  Google Scholar 

  • Gerald, D., Berra, E., Frapart, Y.M., et al. (2004). JunD reduces tumor angiogenesis by protecting cells from oxidative stress. Cell 118(6), 781–794.

    Article  PubMed  CAS  Google Scholar 

  • Goldhaber, S.B. (2003). Trace element risk assessment: essentiality vs. toxicity. Regul. Toxicol. Pharmacol. 38(2), 232–242.

    Article  PubMed  CAS  Google Scholar 

  • Hussain, S. Perwez, H.E. Peijun, H., Subleski, J., Hofseth, L., et al. (2008). Nitric oxide is a key component in inflammation-accelerated tumorigenesis. Cancer Res. 68(17), 7130–7136.

    Article  PubMed  CAS  Google Scholar 

  • Institute of Medicine. (2000). Dietary reference intakes for vitamin C, vitamin E, selenium and carotenoids (58–72). National Academies Press, Washington, DC.

    Google Scholar 

  • Last, K.W., Cornelius, V., Delves, T., et al. (2003). Presentation serum selenium predicts for overall survival, dose delivery, and first treatment response in aggressive non-Hodgkin’s lymphoma. J. Clin. Oncol. 21(12), 2335–2341.

    Article  PubMed  Google Scholar 

  • Lee, H., An, S., Lee, H., Woo, S., et al. (2008). Activation of epidermal growth factor receptor and its downstream signaling pathway by nitric oxide in response to ionizing radiation. Mol. Cancer Res. 6, 996–1002.

    Article  PubMed  CAS  Google Scholar 

  • Liao, D., Johnson, R.S. (2007). Hypoxia: a key regulator of angiogenesis in cancer. Cancer Metastasis Rev. 26(2), 281–290.

    Article  PubMed  CAS  Google Scholar 

  • Lippman, S.M., Klein, E.A., Goodman, P.J., et al. (2009). Effect of selenium and vitamin E on risk of prostate cancer and other cancers: the Selenium and Vitamin E Cancer Prevention Trial (SELECT). JAMA 301(1), 39–51.

    Article  PubMed  CAS  Google Scholar 

  • Lopez-Lazaro, M. (2006). Hypoxia-inducible factor 1 as a possible target for cancer chemoprevention. Cancer Epidemiol. Biomarkers Prev. 15(12), 2332–2335.

    Article  PubMed  CAS  Google Scholar 

  • Mansfield, K.D., Guzy, R.D., Pan, Y., et al. (2005). Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation. Cell Metab. 1(6), 393–399.

    Article  PubMed  CAS  Google Scholar 

  • Mazur, A., Nassir, F., Gueux, E., et al. (1996). Diets deficient in selenium and vitamin E affect plasma lipoprotein and apolipoprotein concentrations in the rat. Br. J. Nutr. 76(6),899–907.

    Article  PubMed  CAS  Google Scholar 

  • Maxwell, P.H. (2005). Hypoxia-inducible factor as a physiological regulator. Exp. Physiol. 90(6), 791–797

    Article  PubMed  CAS  Google Scholar 

  • Papp, L.V., Lu, J., Holmgren, A., Khanna, K.K. (2007). From selenium to selenoproteins: synthesis, identity, and their role in human health. Antioxid. Redox. Signal 9(7), 775–806.

    Article  PubMed  CAS  Google Scholar 

  • Pastorekova, S., Ratcliffe, P.J., Pastorek, J. (2008). Molecular mechanisms of carbonic anhydrase IX-mediated pH regulation under hypoxia. BJU international 101(Suppl 4), 8–15.

    Article  PubMed  CAS  Google Scholar 

  • Patiar, S., Harris, AL. (2006). Role of hypoxia-inducible factor-1alpha as a cancer therapy target. Endocrine-related cancer 13(Suppl 1), S61–S75.

    Article  PubMed  CAS  Google Scholar 

  • Quintero, M., Brennan, P., Thomas, G., and Moncada, S. (2006). Nitric Oxide Is a Factor in the Stabilization of Hypoxia-Inducible Factor-1 in Cancer: Role of Free Radical Formation. Cancer Res. 66, 770–774.

    Article  PubMed  CAS  Google Scholar 

  • Semenza, G.L. (2003). Targeting HIF-1 for cancer therapy. Nature reviews 3(10), 721–732.

    Article  PubMed  CAS  Google Scholar 

  • Sulkowska, M., Wincewicz, A., Sulkowski, S., Koda, M., Kanczuga-Koda, L. (2009). Relations of TGF-beta1 with HIF-1alpha, GLUT-1 and longer survival of colorectal cancer patients. Pathology 41(3), 254–260.

    Google Scholar 

  • Thomson, C.D. (2004). Assessment of requirements for selenium and adequacy of selenium status: a review. Eur. J. Clin. Nutr. 58(3), 391–402.

    Article  PubMed  CAS  Google Scholar 

  • Wincewicz, A., Sulkowska, M., Koda, M., Kanczuga-Koda, L., Witkowska, E., Sulkowski, S. (2007). Significant coexpression of GLUT-1, Bcl-xL, and Bax in colorectal cancer. Ann. N Y Acad. Sci. 1095, 53–61.

    Article  PubMed  CAS  Google Scholar 

  • Wincewicz, A., Sulkowska, M., Koda, M., Sulkowski, S. (2007). Clinicopathological significance and linkage of the distribution of HIF-1alpha and GLUT-1 in human primary colorectal cancer. Pathol. Oncol. Res. 13(1), 15–20.

    Article  PubMed  CAS  Google Scholar 

  • Yin, M.B., Li, Z.R., Toth, K., et al. (2006). Potentiation of irinotecan sensitivity by Se-methylselenocysteine in an in vivo tumor model is associated with downregulation of cyclooxygenase-2, inducible nitric oxide synthase, and hypoxia-inducible factor 1alpha expression, resulting in reduced angiogenesis. Oncogene 25(17), 2509–2519.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Cancer Biology, Roswell Park Cancer Institute, Buffalo, NY, 14263, USA

    Sreenivasulu Chintala, Shousong Cao & Youcef M. Rustum

Authors
  1. Sreenivasulu Chintala
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shousong Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Youcef M. Rustum
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Youcef M. Rustum .

Editor information

Editors and Affiliations

  1. Dept. Microbiology, Immunology &, Molecular Genetics, University of California, Los Angeles, Charles E. Young Dr. E. 609, Los Angeles, 90095, California, USA

    Benjamin Bonavida

Rights and permissions

Reprints and permissions

Copyright information

© 2010 Springer Science + Business Media, LLC

About this chapter

Cite this chapter

Chintala, S., Cao, S., Rustum, Y.M. (2010). Role of Inducible Nitric Oxide Synthase (iNOS) in Regulation of Nitric Oxide (NO) Production and Stabilization of HIF-1α: Potential Role of Se-Methylselenocysteine (MSC), an Antioxidant Multi-targeted Small Molecule. In: Bonavida, B. (eds) Nitric Oxide (NO) and Cancer. Cancer Drug Discovery and Development. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-1432-3_25

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-1432-3_25

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-1431-6

  • Online ISBN: 978-1-4419-1432-3

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation