Aging and cancer

The incidence of cancer increases with age. Our laboratory is interested in basic science understanding of normal cell aging and its impact on epithelial cancer progression and response to therapy. Replicative and chronological life spans are two modes of normal cell aging. Replicative lifespan refers to a finite number of normal cell division after which cells cease to divide. Chronological lifespan refers to the duration of quiescence (stationary phase of growth) during which cells retain their proliferative capacity. Because, majority of cells in vivo reside in quiescence, we are interested in studying the cellular and molecular mechanisms that regulate chronological lifespan. We reported a significant role of mitochondrial antioxidant network and morphology (fission and fusion) regulating chronological lifespan of normal human fibroblasts (1-3). Additionally, we reported that normal cells nearing the end of their chronological lifespan promote progression and therapy resistance of epithelial cancers. Our results showed an age-related increase in lipid metabolism (lipolysis) of normal cells contributes to the progression and therapy resistance of cancer cells (4). We propose lipolytic signaling pathway as a novel target for cancer therapy.

Key words: chronological lifespan, lipolysis, cancer progression and therapy, mitochondria fission and fusion, manganese superoxide dismutase.

Exemplar Publications

  1. Evidence for oxidative stress in NSAID-induced colitis in IL10-/- mice. Free Radic Biol Med. 2003 May 1;34(9):1153-66. doi: 10.1016/s0891-5849(03)00065-0. PMID: 12706496.
  2. Control of lupus nephritis by changes of gut microbiota. Microbiome. 2017 Jul 11;5(1):73. doi: 10.1186/s40168-017-0300-8. PMID: 28697806; PMCID: PMC5505136.
  3. Elevated mitochondrial superoxide disrupts normal T cell development, impairing adaptive immune responses to an influenza challenge. Free Radic Biol Med. 2011 Feb 1;50(3):448-58. doi: 10.1016/j.freeradbiomed.2010.11.025. Epub 2010 Dec 2. PMID: 21130157; PMCID: PMC3026081.
  4. Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses. J Immunol. 2014 Mar 1;192(5):2326-38. doi: 10.4049/jimmunol.1301758. Epub 2014 Jan 29. PMID: 24477906; PMCID: PMC3943971.
  5. Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis. Sci Transl Med. 2018 Feb 7;10(427):eaan5372. doi: 10.1126/scitranslmed.aan5372. PMID: 29437147; PMCID: PMC5987523.

Cardiovascular Diseases

FRRB faculty are engaged in a broad range of studies with a goal to better understand the cardiovascular system.  These range from how elements, such as blood platelets function, the fundamental redox properties of red blood cells, as well as how nutritional antioxidants such as vitamins C and E function to maintain health. 

Exemplar publications:

  1. Sonkar VK, Kumar R, Jensen M, Wagner BA, Sharathkumar AA, Miller FJ Jr, Fasano M, Lentz SR, Buettner GR, Dayal S. (2019) Nox2 NADPH oxidase is dispensable for platelet activation or arterial thrombosis in mice. Blood Adv. 3(8):1272-1284. http://doi.org/10.1182/bloodadvances.2018025569  PMID: 30995985  PMCID: PMC6482355 
  2. Traber MG, Buettner GR, Bruno RS. (2019) The relationship between vitamin C status, the gut-liver axis, and metabolic syndrome. Redox Biol. 21:10191   https://doi.org/10.1016/j.redox.2018.101091  PMID: 30640128 PMCID: PMC6327911 
  3. van ‘t Erve TJ, Wagner BA, Rykman KK, Raife TJ, Buettner GR. (2013) The concentration of glutathione in human erythrocytes is a heritable trait. Free Radic Biol Med. 65:742-749.  PMID: 23938402    http://dx.doi.org/10.1016/j.freeradbiomed.2013.08.002  PMCID: PMC3859832
  4. van 't Erve TJ, Doskey CM, Wagner BA, Hess JR, Darbro BW, Ryckman KK, Murray JC, Raife TJ, Buettner GR. (2014) The heritability of glutathione and related metabolites in stored red blood cells. Free Radic Biol Med. 76:107-113.   PMID: 25108189 http://dx.doi.org/10.1016/j.freeradbiomed.2014.07.040  PMCID: PMC4252477 
  5. Wert KJ, Velez G, Cross MR, Wagner BA, Teoh-Fitzgerald ML, Buettner GR, McAnany JJ, Olivier A, Tsang SH, Harper MM, Domann FE, Bassuk AG, Mahajan VB. (2018) Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface. Free Radic Biol Med. 124:408-419.  PMID: 29940351  http://doi.org/10.1016/j.freeradbiomed.2018.06.024 .  PMCID: PMC6233711 
  6. Clark CB, Zhang Y, Martin SM, Davies RL, Xu L, Kregel KC, Miller FJ, Buettner GR, Kerber RE. (2003) The nitric oxide synthase inhibitor NG-nitro-L-arginine decreases defibrillation-induced free radical generation. Resuscitation. 57:101-108.  PMID: 12668306   http://dx.doi.org/doi:10.1016/S0300-9572(02)00413-6 

Toxicology in cancer therapy

FRRB labs are involved in a wide range of studies addressing the redox toxicology of xenobiotics, ranging from environmental toxins to drugs used in cancer treatment.  Many xenobiotics act as redox toxins, poisoning cellular processes by oxidative mechanisms. 

Toxicology and Cancer therapy

Exemplar publications:

  1. Kalen AL, Wagner BA, Sarsour EH, Kumar MG, Reedy JL, Buettner GR, Barua NC, Goswami PC. (2020) Hydrogen Peroxide Mediates Artemisinin-Derived C-16 Carba-Dimer-Induced Toxicity of Human Cancer Cells. Antioxidants (Basel). 9(2):E108.  PMID: 31991904  http://doi.org/10.3390/antiox9020108  PMCID: PMC7070254 
  2. Falls-Hubert KC, Butler AL, Gui K, Anderson M, Li M, Stolwijk JM, Rodman SN 3rd, Solst SR, Tomanek-Chalkley A, Searby CC, Sheffield VC, Sandfort V, Schmidt H, McCormick ML, Wels BR, Allen BG, Buettner GR, Schultz MK, Spitz DR. (2020) Disulfiram causes selective hypoxic cancer cell toxicity and radio-chemo-sensitization via redox cycling of copper. Free Radic Biol Med.;150:1-11.  http://doi.org/10.1016/j.freeradbiomed.2020.01.186  PMID: 32032663  PMCID: PMC7299833 
  3. Gibson AR, O'Leary BR, Du J, Sarsour EH, Kalen AL, Wagner BA, Stolwijk JM, Falls-Hubert KC, Alexander MS, Carroll RS, Spitz DR, Buettner GR, Goswami PC, Cullen JJ. (2020) Dual oxidase-induced sustained generation of hydrogen peroxide contributes to pharmacologic ascorbate-induced cytotoxicity. Cancer Res. 80(7):1401-1413. http://doi.org/10.1158/0008-5472.CAN-19-3094  PMID: 32041838  PMCID: PMC7127976 
  4. Buranasudja V, Doskey CM, Gibson AR, Wagner BA, Du J, Gordon DJ, Koppenhafer SL, Cullen JJ, Buettner GR. (2019) Pharmacological ascorbate primes pancreatic cancer cells for death by rewiring cellular energetics and inducing DNA damage. Molecular Cancer Research. 17(10):2102-2114, PMID: 31337671;  https://doi.org/10.1158/1541-7786.MCR-19-0381  Supplemental data at: https://mcr.aacrjournals.org/content/molcanres/suppl/2019/07/23/1541-7786.MCR-19-0381.DC1/220509_2_supp_5635724_pvrvv2.pdf  PMCID: PMC6774825. 
  5. Schoenfeld JD, Alexander MS, Waldron TJ, Sibenaller ZA, Spitz DR, Buettner GR, Allen BG, Cullen JJ. (2019) Pharmacological ascorbate as a means of sensitizing cancer cells to radio-chemotherapy while protecting normal tissue. Semin Radiat Oncol. 29(1):25-32.  doi: http://doi.org/10.1016/j.semradonc.2018.10.006   PMID: 30573181 PMCID: PMC6310038

Methods in Redox Toxicology 

  1. Doskey CM, van ‘t Erve TJ, Wagner BA, Buettner GR. (2015) Moles of a substance per cell is a highly informative dosing metric in cell culture. PLoS ONE 10(7): e0132572. PMID: 26172833  http://dx.doi.org/doi:10.1371/journal.pone.0132572  Open Access  PMCID: PMC4501792 
  2. Stolwijk JM, Falls-Hubert KC, Searby CC, Wagner BA, Buettner GR. (2020) Simultaneous detection of the enzyme activities of GPx1 and GPx4 guide optimization of selenium in cell biological experiments. Redox Biology. 32:10158.  https://doi.org/10.1016/j.redox.2020.101518  PMID: 32278283  PMCID: PMC7150527 

Selenium in Redox Toxicology 

  1. Stolwijk JM, Garje R, Sieren JC, Buettner GR, Zakharia Y. (2020) Understanding the redox biology of selenium in the search of targeted cancer therapies. Antioxidants (Basel). 9(5):E420. PMID: 32414091  http://doi.org/10.3390/antiox9050420  PMCID: PMC7150527 
  2. Stolwijk JM, Falls-Hubert KC, Searby CC, Wagner BA, Buettner GR (2020) Simultaneous detection of the enzyme activities of GPx1 and GPx4 guide optimization of selenium in cell biological experiments. Redox Biology. 32:10158.  https://doi.org/10.1016/j.redox.2020.101518  PMID: 32278283  PMCID: PMC7150527 
  3. Lafin JT, Sarsour EH, Kalen AL, Wagner BA, Buettner GR, Goswami PC. (2019) Methylseleninic acid induces lipid peroxidation and radiation sensitivity in head and neck cancer cells. Int J Mol Sci. 20(1): 20(1):pii: E225.  https://doi.org/10.3390/ijms20010225   PMID: 30626124  PMCID: PMC6337472  

Biophysical challenges and Redox Toxicology 

  1. Carter CS, Huang SC, Searby CC, Cassaidy B, Miller MJ, Grzesik WJ, Piorczynski TB, Pak TK, Walsh SA, Acevedo M, Zhang Q, Mapuskar KA, Milne GL, Hinton AO Jr, Guo DF, Weiss R, Bradberry K, Taylor EB, Rauckhorst AJ, Dick DW, Akurathi V, Falls-Hubert KC, Wagner BA, Carter WA, Wang K, Norris AW, Rahmouni K, Buettner GR, Hansen JM, Spitz DR, Abel ED, Sheffield VC. (2020) Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes. Cell Metab. 32(4):561-574.e7. http://doi.org/10.1016/j.cmet.2020.09.012  .PMID: 33027675 
  2. Spitz DR, Buettner GR, Petronek MS, St-Aubin JJ, Flynn RT, Waldron TJ, Limoli CL. (2019) An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses. Radiother Oncol. 139:23-27.  http://doi.org/10.1016/j.radonc.2019.03.028    PMID: 31010709  PMCID: PMC6761031 
  3. Buettner GR, Spitz DR, Limoli CL. (2020) Response to Ling et al. regarding "An integrated physico-chemical approach for explaining the differential impact of FLASH versus conventional dose rate irradiation on cancer and normal tissue responses". Radiother Oncol. pii: S0167-8140(20)30109-2.  http://doi.org/10.1016/j.radonc.2020.03.001  PMID: 32222332

Neuro-oncology

Our faculty are interested in brain tumors focusing in many aspects of free radical biology in 1- therapy resistance (PMID: 32899427), 2- development of therapeutic strategies (PMID: 28455961, PMID: 28366679, PMID: 31427282) 3- tumor heterogeneity (PMID: 30231881).

Exemplar publications:

 

  1. Radioresistance in Glioblastoma and the Development of Radiosensitizers. Cancers (Basel). 2020 Sep 3;12(9):2511. doi: 10.3390/cancers12092511. PMID: 32899427; PMCID: PMC7564557.
  2. Repositioning chlorpromazine for treating chemoresistant glioma through the inhibition of cytochrome c oxidase bearing the COX4-1 regulatory subunit. Oncotarget. 2017 Jun 6;8(23):37568-37583. doi: 10.18632/oncotarget.17247. PMID: 28455961; PMCID: PMC5514931.
  3. O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30. Erratum in: Cancer Cell. 2017 Aug 14;32(2):268. PMID: 28366679; PMCID: PMC5497844.
  4. First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clin Cancer Res. 2019 Nov 15;25(22):6590-6597. doi: 10.1158/1078-0432.CCR-19-0594. Epub 2019 Aug 19. PMID: 31427282; PMCID: PMC6858950.
  5. IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling. Cell Commun Signal. 2018 Sep 19;16(1):61. doi: 10.1186/s12964-018-0273-7. PMID: 30231881; PMCID: PMC6148802.