Radioprotective effects of oral 17-dimethylaminoethylamino-17-demethoxygeldanamycin in mice: bone marrow and small intestine

Cell & Bioscience

Juliann G Kiang¹  Thomas B Elliott²  David L Bolduc²  Dilber Nurmemet²  Xinyue Lu² 

[1] Department of Medicine, Uniformed Services University of the Health Sciences, Bethesda, MD, USA;Radiation Combined Injury Program, Scientific Research Department, Armed Forces Radiobiology Research Institute, 8901 Wisconsin Avenue, Bethesda, MD 20889-5603, USA

关键词: Mice;    G-CSF;    Survivin;    Lgr5;    Intestine;    Stem cell;    Bone marrow;    17-DMAG;    Survival;    Radiation;   

Others  :  791544
DOI  :  10.1186/2045-3701-3-36

 received in 2013-01-30, accepted in 2013-08-01,  发布年份 2013

【 摘 要 】

Background

Our previous research demonstrated that one subcutaneous injection of 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) 24 hours (h) before irradiation (8.75 Gy) increased mouse survival by 75%. However, the protective mechanism of 17-DMAG is currently unknown. The present study aimed to investigate whether oral administration of 17-DMAG was also radioprotective and the potential role it may play in radioprotection.

Results

A single dose of orally pre-administered (24, 48, or 72 h) 17-DMAG (10 mg/kg) increased irradiated mouse survival, reduced body weight loss, improved water consumption, and decreased facial dropsy, whereas orally post-administered 17-DMAG failed. Additional oral doses of pre-treatment did not improve 30-day survival. The protective effect of multiple pre-administrations (2−3 times) of 17-DMAG at 10 mg/kg was equal to the outcome of a single pre-treatment. In 17-DMAG-pretreated mice, attenuation of bone marrow aplasia in femurs 30 days after irradiation with recovered expressions of cluster of differentiation 34, 44 (CD34, CD44), and survivin in bone marrow cells were observed. 17-DMAG also elevated serum granulocyte-colony stimulating factor (G-CSF), decreased serum fms-related tyrosine kinase 3 ligand, and reduced white blood cell depletion. 17-DMAG ameliorated small intestinal histological damage, promoted recovery of villus heights and intestinal crypts including stem cells, where increased leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5) was found 30 days after irradiation.

Conclusions

17-DMAG is a potential radioprotectant for bone marrow and small intestine that results in survival improvement.

【 授权许可】

   
2013 Lu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

【 参考文献 】

• [1]Whitesell L, Mimnaugh EG, De Costa B, Myers CE, Neckers LM: Inhibition of heat shock protein HSP90–pp60v-src heteroprotein complex formation by benzoquinone ansamycins: essential role for stress proteins in oncogenic transformation. Proc Natl Acad Sci USA 1994, 91:8324-8328.
• [2]Stebbins CE, Russo AA, Schneider C, Rosen N, Hartl FU, Pavletich NP: Crystal structure of an Hsp90-geldanamycin complex: targeting of a protein chaperone by an antitumor agent. Cell 1997, 89:239-250.
• [3]Jez JM, Chen JC, Rastelli G, Stroud RM, Santi DV: Crystal structure and molecular modeling of 17-DMAG in complex with human Hsp90. Chem Biol 2003, 10:361-368.
• [4]Kabakov AE, Kudryavtsev VA, Gabai VL: Hsp90 inhibitors as promising agents for radiotherapy. J Mol Med (Berlin, Germany) 2010, 88:241-247.
• [5]Li Y, Zhang T, Schwartz SJ, Sun D: New developments in Hsp90 inhibitors as anti-cancer therapeutics: mechanisms, clinical perspective and more potential. Drug Resist Update 2009, 12:17-27.
• [6]Kummar S, Gutierrez ME, Gardner ER, Chen X, Figg WD, Zajac-Kaye M, Chen M, Steinberg SM, Muir CA, Yancey MA, Horneffer YR, Juwara L, Melillo G, Ivy SP, Merino M, Neckers L, Steeg PS, Conley BA, Giaccone G, Doroshow JH, Murgo AJ: Phase I trial of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), a heat shock protein inhibitor, administered twice weekly in patients with advanced malignancies. Euro J Cancer 2010, 46:340-347.
• [7]Ramanathan RK, Egorin MJ, Erlichman C, Remick SC, Ramalingam SS, Naret C, Holleran JL, TenEyck CJ, Ivy SP, Belani CP: Phase I pharmacokinetic and pharmacodynamic study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of heat-shock protein 90, in patients with advanced solid tumors. J Clin Oncol 2010, 28:1520-1526.
• [8]Egorin MJ, Lagattuta TF, Hamburger DR, Covey JM, White KD, Musser SM, Eiseman JL: Pharmacokinetics, tissue distribution, and metabolism of 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (NSC 707545) in CD2F1 mice and Fischer 344 rats. Cancer Chemother Pharmacol 2002, 49:7-19.
• [9]Rao R, Lee P, Fiskus W, Yang Y, Joshi R, Wang Y, Buckley K, Balusu R, Chen J, Koul S, Joshi A, Upadhyay S, Tao J, Sotomayor E, Bhalla KN: Co-treatment with heat shock protein 90 inhibitor 17-dimethylaminoethylamino-17-demethoxygeldanamycin (DMAG) and vorinostat: a highly active combination against human mantle cell lymphoma (MCL) cells. Cancer Biol & Ther 2009, 8:1273-1280.
• [10]Kamal A, Thao L, Sensintaffar J, Zhang L, Boehm MF, Fritz LC, Burrows FJ: A high affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature 2003, 425:407-410.
• [11]Whitesell L, Lindquist SL: HSP90 and the chaperoning of cancer. Nat Rev Cancer 2005, 5:761-772.
• [12]Kiang JG, Smith JT, Agravante NG: Geldanamycin analog 17-DMAG inhibits iNOS and caspases in gamma-irradiated human T cells. Radiat Res 2009, 172:321-330.
• [13]Fukumoto R, Kiang JG: Geldanamycin analog 17-DMAG limits apoptosis in human peripheral blood cells by inhibition of p53 activation and its interaction with heat shock protein 90 kDa after ionizing radiation. Radiat Res 2011, 176:333-345.
• [14]Mettler FA Jr, Voelz GL: Major radiation exposure—what to expect and how to respond. N Eng J Med 2002, 346:1554-1561.
• [15]Coleman CN, Stone HB, Moulder JE, Pellmar TC: Modulation of radiation injury. Science 2004, 304:693-694.
• [16]Moulder JE: Post-irradiation approaches to treatment of radiation injuries in the context of radiological terrorism and radiation accidents: a review. Int J Radiat Biol 2004, 80:3-10.
• [17]Wilson JW, Cucinotta FA, Shinn JL, Simonsen LC, Dubey RR, Jordan WR, Jones TD, Chang CK, Kim MY: Shielding from solar particle event exposures in deep space. Radiat Res 1999, 30:361-382.
• [18]Wambi CO, Sanzari JK, Sayers CM, Nuth M, Zhou ZZ, Davis J, Finnberg N, Lewis-Wambi JS, Ware JH, El-Deiry WS, Kennedy AR: Protective effects of dietary antioxidants on proton total-body irradiation-mediated hematopoietic cell and Animal survival. Radiat Res 2009, 172:175-186.
• [19]Li XH, Fu D, Latif NH, Mullaney CP, Ney PH, Mog SR, Whitnall MH, Srinivasan V, Xiao M: Delta-tocotrienol protects mouse and human hematopoietic progenitors from gamma-irradiation through extracellular signal-regulated kinase/mammalian target of rapamycin signaling. Haematologica 2010, 95:1996-2004.
• [20]Kiang JG: Geldanamycin analog 17-DMAG confers radioprotection by inhibiting apoptosis and autophagy. In Proceedings of 55th Radiation Research Society Annual Meeting: 4-7 October 2009; Savannah GA. Edited by Radiation Research Society. Savannah, GA: Allen Press; 2009:77.
• [21]Kiang JG, Garrison BR, Burns TM, Zhai M, Dews IC, Ney PH, Cary LH, Fukumoto R, Cary LH, Elliott TB, Ledney GD: Wound trauma alters ionizing radiation dose assessment. Cell Biosci 2012, 2:20. BioMed Central Full Text
• [22]Brandt GE, Blagg BS: Alternate strategies of Hsp90 modulation for the treatment of cancer and other diseases. Curr Top Med Chem 2009, 9:1447-1461.
• [23]Leung CG, Xu Y, Mularski B, Liu H, Gurbuxani S, Crispino JD: Requirements for survivin in terminal differentiation of erythroid cells and maintenance of hematopoietic stem and progenitor cells. J Exp Med 2007, 204:1603-1611.
• [24]Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, Reed JC: IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res 1998, 58:5315-5320.
• [25]Williams GT, Smith CA, Spooncer E, Dexter TM, Taylor DR: Haemopoietic colony stimulating factors promote cell survival by suppressing apoptosis. Nature 1990, 343:76-79.
• [26]Wodnar-Filipowicz A, Lyman SD, Gratwohl A, Tichelli A, Speck B, Nissen C: Flt3 ligand level reflects hematopoietic progenitor cell function in aplastic anemia and chemotherapy-induced bone marrow aplasia. Blood 1996, 88:4493-4499.
• [27]Molyneux G, Gibson FM, Whayman M, Turton JA: Serum Flt-3 ligand in a busulphan–induced model of chronic bone marrow hypoplasia in the female CD-1 mouse. Int J Exp Path 2008, 89:159-170.
• [28]Fang J, Menon M, Kapelle W, Bogacheva O, Bogachev O, Houde E, Browne S, Sathyanarayana P, Wojchowski DM: EPO modulation of cell-cycle regulatory genes, and cell division, in primary bone marrow erythroblasts. Blood 2007, 110:2361-2370.
• [29]Kiang JG, Jiao W, Cary L, Mog SR, Elliott TB, Pellmar TC, Ledney GD: Wound trauma increases radiation-induced mortality by increasing iNOS, cytokine concentrations, and bacterial infections. Radiat Res 2010, 173:319-332.
• [30]Withers HR, Elkind MM: Microcolony survival assay for cells of mouse intestinal mucosa exposed to radiation. Int J Radiat Biol Relat Stud Phys Chem Med 1970, 17:261-267.
• [31]Barker N, van Es JH, Kuipers J, Kujala P, van den Born M, Cozijnsen M, Haegebarth A, Korving J, Begthel H, Peters PJ, Clevers H: Identification of stem cells in small intestine and colon by marker gene Lgr5. Nature 2007, 449:1003-1007.
• [32]Yan KS, Chia LA, Li X, Ootani A, Su J, Lee JY, Su N, Luo Y, Heilshorn SC, Amieva MR, Sangiorgi E, Capecchi MR, Kuo CJ: The intestinal stem cell markers Bmi1 and Lgr5 identify two functionally distinct populations. Proc Natl Acad Sci USA 2012, 109:466-471.
• [33]Bull EE, Dote H, Brady KJ, Burgan WE, Carter DJ, Cerra MA, Oswald KA, Hollingshead MG, Camphausen K, Tofilon PJ: Enhanced tumor cell radiosensitivity and abrogation of G2 and S phase arrest by the Hsp90 inhibitor 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin. Clin Cancer Res 2004, 10:8077-8084.
• [34]Camphausen K, Tofilon PJ: Inhibition of HSP90: a multi-target approach to radiosensitization. Clin Cancer Res 2007, 13:4326-4330.
• [35]Harrison EM, Sharpe E, Bellamy CO, McNally SJ, Devey L, Garden OJ, Ross JA, Wigmore SJ: Heat shock protein 90-binding agents protect renal cells from oxidative stress and reduce kidney ischemia reperfusion injury. Am J Physiol Renal Physiol 2008, 295:F397-F405.
• [36]Naito AT, Okada S, Minamino T, Iwanaga K, Liu ML, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A, Akazawa H, Nagai T, Shiojima I, Komuro I: Promotion of CHIP mediated p53 degradation protects the heart from ischemic injury. Circ Res 2010, 106:1692-1702.
• [37]Kiang JG, Agravante NG, Smith JT, Bowman PD: 17-DMAG diminishes hemorrhage-induce small intestine injury by elevating Bcl-2 protein and inhibiting iNOS pathway, TNF-α increase, and caspase-3 activation. Cell Biosci 2011, 1:21. BioMed Central Full Text
• [38]Borgel SD, Carter JP, Sausville EA, Holliingshead MG: The impact of tumor location on the activity of 17-DMAG (NSC-707545), a water soluble geldanamycin analog. Clin Cancer Res 2003, 9:6215s.
• [39]Glaze ER, Lambert AL, Smith AC, Page JG, Johnson WD, McCormick DL, Brown AP, Levine BS, Covey JM, Egorin MJ, Eiseman JL, Holleran JL, Sausville EA, Tomaszewski JE: Preclinical toxicity of a geldanamycin analog, 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), in rats and dogs: potential clinical relevance. Cancer Chemother Pharmacol 2005, 56:637-47.
• [40]Hollingshead M, Alley M, Burger AM, Borgel S, Pacula-Cox C, Fiebig HH, Sausville EA: In vivo antitumor efficacy of 17-DMAG (17-dimethylaminoethylamino-17-demethoxygeldanamycin hydrochloride), a water-soluble geldanamycin derivative. Cancer Chemother Pharmacol 2005, 56:115-125.
• [41]Eiseman JL, Lan J, Lagattuta TF, Hamburger DR, Joseph E, Covey JM, Egorin MJ: Pharmacokinetics and pharmacodynamics of 17-demethoxy 17-[[(2-dimethylamino) ethyl] amino] geldanamycin (17DMAG, NSC 707545) in C.B-17 SCID mice bearing MDA-MB-231 human breast cancer xenografts. Cancer Chemother Pharmacol 2005, 55:21-32.
• [42]Kiang JG, Fukumoto R, Gorbunov NV: Lipid peroxidation after ionizing irradiation leads to apoptosis and autophagy. In origins of Lipid Peroxidation 1st edition. Edited by Angel C. 2012, 261-278. Tech Open Access Publisher (http://www.intechweb.org webcite) Croatia
• [43]Capalbo G, Dittmann K, Weiss C, Reichert S, Hausmann E, Rődel C, Rődel F: Radiation-induced survivin nuclear accumulation is linked to DNA damage repair. Int J Radiat Oncol Biol Phys 2010, 77:226-234.
• [44]Zhao X, Cao M, Joy J, Liu JJ, Zhu H, Nelson DR, Liu C: Reactive oxygen species is essential for cycloheximide to sensitize lexatumumab-induced apoptosis in hepatocellular carcinoma cells. PLoS One 2011, 6:e16966.
• [45]Zhang M, Yang J, Li F: Transcriptional and posttranscriptional controls of survivin in cancer cells: Essential interfaces for developing novel approaches for cancer treatment. J Exp Clin Cancer Res 2006, 25:391-402.
• [46]Bertho JM, Demarquay C, Frick J, Joubert C, Arenales S, Jacquet N, Sorokine-Durm I, Chau Q, Lopez M, Gourmelon P: Level of Flt3-ligand in plasma: a possible new bio-indicator for radiation-induced aplasia. Int J Radiat Biol 2001, 77:703-712.
• [47]Huchet A, Belkacemi Y, Frick J, Prat M, Muresan-Kloos I, Altan D, Chapel A, Gorin NC, Gourmelon P, Bertho JM: Plasma Flt-3 ligand concentration correlated with radiation- induced bone marrow damage during local fractionated radiotherapy. Int J Radiat Oncol Biol Phys 2003, 57:508-515.
• [48]Prat M, Demarquay C, Frick J, Thierry D, Gorin NC, Bertho JM: Radiation-induced increase in plasma Flt3 ligand concentration in mice: evidence for the implication of several cell types. Radiat Res 2005, 163:408-417.
• [49]Bociek RG, Armitage JO: Hematopoietic growth factors. CA: Cancer J Clinicians 1996, 46:165-184.
• [50]Gerber A, Struy H, Weiss G, Lippert H, Ansorge S, Schulz HU: Effect of granulocyte colony-stimulating factor treatment on ex vivo neutrophil functions in nonneutropenic surgical intensive care patients. Journal Interferon Cytokine Res 2000, 20:1083-1090.
• [51]Wenisch C, Werkgartner T, Sailer H, Patruta S, Krause R, Daxboeck F, Parschalk B: Effect of preoperative prophylaxis with filgrastim in cancer neck dissection. Eur J Clin Inv 2000, 30:460-466.
• [52]Neta R, Oppenheim JJ, Douches SD: Interdependence of the radioprotective effects of human recombinant interleukin 1 alpha, tumor necrosis factor alpha, granulocyte colony stimulating factor, and murine recombinant granulocyte-macrophage colony stimulating factor. J Immunol 1988, 140:108-111.
• [53]Uckun FM, Souza L, Waddick KG, Wick M, Song CW: In vivo radioprotective effects of recombinant human granulocyte colony-stimulating factor in lethally irradiated mice. Blood 1990, 5:638-645.
• [54]Singh VK, Shafran RL, Jackson WE III, Seed TM, Kumar KS: Induction of cytokines by radioprotective tocopherol analogs. Exp Mol Pathol 2006, 81:55-61.
• [55]Singh VK, Brown DS, Kao ZC: Alpha-tocopherol succinate protects mice from gamma-radiation by induction of granulocyte-colony stimulating factor. Int J Radiat Biol 2010, 86:12-21.
• [56]Hofer M, Pospisil M, Znojil V, Hola J, Vacek A, Streitova D: Meloxicam, an inhibitor of cyclooxygenase-2, increases the level of serum G-CSF and might be usable as an auxiliary means in G-CSF therapy. Physiol Res 2008, 57:307-310.
• [57]Singh VK, Shafran RL, Inal CE, Jackson WE III, Whitnall MH: Effects of whole-body gamma irradiation and 5-androstenediol administration on serum G-CSF. Immunopharmacol Immunotoxicol 2005, 27:521-534.
• [58]Herbert KE, Walkley CR, Winkler IG, Hendy J, Olsen GH, Yuan YD, Chandraratna RA, Prince HM, Levesque JP, Purton LE: Granulocyte colony-stimulating factor and a RARalpha specific agonist, VTP195183, synergize to enhance the mobilization of hematopoietic progenitor cells. Transplantation 2007, 83:375-384.
• [59]Hermans MH, van de Geijn GJ, Antonissen C, Gits J, van Leeuwen D, Ward AC, Touw IP: Signaling mechanisms coupled to tyrosines in the granulocyte colony-stimulating factor receptor orchestrate G-CSF- induced expansion of myeloid progenitor cells. Blood 2003, 101:2584-2590.
• [60]Bhanja P, Saha S, Kabarriti R, Liu L, Roy-Chowdhury N, Roy-Chowdhury J, Sellers RS, Alfieri AA, Guha C: Protective role of R-spondin1, an intestinal stem cell growth factor, against radiation-induced gastrointestinal syndrome in mice. PLoS ONE 2009, 4:e8014.
• [61]Day RM, Barshishat-Kupper M, Mog SR, McCart EA, Prasanna PG, Davis TA, Landauer MR: Genistein protects against biomarkers of delayed lung sequelae in mice surviving high-dose total body irradiation. J Radiat Res 2008, 49:361-372.
• [62]Lu X, Li Y, Simovic MO, Peckham R, Wang Y, Tsokos GC, Dalle Lucca JJ: Decay-accelerating factor attenuates C-reactive protein-potentiated tissue injury after mesenteric ischemia/reperfusion. J Surg Res 2011, 167:e103-15.