Michael L. Freeman, Ph.D.

Professor

michael.freeman@vanderbilt.edu
Faculty Appointments
Professor of Radiation Oncology Professor of Cancer BiologyProfessor of Radiology and Radiological Sciences
Education
Ph.D., Radiation Biology, Colorado State University, Fort Collins, ColoradoB.S., Zoology, Colorado State University, Fort Collins, Colorado
Office Address
1161 21st Avenue, South
MCN CCC-1121
Nashville, TN 37232-2675
Research Description
Radiation Oncology leverages cutting edge advancements in physics and engineering for the treatment of cancer. Co-registration of diagnostic data sets into a coherent 3D-treatment plan allows individualized precision tumor targeting. Radiation oncology has the potential to provide outstanding personalized cancer treatment. However, cancer cell radioresistance and normal tissue injury represent two important limitations that can limit the ability of ionizing radiation to provide local/regional control of tumor growth. To addresses these limitations our laboratory initiated a cancer drug discovery program that seeks to develop efficacious radiation sensitizers. Two-indol-3-yl-methylenequinuclidin-3-ols and 5-((N-benzyl-1H-indol-3-yl)-methylene)pyrimidine-2,4,6(1H,3H,5H) trione have been synthesized and are currently being evaluated using defined DNA substrates, cell-based and murine mouse models. Elucidating the underlying mechanisms that drive the pathophysiology of normal tissue injury produced by ionizing radiation is also a focus of this laboratory. A holistic approach is used that encompasses well defined biochemical assays, cell-based assays such as ChIP Exo and transcriptome profiling, as well as GEMMs.


Research Keywords
Drug Discovery/Radiation Sensitizers, Development of novel compounds that target tumor angiogenesis, Nrf2/Keap1 in cancer and inflammation, Smad-mediated transcription in cancer.
Publications
Sekhar KR, Benamar M, Venkateswaran A, Sasi S, Penthala NR, Crooks PA, Hann SR, Geng L, Balusu R, Abbas T, Freeman ML. Targeting nucleophosmin 1 represents a rational strategy for radiation sensitization. Int. J. Radiat. Oncol. Biol. Phys [print-electronic]. 2014 Aug 8/1/2014; 89(5): 1106-14. PMID: 25035215, PMCID: PMC4105849, PII: S0360-3016(14)00461-1, DOI: 10.1016/j.ijrobp.2014.04.012, ISSN: 1879-355X.

Schultz MA, Hagan SS, Datta A, Zhang Y, Freeman ML, Sikka SC, Abdel-Mageed AB, Mondal D. Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells. PLoS ONE. 2014; 9(1): e87204. PMID: 24466341, PMCID: PMC3899380, PII: PONE-D-13-07563, DOI: 10.1371/journal.pone.0087204, ISSN: 1932-6203.

Hallahan DE, Freeman ML. Thoughts on the future of research, teaching, and testing in the biological sciences of radiation oncology [editorial]. Int. J. Radiat. Oncol. Biol. Phys. 2014 Jan 1/1/2014; 88(1): 1-2. PMID: 24331646, PII: S0360-3016(13)03188-X, DOI: 10.1016/j.ijrobp.2013.09.048, ISSN: 1879-355X.

Venkateswaran A, Sekhar KR, Levic DS, Melville DB, Clark TA, Rybski WM, Walsh AJ, Skala MC, Crooks PA, Knapik EW, Freeman ML. The NADH oxidase ENOX1, a critical mediator of endothelial cell radiosensitization, is crucial for vascular development. Cancer Res [print-electronic]. 2014 Jan 1/1/2014; 74(1): 38-43. PMID: 24247717, PMCID: PMC3947320, PII: 0008-5472.CAN-13-1981, DOI: 10.1158/0008-5472.CAN-13-1981, ISSN: 1538-7445.

Venkateswaran A, Friedman DB, Walsh AJ, Skala MC, Sasi S, Rachakonda G, Crooks PA, Freeman ML, Sekhar KR. The novel antiangiogenic VJ115 inhibits the NADH oxidase ENOX1 and cytoskeleton-remodeling proteins. Invest New Drugs [print-electronic]. 2013 Jun; 31(3): 535-44. PMID: 23054211, PMCID: PMC3553230, DOI: 10.1007/s10637-012-9884-9, ISSN: 1573-0646.

Rana T, Schultz MA, Freeman ML, Biswas S. Loss of Nrf2 accelerates ionizing radiation-induced bone loss by upregulating RANKL. Free Radic. Biol. Med [print-electronic]. 2012 Dec 12/15/2012; 53(12): 2298-307. PMID: 23085426, PMCID: PMC3762920, PII: S0891-5849(12)01767-4, DOI: 10.1016/j.freeradbiomed.2012.10.536, ISSN: 1873-4596.

Sekhar KR, Reddy YT, Reddy PN, Crooks PA, Venkateswaran A, McDonald WH, Geng L, Sasi S, Van Der Waal RP, Roti JL, Salleng KJ, Rachakonda G, Freeman ML. The novel chemical entity YTR107 inhibits recruitment of nucleophosmin to sites of DNA damage, suppressing repair of DNA double-strand breaks and enhancing radiosensitization. Clin. Cancer Res [print-electronic]. 2011 Oct 10/15/2011; 17(20): 6490-9. PMID: 21878537, PMCID: PMC3195947, PII: 1078-0432.CCR-11-1054, DOI: 10.1158/1078-0432.CCR-11-1054, ISSN: 1078-0432.

Dworski R, Han W, Blackwell TS, Hoskins A, Freeman ML. Vitamin E prevents NRF2 suppression by allergens in asthmatic alveolar macrophages in vivo. Free Radic. Biol. Med [print-electronic]. 2011 Jul 7/15/2011; 51(2): 516-21. PMID: 21605660, PMCID: PMC3439844, PII: S0891-5849(11)00281-4, DOI: 10.1016/j.freeradbiomed.2011.04.040, ISSN: 1873-4596.

Zhao Z, Chen Y, Wang J, Sternberg P, Freeman ML, Grossniklaus HE, Cai J. Age-related retinopathy in NRF2-deficient mice. PLoS ONE. 2011; 6(4): e19456. PMID: 21559389, PMCID: PMC3084871, PII: PONE-D-11-01904, DOI: 10.1371/journal.pone.0019456, ISSN: 1932-6203.

Venkateswaran A, Reddy YT, Sonar VN, Muthusamy V, Crooks PA, Freeman ML, Sekhar KR. Antiangiogenic properties of substituted (Z)-(±)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol/one analogs and their derivatives. Bioorg. Med. Chem. Lett [print-electronic]. 2010 Dec 12/15/2010; 20(24): 7323-6. PMID: 21055930, PMCID: PMC3001633, PII: S0960-894X(10)01521-0, DOI: 10.1016/j.bmcl.2010.10.060, ISSN: 1464-3405.

Pruitt R, Sasi N, Freeman ML, Sekhar KR. Radiosensitization of cancer cells by hydroxychalcones. Bioorg. Med. Chem. Lett [print-electronic]. 2010 Oct 10/15/2010; 20(20): 5997-6000. PMID: 20826087, PMCID: PMC2946792, PII: S0960-894X(10)01217-5, DOI: 10.1016/j.bmcl.2010.08.081, ISSN: 1464-3405.

Rachakonda G, Sekhar KR, Jowhar D, Samson PC, Wikswo JP, Beauchamp RD, Datta PK, Freeman ML. Increased cell migration and plasticity in Nrf2-deficient cancer cell lines. Oncogene [print-electronic]. 2010 Jun 6/24/2010; 29(25): 3703-14. PMID: 20440267, PMCID: PMC2892014, PII: onc2010118, DOI: 10.1038/onc.2010.118, ISSN: 1476-5594.

Sekhar KR, Rachakonda G, Freeman ML. Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicol. Appl. Pharmacol [print-electronic]. 2010 Apr 4/1/2010; 244(1): 21-6. PMID: 19560482, PMCID: PMC2837771, PII: S0041-008X(09)00265-8, DOI: 10.1016/j.taap.2009.06.016, ISSN: 1096-0333.

Reddy YT, Sekhar KR, Sasi N, Reddy PN, Freeman ML, Crooks PA. Novel substituted (Z)-5-((N-benzyl-1H-indol-3-yl)methylene)imidazolidine-2,4-diones and 5-((N-benzyl-1H-indol-3-yl)methylene)pyrimidine-2,4,6(1H,3H,5H)-triones as potent radio-sensitizing agents. Bioorg. Med. Chem. Lett [print-electronic]. 2010 Jan 1/15/2010; 20(2): 600-2. PMID: 20005706, PMCID: PMC4159675, PII: S0960-894X(09)01652-7, DOI: 10.1016/j.bmcl.2009.11.082, ISSN: 1464-3405.

Segal BH, Han W, Bushey JJ, Joo M, Bhatti Z, Feminella J, Dennis CG, Vethanayagam RR, Yull FE, Capitano M, Wallace PK, Minderman H, Christman JW, Sporn MB, Chan J, Vinh DC, Holland SM, Romani LR, Gaffen SL, Freeman ML, Blackwell TS. NADPH oxidase limits innate immune responses in the lungs in mice. PLoS ONE. 2010; 5(3): e9631. PMID: 20300512, PMCID: PMC2838778, DOI: 10.1371/journal.pone.0009631, ISSN: 1932-6203.

Geng L, Rachakonda G, Morré DJ, Morré DM, Crooks PA, Sonar VN, Roti JL, Rogers BE, Greco S, Ye F, Salleng KJ, Sasi S, Freeman ML, Sekhar KR. Indolyl-quinuclidinols inhibit ENOX activity and endothelial cell morphogenesis while enhancing radiation-mediated control of tumor vasculature. FASEB J [print-electronic]. 2009 Sep; 23(9): 2986-95. PMID: 19395476, PMCID: PMC2796904, PII: fj.09-130005, DOI: 10.1096/fj.09-130005, ISSN: 1530-6860.

Fukuyo Y, Inoue M, Nakajima T, Higashikubo R, Horikoshi NT, Hunt C, Usheva A, Freeman ML, Horikoshi N. Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives. Cancer Res. 2008 Aug 8/1/2008; 68(15): 6324-30. PMID: 18676857, PMCID: PMC2693332, PII: 68/15/6324, DOI: 10.1158/0008-5472.CAN-07-6602, ISSN: 1538-7445.

Burk RF, Hill KE, Nakayama A, Mostert V, Levander XA, Motley AK, Johnson DA, Johnson JA, Freeman ML, Austin LM. Selenium deficiency activates mouse liver Nrf2-ARE but vitamin E deficiency does not. Free Radic. Biol. Med [print-electronic]. 2008 Apr 4/15/2008; 44(8): 1617-23. PMID: 18279678, PMCID: PMC2346531, PII: S0891-5849(08)00038-5, DOI: 10.1016/j.freeradbiomed.2008.01.016, ISSN: 0891-5849.

Rachakonda G, Xiong Y, Sekhar KR, Stamer SL, Liebler DC, Freeman ML. Covalent modification at Cys151 dissociates the electrophile sensor Keap1 from the ubiquitin ligase CUL3. Chem. Res. Toxicol [print-electronic]. 2008 Mar; 21(3): 705-10. PMID: 18251510, DOI: 10.1021/tx700302s, ISSN: 0893-228X.

Brown SL, Sekhar KR, Rachakonda G, Sasi S, Freeman ML. Activating transcription factor 3 is a novel repressor of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2)-regulated stress pathway. Cancer Res. 2008 Jan 1/15/2008; 68(2): 364-8. PMID: 18199529, PII: 68/2/364, DOI: 10.1158/0008-5472.CAN-07-2170, ISSN: 1538-7445.

Sonar VN, Thirupathi Reddy Y, Sekhar KR, Sasi S, Freeman ML, Crooks PA. Novel substituted (Z)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-one and (Z)-(+/-)-2-(N-benzylindol-3-ylmethylene)quinuclidin-3-ol derivatives as potent thermal sensitizing agents. Bioorg. Med. Chem. Lett [print-electronic]. 2007 Dec 12/15/2007; 17(24): 6821-4. PMID: 17980582, PMCID: PMC3726020, PII: S0960-894X(07)01204-8, DOI: 10.1016/j.bmcl.2007.10.035, ISSN: 1464-3405.

Al-Ghananeem AM, Albayati ZF, Malkawi A, Sonar VN, Freeman ML, Crooks PA. A pharmacokinetic study on Z-(+/-)-2-(1-benzylindole-3-yl-methylene)azabicyclo[2.2.2]octane-3-ol; a novel radio-sensitization agent. Cancer Chemother. Pharmacol [print-electronic]. 2007 Nov; 60(6): 915-9. PMID: 17294191, DOI: 10.1007/s00280-007-0425-8, ISSN: 0344-5704.

Brunoldi EM, Zanoni G, Vidari G, Sasi S, Freeman ML, Milne GL, Morrow JD. Cyclopentenone prostaglandin, 15-deoxy-Delta12,14-PGJ2, is metabolized by HepG2 cells via conjugation with glutathione. Chem. Res. Toxicol [print-electronic]. 2007 Oct; 20(10): 1528-35. PMID: 17854155, DOI: 10.1021/tx700231a, ISSN: 0893-228X.

Pi J, Bai Y, Reece JM, Williams J, Liu D, Freeman ML, Fahl WE, Shugar D, Liu J, Qu W, Collins S, Waalkes MP. Molecular mechanism of human Nrf2 activation and degradation: role of sequential phosphorylation by protein kinase CK2. Free Radic. Biol. Med [print-electronic]. 2007 Jun 6/15/2007; 42(12): 1797-806. PMID: 17512459, PMCID: PMC1950666, PII: S0891-5849(07)00176-1, DOI: 10.1016/j.freeradbiomed.2007.03.001, ISSN: 0891-5849.

Biswas S, Guix M, Rinehart C, Dugger TC, Chytil A, Moses HL, Freeman ML, Arteaga CL. Inhibition of TGF-beta with neutralizing antibodies prevents radiation-induced acceleration of metastatic cancer progression. J. Clin. Invest [print-electronic]. 2007 May; 117(5): 1305-13. PMID: 17415413, PMCID: PMC1838926, DOI: 10.1172/JCI30740, ISSN: 0021-9738.

Gao L, Wang J, Sekhar KR, Yin H, Yared NF, Schneider SN, Sasi S, Dalton TP, Anderson ME, Chan JY, Morrow JD, Freeman ML. Novel n-3 fatty acid oxidation products activate Nrf2 by destabilizing the association between Keap1 and Cullin3. J. Biol. Chem [print-electronic]. 2007 Jan 1/26/2007; 282(4): 2529-37. PMID: 17127771, PII: M607622200, DOI: 10.1074/jbc.M607622200, ISSN: 0021-9258.

Sekhar KR, Sonar VN, Muthusamy V, Sasi S, Laszlo A, Sawani J, Horikoshi N, Higashikubo R, Bristow RG, Borrelli MJ, Crooks PA, Lepock JR, Roti Roti JL, Freeman ML. Novel chemical enhancers of heat shock increase thermal radiosensitization through a mitotic catastrophe pathway. Cancer Res. 2007 Jan 1/15/2007; 67(2): 695-701. PMID: 17234780, PII: 67/2/695, DOI: 10.1158/0008-5472.CAN-06-3212, ISSN: 0008-5472.

Stacy DR, Ely K, Massion PP, Yarbrough WG, Hallahan DE, Sekhar KR, Freeman ML. Increased expression of nuclear factor E2 p45-related factor 2 (NRF2) in head and neck squamous cell carcinomas. Head Neck. 2006 Sep; 28(9): 813-8. PMID: 16637057, DOI: 10.1002/hed.20430, ISSN: 1043-3074.

Cao C, Shinohara ET, Li H, Niermann KJ, Kim KW, Sekhar KR, Gleave M, Freeman M, Lu B. Clusterin as a therapeutic target for radiation sensitization in a lung cancer model. Int. J. Radiat. Oncol. Biol. Phys. 2005 Nov 11/15/2005; 63(4): 1228-36. PMID: 16253777, PII: S0360-3016(05)02143-7, DOI: 10.1016/j.ijrobp.2005.07.956, ISSN: 0360-3016.

Hong F, Sekhar KR, Freeman ML, Liebler DC. Specific patterns of electrophile adduction trigger Keap1 ubiquitination and Nrf2 activation. J. Biol. Chem [print-electronic]. 2005 Sep 9/9/2005; 280(36): 31768-75. PMID: 15985429, PII: M503346200, DOI: 10.1074/jbc.M503346200, ISSN: 0021-9258.

Bakin AV, Stourman NV, Sekhar KR, Rinehart C, Yan X, Meredith MJ, Arteaga CL, Freeman ML. Smad3-ATF3 signaling mediates TGF-beta suppression of genes encoding Phase II detoxifying proteins. Free Radic. Biol. Med. 2005 Feb 2/1/2005; 38(3): 375-87. PMID: 15629866, PII: S0891-5849(04)00882-2, DOI: 10.1016/j.freeradbiomed.2004.10.033, ISSN: 0891-5849.

Andrei V. Bakin, Konjeti R. Sekhar, Cammie Rinehart, Xuexian Yan, Michael J. Meredith, Carlos L. Arteaga, and Michael L. Freeman.. Smad3-ATF3 signaling mediates TGF-b suppression of genes encoding Phase II detoxifying proteins. Free Radical Biology & Medicine. 2005; 38: 375-87.

Hong, F, Freeman, ML, Liebler DC. Identification of sensor cysteines in human Keap1 modified by the cancer chemopreventive agent sulforaphane. Chem Res. Toxicol. 2005; 19: 1917-26.

Milne GL, Zanoni G, Porta A, Sasi S, Vidari G, Musiek ES, Freeman ML, Morrow JD. The cyclopentenone product of lipid peroxidation, 15-A2t-isoprostane, is efficiently metabolized by HepG2 cells via conjugation with glutathione. Chem. Res. Toxicol. 2004 Jan; 17(1): 17-25. PMID: 14727915, DOI: 10.1021/tx034213o, ISSN: 0893-228X.

Ginger L. Milne, Guiseppe Zanoni, Soumya Sasi, Giovanni Vidari, Erik S. Musiek, Michael L. Freeman, and Jason D. Morrow. The Cyclopentenone Product of Lipid Peroxidation, 15-A2t-Isoprostane, is Efficiently Metabolized by HepG2 Cells Via Conjugation with Glutathione. Chem Res. Tox. 17: 17-25, 2004. Chem Res. 2004; 17: 17-25.

Lu B, Mu Y, Cao C, Zeng F, Schneider S, Tan J, Price J, Chen J, Freeman M, Hallahan DE.. Survivin as a therapeutic target for radiation sensitization in lung cancer. Cancer Res. 2004; 64: 2840-5.

Saha D, Sekhar KR, Cao C, Morrow JD, Choy H, Freeman ML. The antiangiogenic agent SU5416 down-regulates phorbol ester-mediated induction of cyclooxygenase 2 expression by inhibiting nicotinamide adenine dinucleotide phosphate oxidase activity. Cancer Res. 2003 Oct 10/15/2003; 63(20): 6920-7. PMID: 14583492, ISSN: 0008-5472.

Sekhar KR, Crooks PA, Sonar VN, Friedman DB, Chan JY, Meredith MJ, Starnes JH, Kelton KR, Summar SR, Sasi S, Freeman ML. NADPH oxidase activity is essential for Keap1/Nrf2-mediated induction of GCLC in response to 2-indol-3-yl-methylenequinuclidin-3-ols. Cancer Res. 2003 Sep 9/1/2003; 63(17): 5636-45. PMID: 14500406, ISSN: 0008-5472.

Willis AS, Freeman ML, Summar SR, Barr FE, Williams SM, Dawson E, Summar ML. Ethnic diversity in a critical gene responsible for glutathione synthesis. Free Radic. Biol. Med. 2003 Jan 1/1/2003; 34(1): 72-6. PMID: 12498981, PII: S0891584902011784, ISSN: 0891-5849.

Willis AS, Freeman ML, Summar SR, Williams SM, Dawson E, and Summar ML.. Ethnic specific changes in a critical gene responsible for glutathione synthesis. Free Radical Biology and Medicine. 2003; 34: 72-6.

Sekhar KR, Crooks PA, Sonar VN, Friedman DB, Chan JY, Meredith MJ, Starnes JH, Kelton KR, Summar SR, Sasi S, and Freeman ML.. NADPH Oxidase Activity is Essential for Keap1/ Nrf2-Mediated Induction of GCLC in Response to 2-Indol-3-yl-methylenequinuclidin-3-ols. Cancer Res. 2003; 63: 5636-45.

Willis AS, Freeman ML, Summar SR, Williams SM, Dawson E, and Summar ML.. Ethnic specific changes in a critical gene responsible for glutathione synthesis. Free Radical Biology and Medicine. 34: 72-76, 2003. Free Radical Biology and Medicine. 2003; 34: 72-6.

Sekhar KR, Crooks PA, Sonar VN, Friedman DB, Chan JY, Meredith MJ, Starnes JH, Kelton KR, Summar SR, Sasi S, and Freeman ML.. NADPH Oxidase Activity is Essential for Keap1/ Nrf2-Mediated Induction of GCLC in Response to 2-Indol-3-yl-methylenequinuclidin-3-ols. Cancer Res. 2003; 63: 5636-45.

Saha, D., Sekhar, KR, Cao C, Morrow, JD, Choy, H, and Freeman, ML.. The antiangiogenic agent SU5416 downregulates phorbol ester-mediated induction of cyclooxygenase-2 expression by inhibiting NADPH Oxidase activity. Cancer Res. 2003; 63: 6920-7.

Sekhar KR, Yan XX, Freeman ML. Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2. Oncogene. 2002 Oct 10/3/2002; 21(44): 6829-34. PMID: 12360409, DOI: 10.1038/sj.onc.1205905, ISSN: 0950-9232.

Borrelli MJ, Bernock LJ, Landry J, Spitz DR, Weber LA, Hickey E, Freeman ML, Corry PM. Stress protection by a fluorescent Hsp27 chimera that is independent of nuclear translocation or multimeric dissociation. Cell Stress Chaperones. 2002 Jul; 7(3): 281-96. PMID: 12482204, PMCID: PMC514828, ISSN: 1355-8145.

Sekhar KR, Spitz DR, Harris S, Nguyen TT, Meredith MJ, Holt JT, Gius D, Marnett LJ, Summar ML, Freeman ML. Redox-sensitive interaction between KIAA0132 and Nrf2 mediates indomethacin-induced expression of gamma-glutamylcysteine synthetase. Free Radic. Biol. Med. 2002 Apr 4/1/2002; 32(7): 650-62. PMID: 11909699, PII: S0891584902007554, ISSN: 0891-5849.

Sekhar KR, Spitz DR, Harris s, Nguyen TT, Meredith MJ, Holt JT, Gius D, Marnett LJ, Summar ML, and Freeman ML.. Redox sensitivie interaction between KIAA0132 and Nrf2 mediates indomethacin –induced expression of g-glutamylcysteine synthetase. Free Radical Biology and Medicine. 2002; 32: 650-62.

Sekhar KR, Spitz DR, Harris s, Nguyen TT, Meredith MJ, Holt JT, Gius D, Marnett LJ, Summar ML, and Freeman ML.. Redox sensitivie interaction between KIAA0132 and Nrf2 mediates indomethacin –induced expression of g-glutamylcysteine synthetase. Free Radical Biology and Medicine. 2002; 32: 650-62.

Sekhar KR, Yan X, and Freeman ML.. Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to Inrf2. Oncogene. 2002; 21: 6829-34.

Freeman ML, Henle KJ, Dewhirst M W. Hyperthermia. Molecular Biology of Cancer (ed. JR Bertino). 2001; 888-900.

Sekhar KR, Soltaninassab SR, Borrelli MJ, Xu ZQ, Meredith MJ, Domann FE, Freeman ML. Inhibition of the 26S proteasome induces expression of GLCLC, the catalytic subunit for gamma-glutamylcysteine synthetase. Biochem. Biophys. Res. Commun. 2000 Apr 4/2/2000; 270(1): 311-7. PMID: 10733945, PII: S0006-291X(00)92419-7, DOI: 10.1006/bbrc.2000.2419, ISSN: 0006-291X.

Amorino GP, Freeman ML, Choy H. Enhancement of radiation effects in vitro by the estrogen metabolite 2-methoxyestradiol. Radiat. Res. 2000 Apr; 153(4): 384-91. PMID: 10760997, ISSN: 0033-7587.

Soltaninassab SR, Sekhar KR, Meredith MJ, Freeman ML. Multi-faceted regulation of gamma-glutamylcysteine synthetase. J. Cell. Physiol. 2000 Feb; 182(2): 163-70. PMID: 10623879, PII: 10.1002/(SICI)1097-4652(200002)182:2<163::AID-JCP4>3.0.CO;2-1, DOI: 10.1002/(SICI)1097-4652(200002)182:2<163::AID-JCP4>3.0.CO;2-1, ISSN: 0021-9541.

Soltaninassab SR, Sekhar KR, Meredith ML, and Freeman ML. Multi-faceted regulation of gamma glutamylcysteine synthetase. J. Cell Physiol. 2000; 182: 163-70.

Amorino GP, Freeman ML, Choy H. Enhancement of radiation effects by the estrogen metabolite 2-methoxyestradiol. Radiation Research. 2000; 153: 384-91.

Brown NJ, Nakamura S, Ma LJ, Nakamura I, Donnert E, Freeman M, Vaughan DE, and Fogo AB. Aldosterone modulates plasminogen activator inhibitor-1 and glomerulosclerosis in vivo. Kidney Int. 2000; 58: 1219-27.

Sekhar KR,Soltaninassab SR, Borrelli MJ, Xu ZQ, Meredith MJ, Domann FE, and Freeman ML. Inhibition of the 26S proteasome induces expression of GLCLC, the Catalytic Subunit for -Glutamylcysteine Synthetase. BBRC. 2000; 270: 311-7.

GA Senisterra, HE Frey, ML Freeman, MJ Borrelli, and JR Lepock. Protein destabilization and denaturation: Implications for hyperthermia and the heat shock response. Recent. Res. Devel. Biochem. 2000; 2: 65-96.

Amorino GP, Freeman ML, Carbone DP, Lebwohl DE, Choy H. Radiopotentiation by the oral platinum agent, JM216: role of repair inhibition. Int. J. Radiat. Oncol. Biol. Phys. 1999 May 5/1/1999; 44(2): 399-405. PMID: 10760436, PII: S0360-3016(99)00033-4, ISSN: 0360-3016.

Freeman ML, Borrelli MJ, Meredith MJ, Lepock JR. On the path to the heat shock response: destabilization and formation of partially folded protein intermediates, a consequence of protein thiol modification. Free Radic. Biol. Med. 1999 Mar; 26(5-6): 737-45. PMID: 10218664, PII: S0891-5849(98)00258-5, ISSN: 0891-5849.

Sekhar KR, Freeman ML. Autophosphorylation inhibits the activity of gamma-glutamylcysteine synthetase. J. Enzym. Inhib. 1999; 14(4): 323-30. PMID: 10445052, ISSN: 8755-5093.

Freeman ML, Borrelli MJ, Meredith MJ, and Lepock JR. On the Path to the Heat Shock Response: Destabilization and Formation of Molten Globule Intermediates, a Consequence of Protein Thiol Modification. Free Radical Biology and Medicine. 1999; 26: 737-45.

Sekhar KR and Freeman ML. Autophosphorylation inhibits the activity of gamma- glutamylcysteine synthetase. J. Enzyme Inhibition. 1999; 14: 323-30.

Amorino G, Freeman ML, Carbone DP, Lebwohl DE, and Choy H. Radioprotection by the oral platinum agent, JM216: Role of repair inhibition. Inter. J. Radiation Oncology, Biology, Physics. 1999; 44: 399-405.

Borrelli MJ, Stafford DM, Rausch CM, Bernock LJ, Freeman ML, Lepock JR, Corry PM. Diamide-induced cytotoxicity and thermotolerance in CHO cells. J. Cell. Physiol. 1998 Dec; 177(3): 483-92. PMID: 9808156, PII: 10.1002/(SICI)1097-4652(199812)177:3<483::AID-JCP11>3.0.CO;2-H, DOI: 10.1002/(SICI)1097-4652(199812)177:3<483::AID-JCP11>3.0.CO;2-H, ISSN: 0021-9541.

Meredith MJ, Cusick CL, Soltaninassab S, Sekhar KS, Lu S, Freeman ML. Expression of Bcl-2 increases intracellular glutathione by inhibiting methionine-dependent GSH efflux. Biochem. Biophys. Res. Commun. 1998 Jul 7/30/1998; 248(3): 458-63. PMID: 9703946, PII: S0006-291X(98)98998-7, DOI: 10.1006/bbrc.1998.8998, ISSN: 0006-291X.

Abbott DW, Freeman ML, Holt JT. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. J. Natl. Cancer Inst. 1998 Jul 7/1/1998; 90(13): 978-85. PMID: 9665145, ISSN: 0027-8874.

Sekhar KR, Freeman ML. PEST sequences in proteins involved in cyclic nucleotide signalling pathways. J. Recept. Signal Transduct. Res. 1998 Mar; 18(2-3): 113-32. PMID: 9651881, DOI: 10.3109/10799899809047740, ISSN: 1079-9893.

Brown KE, Kinter MT, Oberley TD, Freeman ML, Frierson HF, Ridnour LA, Tao Y, Oberley LW, Spitz DR. Enhanced gamma-glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload. Free Radic. Biol. Med. 1998 Mar 3/1/1998; 24(4): 545-55. PMID: 9559866, PII: S0891-5849(97)00284-0, ISSN: 0891-5849.

Brown KE, Kinter MT, Oberley TD, Freeman ML, Frierson HF, Ridnour LA, Tao Y, Oberley LW, and Spitz DR. Enhanced -glutamyl transpeptidase expression and selective loss of CuZn superoxide dismutase in hepatic iron overload. Free Radical Biology and Medicine. 1998; 24: 545-55.

Abbott DW, Freeman ML, and Holt JT. Double-Strand Break Repair Deficiency and Radiation Sensitivity in BRCA2 Mutant Cancer Cells. JNCI. 1998; 90: 978-85.

Borrelli MJ, Stafford DM, Rausch CM, Freeman ML, Lepock JR, and Corry PM. Diamide induced cytoxicity and thermotolerance in CHO cells. J. Cell. Physiol. 1998; 177: 483-92.

Meredith MJ, Cusick CL, Soltaninassab S, Sekhar KS, Lu S and Freeman ML. Expression of Bcl-2 increases intracellular glutathione by inhibiting methionine dependent GSH efflux. BBRC. 1998; 248: 458-63.

Sekhar KR and Freeman ML. PEST sequences in proteins involved in cyclic nucliotide signalling pathways. J. Receptor and Signal Transduction Research. 1998; 18: 113-32.

Senisterra GA, Huntley SA, Escaravage M, Sekhar KR, Freeman ML, Borrelli M, Lepock JR. Destabilization of the Ca2+-ATPase of sarcoplasmic reticulum by thiol-specific, heat shock inducers results in thermal denaturation at 37 degrees C. Biochemistry. 1997 Sep 9/9/1997; 36(36): 11002-11. PMID: 9283092, PII: bi9711590, DOI: 10.1021/bi9711590, ISSN: 0006-2960.

Freeman ML, Huntley SA, Meredith MJ, Senisterra GA, Lepock J. Destabilization and denaturation of cellular protein by glutathione depletion. Cell Stress Chaperones. 1997 Sep; 2(3): 191-8. PMID: 9314607, PMCID: PMC312997, ISSN: 1355-8145.

Sekhar KR, Meredith MJ, Kerr LD, Soltaninassab SR, Spitz DR, Xu ZQ, Freeman ML. Expression of glutathione and gamma-glutamylcysteine synthetase mRNA is Jun dependent. Biochem. Biophys. Res. Commun. 1997 May 5/29/1997; 234(3): 588-93. PMID: 9175757, PII: S0006-291X(97)96697-3, DOI: 10.1006/bbrc.1997.6697, ISSN: 0006-291X.

Sekhar KR, Long M, Long J, Xu ZQ, Summar ML, Freeman ML. Alteration of transcriptional and post-transcriptional expression of gamma-glutamylcysteine synthetase by diethyl maleate. Radiat. Res. 1997 May; 147(5): 592-7. PMID: 9146705, ISSN: 0033-7587.

McDuffee AT, Senisterra G, Huntley S, Lepock JR, Sekhar KR, Meredith MJ, Borrelli MJ, Morrow JD, Freeman ML. Proteins containing non-native disulfide bonds generated by oxidative stress can act as signals for the induction of the heat shock response. J. Cell. Physiol. 1997 May; 171(2): 143-51. PMID: 9130461, PII: 10.1002/(SICI)1097-4652(199705)171:2<143::AID-JCP4>3.0.CO;2-O, DOI: 10.1002/(SICI)1097-4652(199705)171:2<143::AID-JCP4>3.0.CO;2-O, ISSN: 0021-9541.

Sekhar KR, Meredith MJ, Kerr KD, Soltaninassab SR, Spitz DR, Xu ZQ, and Freeman ML. Expression of glutathione and - glutamylcysteine synthetase mRNA is Jun dependent. 1997.

McDuffee AT, Senisterra GA, Huntley SA, Lepock JR, Senkhar KR, Morrow JD, and Freeman ML. Proteins containing non-native disulfide bonds generated by oxidative stress may act as signals for the induction of the heat shock response. J. Cellular Physiology. 1997; 171: 143-51.

Sekhar KR, Long M, Long, J, Xu ZQ, Summar, ML, and Freeman, ML. Alteration of transcriptional and post-transcriptional expression of -glutamylcysteine synthetase by diethyl maleate. Radiation Res. 1997; 147: 592-7.

Freeman ML, Huntely SA, Meredith MJ, Senisterra GA, and Lepock JR. Destabilization and denaturation of cellular protein by glutathione depletion. Cell Stress and Chaperones. 1997; 2: 191-8.

Senisterra GA, Huntley SA, Escaravage M, Sekhar KR, Freeman ML, Borrelli M, and Lepock JR. Destabilization of the Ca2+-ATPase of Sarcoplasmic reticulum by thiol specific-specific, heat shock inducers results in thermal denaturation at 37 C. Biochemistry. 1997; 36: 11002-11.

Jennings MT, Freeman ML, Murray MJ. Strategies in the treatment of diffuse pontine gliomas: the therapeutic role of hyperfractionated radiotherapy and chemotherapy. J. Neurooncol. 1996 May; 28(2-3): 207-22. PMID: 8832463, ISSN: 0167-594X.

Sierra-Rivera E, Dasouki M, Summar ML, Krishnamani MRS, Meredith M, Rao PN, Phillips JA, and Freeman ML. Chromosomal localization of the human gene that encodes the regulatory subunit of -glutamylcysteine synthetase to chromosome 1p21. 1996.

Sierra-Rivera E, Dasouki M, Summar ML, Krishnamani MR, Meredith M, Rao PN, Phillips JA, Freeman ML. Assignment of the human gene (GLCLR) that encodes the regulatory subunit of gamma-glutamylcysteine synthetase to chromosome 1p21. Cytogenet. Cell Genet. 1996; 72(2-3): 252-4. PMID: 8978789, ISSN: 0301-0171.

Freeman ML and Henle KJ.. Hyperthermia. Molecular Biology of Cancer (ed. JR Bertino) Academic Press. 1996; 888-900.

Freeman ML, Borrelli MJ, Syed K, Senisterra G, Stafford DM, Lepock JR. Characterization of a signal generated by oxidation of protein thiols that activates the heat shock transcription factor. J. Cell. Physiol. 1995 Aug; 164(2): 356-66. PMID: 7622581, DOI: 10.1002/jcp.1041640216, ISSN: 0021-9541.

Sierra-Rivera E, Summar ML, Krishnamani MRS, Phillips III JA, and Freeman ML. Assignment of the gene that codes the heavy subunit of -glutamylcysteine synthetase to human chromosome 6. 1995.

Sierra-Rivera E, Summar ML, Dasouki M, Krishnamani MR, Phillips JA, Freeman ML. Assignment of the gene (GLCLC) that encodes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6. Cytogenet. Cell Genet. 1995; 70(3-4): 278-9. PMID: 7789189, ISSN: 0301-0171.

Sierra-Rivera E, Summar ML, Krishnamani MRS, Phillips III JA, and Freeman ML.. Assignment of the gene that codes the heavy subunit of gamma-glutamylcysteine synthetase to human chromosome 6. Cytogenetics and Cell Genetics. 1995; 70: 278-9.

Sierra-Rivera E, Meredith MJ, Voorhees GJ, Oberley LW, Eisert DR, Freeman ML. Synthesis of heat shock proteins following oxidative challenge: role of glutathione. Int J Hyperthermia. 1994 Jul; 10(4): 573-86. PMID: 7963812, ISSN: 0265-6736.

Sierra-Rivera E, Meredith MJ, Summar ML, Smith MD, Voorhees GJ, Stoffel CM, Freeman ML. Genes regulating glutathione concentrations in X-ray-transformed rat embryo fibroblasts: changes in gamma-glutamylcysteine synthetase and gamma-glutamyltranspeptidase expression. Carcinogenesis. 1994 Jul; 15(7): 1301-7. PMID: 7913422, ISSN: 0143-3334.

Freeman ML, Sierra-Rivera E, Voorhees GJ, Eisert DR, Meredith MJ. Synthesis of hsp-70 is enhanced in glutathione-depleted Hep G2 cells. Radiat. Res. 1993 Sep; 135(3): 387-93. PMID: 8378532, DOI: 10.2307/3578879, ISSN: 0033-7587.

Sierra-Rivera E, Voorhees GJ, Freeman ML. Gamma irradiation increases hsp-70 in Chinese hamster ovary cells. Radiat. Res. 1993 Jul; 135(1): 40-5. PMID: 8327659, DOI: 10.2307/3578394, ISSN: 0033-7587.

Oikawa T, Freeman ML, Lo W, Vaughan DE, and Fogo A.. Modulation of plasminogen activator inhibitor-1(PAI-1) in vivo: A new mechanism for the anti-fibrotic effect of rennin-angiotensin inhibition. Kidney Inter. 1992; 51: 164-72.

Saunders EL, Maines MD, Meredith MJ, Freeman ML. Enhancement of heme oxygenase-1 synthesis by glutathione depletion in Chinese hamster ovary cells. Arch. Biochem. Biophys. 1991 Aug 8/1/1991; 288(2): 368-73. PMID: 1898036, ISSN: 0003-9861.

Saunders EL, Meredith MJ, Eisert DR, Freeman ML. Depletion of glutathione after gamma irradiation modifies survival. Radiat. Res. 1991 Mar; 125(3): 267-76. PMID: 2000450, ISSN: 0033-7587.

Atsmon J, Freeman ML, Meredith MJ, Sweetman BJ, Roberts LJ. Modulation of the antiproliferative activity of 9-deoxy-delta 9,delta 12(E)-PGD2 by conjugation with intracellular glutathione. Adv. Prostaglandin Thromboxane Leukot. Res. 1991; 21B: 887-90. PMID: 1825432, ISSN: 0732-8141.

Freeman ML, Spitz DR, Meredith MJ. Does heat shock enhance oxidative stress? Studies with ferrous and ferric iron. Radiat. Res. 1990 Dec; 124(3): 288-93. PMID: 2175921, ISSN: 0033-7587.

Freeman ML, Meredith MJ, Eisert DR. Failure of chronic glutathione elevation to reduce cytotoxicity produced by exposure to cis-diamminedichloroplatinum(II), ionizing radiation, or hyperthermia. Cancer Res. 1990 Sep 9/1/1990; 50(17): 5296-300. PMID: 1974822, ISSN: 0008-5472.

Atsmon J, Freeman ML, Meredith MJ, Sweetman BJ, Roberts LJ. Conjugation of 9-deoxy-delta 9,delta 12(E)-prostaglandin D2 with intracellular glutathione and enhancement of its antiproliferative activity by glutathione depletion. Cancer Res. 1990 Mar 3/15/1990; 50(6): 1879-85. PMID: 2306739, ISSN: 0008-5472.

Freeman ML, Meredith MJ. Modulation of diamide toxicity in thermotolerant cells by inhibition of protein synthesis. Cancer Res. 1989 Aug 8/15/1989; 49(16): 4493-8. PMID: 2743338, ISSN: 0008-5472.

Freeman ML, Meredith MJ. Measurement of protein thiols after heat shock using 3-(-N-maleimido-propionyl) biocytin labeled proteins separated by SDS-PAGE and electroluted onto nitrocellulose: thiol blotting. Radiat. Res. 1989 Feb; 117(2): 326-33. PMID: 2493669, ISSN: 0033-7587.

Freeman ML, Meredith MJ. Glutathione conjugation and induction of a 32,000 dalton stress protein. Biochem. Pharmacol. 1989 Jan 1/15/1989; 38(2): 299-304. PMID: 2914013, PII: 0006-2952(89)90040-3, ISSN: 0006-2952.

Freeman ML, Meredith MJ, Laszlo A. Depletion of glutathione, heat shock protein synthesis, and the development of thermotolerance in Chinese hamster ovary cells. Cancer Res. 1988 Dec 12/15/1988; 48(24 Pt 1): 7033-7. PMID: 3191478, ISSN: 0008-5472.

Freeman ML, Meredith MJ. Subcellular localization of glutathione and thermal sensitivity. Radiat. Res. 1988 Sep; 115(3): 461-71. PMID: 3174930, ISSN: 0033-7587.

Freeman ML, Scidmore NC, Meredith MJ. Inhibition of heat shock protein synthesis and thermotolerance by cycloheximide. Radiat. Res. 1987 Dec; 112(3): 564-74. PMID: 3423221, ISSN: 0033-7587.

Freeman ML, Meredith MJ. The effect of GSH depletion on thermal radiosensitization. Int. J. Radiat. Oncol. Biol. Phys. 1987 Sep; 13(9): 1371-5. PMID: 3624046, PII: 0360-3016(87)90232-X, ISSN: 0360-3016.

Freeman ML, Scidmore NC, Malcolm AW, Meredith MJ. Diamide exposure, thermal resistance, and synthesis of stress (heat shock) proteins. Biochem. Pharmacol. 1987 Jan 1/1/1987; 36(1): 21-9. PMID: 3541939, ISSN: 0006-2952.

Freeman ML, Malcolm AW, Meredith MJ. Role of glutathione in cell survival after hyperthermic treatment of Chinese hamster ovary cells. Cancer Res. 1985 Dec; 45(12 Pt 1): 6308-13. PMID: 4063982, ISSN: 0008-5472.

Freeman ML, Malcolm A. Acid modification of thermal damage and its relationship to nutrient availability. Int. J. Radiat. Oncol. Biol. Phys. 1985 Oct; 11(10): 1823-6. PMID: 3840150, PII: 0360-3016(85)90039-2, ISSN: 0360-3016.

Freeman ML, Malcolm AW, Meredith MJ. Glutathione pool size affects cell survival after hyperthermic treatment. Cell Biol. Toxicol. 1985 Jun; 1(3): 213-21. PMID: 3916982, ISSN: 0742-2091.

Freeman ML, Malcolm AW, Meredith MJ. Decreased intracellular glutathione concentration and increased hyperthermic cytotoxicity in an acid environment. Cancer Res. 1985 Feb; 45(2): 504-8. PMID: 3967225, ISSN: 0008-5472.

Freeman ML, Sierra E. An acidic extracellular environment reduces the fixation of radiation damage. Radiat. Res. 1984 Jan; 97(1): 154-61. PMID: 6695039, ISSN: 0033-7587.

Freeman ML, Sierra E, Hall EJ. The repair of sublethal damage in diploid human fibroblasts: a comparison between human and rodent cell lines. Radiat. Res. 1983 Aug; 95(2): 382-91. PMID: 6611855, ISSN: 0033-7587.

Freeman ML, Sierra E, Deitch AD, Cubbon RM. The repair of potentially lethal and sublethal damage in unfed plateau-phase cultures irradiated at 0.78 Gy/hr. Radiat. Res. 1982 Dec; 92(3): 596-603. PMID: 7178423, ISSN: 0033-7587.

Freeman ML, Goldhagen P, Sierra E, Hall EJ. Studies with encapsulated 125I sources. II. Determination of the relative biological effectiveness using cultured mammalian cells. Int. J. Radiat. Oncol. Biol. Phys. 1982 Aug; 8(8): 1355-61. PMID: 7141915, PII: 0360-3016(82)90586-7, ISSN: 0360-3016.

Goldhagen PE, Freeman ML, Hall EJ. Studies with encapsulated 125I sources. I. Apparatus and dosimetry for determination of relative biological effectiveness. Int. J. Radiat. Oncol. Biol. Phys. 1982 Aug; 8(8): 1347-53. PMID: 7141914, PII: 0360-3016(82)90585-5, ISSN: 0360-3016.

Freeman ML, Boone ML, Ensley BA, Gillette EL. The influence of environmental pH on the interaction and repair of heat and radiation damage. Int. J. Radiat. Oncol. Biol. Phys. 1981 Jun; 7(6): 761-4. PMID: 7287537, PII: 0360-3016(81)90470-3, ISSN: 0360-3016.

Freeman ML, Holahan EV, Highfield DP, Raaphorst GP, Spiro IJ, Dewey WC. The effect of pH on hyperthermic and x ray induced cell killing. Int. J. Radiat. Oncol. Biol. Phys. 1981 Feb; 7(2): 211-6. PMID: 7194329, PII: 0360-3016(81)90439-9, ISSN: 0360-3016.

Freeman ML, Raaphorst GP, Hopwood LE, Dewey WC. The effect of pH on cell lethality induced by hyperthermic treatment. Cancer. 1980 May 5/1/1980; 45(9): 2291-300. PMID: 7379028, ISSN: 0008-543X.

Dewey WC, Freeman ML. Rationale for use of hyperthermia in cancer therapy. Ann. N. Y. Acad. Sci. 1980; 335: 372-8. PMID: 6931531, ISSN: 0077-8923.

Raaphorst GP, Freeman ML, Dewey WC. Radiosensitivity and recovery from radiation damage in cultured CHO cells exposed to hyperthermia at 42.5 or 45.5 degrees C. Radiat. Res. 1979 Aug; 79(2): 390-402. PMID: 482603, ISSN: 0033-7587.

Freeman ML, Raaphorst GP, Dewey WC. The relationship of heat killing and thermal radiosensitization to the duration of heating at 42 degrees C. Radiat. Res. 1979 Apr; 78(1): 172-5. PMID: 451142, ISSN: 0033-7587.

Raaphorst GP, Sapareto SA, Freeman ML, Dewey WC. Changes in cellular heat and/or radiation sensitivity observed at various times after trypsinization and plating. Int. J. Radiat. Biol. Relat. Stud. Phys. Chem. Med. 1979 Feb; 35(2): 193-7. PMID: 376462, ISSN: 0020-7616.

Freeman ML, Dewey WC, Hopwood LE. Effect of pH on hyperthermic cell survival. J. Natl. Cancer Inst. 1977 Jun; 58(6): 1837-9. PMID: 17014, ISSN: 0027-8874.