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                                                                                     Seema Gupta

Seema Gupta

Research Assistant Professor
Unviverstity of Miami
Department of Radiation Oncology
Papanicolaou Cancer Research Building
1550 N.W. 10th Avenue, Suite 117
Miami, FL 33136
email: sgupta3@med.miami.edu
tel: 305-243-7795
fax: 305-243-1854



                                                            Seema Gupta                                               

My Research Interests include
Radiosensitizing effects of histone de-acetylase inhibitors in prostate cancer
One of the most important problems in prostate cancer research is the need to identify a treatment for radiation resistant prostate cancer. Radiation resistance in prostate cancer may be implicated to induction of pro-survival factors by radiation itself.  These radiation-induced pro-survival factors may provide anti-apoptotic signal to evade from cell killing effects of radiation.  It may be possible to inhibit the functions of radiation-induced pro-survival factors and enhance radiation-induced apoptosis by the use of several drugs like histone de-acetylase (HDAC) inhibitors.Acetylation status of the chromatin, modulated by histone acetylases (HATs) and HDACs, is responsible for chromatin remodeling that is required for gene expression.  HATs acetylate histones at the lysine residues thus neutralizing the charge.  The resulting relaxation of the nucleosomal core particle leads to transcriptional activation.  HDACs on the other hand, remove acetyl groups from acetylated histones leading to chromatin compaction and transcriptional repression.  HDACs have been shown to target not only histones but several other transcription factors like RB, p53, NFkB, ATM and MEF2 for deacetylation.  Since, aberrant activity of HDACs leads to the transcriptional repression of tumor suppressor genes contributing to tumor formation, targeting of HDACs with inhibitors would not only disrupt normal transcriptional regulation of specific genes through the relaxation of chromatin conformation but also can be used as a cancer therapy approach.  Thus, HDAC inhibitors can be used in combination with radiation to augment clinical efficacy and/or to reduce toxicity.  Indeed, several types of HDAC inhibitors have been shown to have anti-tumor activities and radiosensitizing effects in both tumor cells and xenografted models but with limited efficacy and side effects.  In addition, the mechanisms of radio-sensitization by these inhibitors have not been studied.Based on the X-ray crystallographic structure of HDAC enzyme, Zn2+-chelating, motif-tethered, short chain fatty acids were developed as novel class of HDAC inhibitors.  We are investigating the effects of two of these novel inhibitors (VAD-18 and VAD-20) as well as an optically active a-branched phenylbutyryl derivative, (S)-11 ((S)-HDAC-42. novel HDAC inhibitor, (S)-HDAC-42 in various prostate cancer cell lines in combination with radiation.  Also, we are comparing the effects of these novel inhibitors with SAHA and trying to understand the mechanisms behind radio-sensitization by elucidating the induced signaling pathways in prostate cancer cell lines.  Further, we will investigate the combined effects of HDAC inhibitors plus ionizing radiation on the regression of prostate cancer xenografts (PC-3) in nude mice and (in-situ prostate tumor in TRAMP mice.
Chemopotentiating effects of low dose fractionated radiation therapy in lung and ovarian cancers. Historically, the gold standard of treatment for patients with advanced solid tumors has been surgery, radiotherapy and chemotherapy. Chemo-resistance is one of the possible causes of the poor response to treatment in advanced stage tumors. Extensive pre-clinical research has demonstrated that chemotherapy eliminates malignant cells by the induction of apoptosis as well as by "mitotic death". Recently, very low doses of radiation have demonstrated an initial hyper-radiation sensitivity (HRS) region (doses less than 1 Gy).  Preliminary as well as published studies from our laboratory indicated that chemotherapy followed by low dose fractionated radiation (LDFRT: four fractions of 0.5 Gy at 8h interval) caused significant potentiation of cell killing with chemotherapeutic drugs: cisplatin, paclitaxel and docetaxel in various lung, head and neck and ovarian cancer cell lines. In particular, with taxanes, LDFRT was able to overcome the anti-apoptotic and pro-survival effects of Bcl-2 and NFkappaB. LDFRT combined with chemotherapy abrogates the "induced chemo-radiation resistance" found in locally advanced solid tumors and enhances cell killing without increasing the toxicity associated with high dose radiation. Our aim is to analyze the pro-survival and pro-apoptotic gene signaling kinetics in cell lines exposed to chemotherapy and adjuvant LDFRT and to determine the effect of chemotherapeutic drugs modified by adjuvant LDFRT on regression of nude mice xenografts and tumor growth delay.  The induction of transcription factors and gene expression signaling events will be correlated with the cell survival profile to elucidate the molecular mechanism of LDFRT mediated chemo-potentiation.

1. Viney Jain and Seema Gupta. Photodynamic therapy-A novel concept in Biomedicine. Indian Photobiology Society Newsletter, No. 39 (2000) 17-24.
2. B. S. Dwarakanath, Seema Gupta and J. S. Adhikari. Applications of flow cytometry in cell death studies. Proccedings of Continuing Education Programme on Flow Cytometry and its Applications (2001) 23-29.
3. T. Lazar Mathew, R. Varshney, S. Gupta and B. S. Dwarakanath. Oxidative stress and antioxidants in human diseases. Trends in Physiological Sciences: Cells to systems (2002) 120-155.
4. Seema Gupta, Viney Jain and K. Muralidhar.  Differences in photodynamic effects of hematoporphyrin derivative in human squamous carcinoma and glioma cell lines. Trends in Physiological Sciences: Cells to systems (2002) 225-247.
5. B. S. Dwarakanath, Seema Gupta and J. S. Adhikari.  Analysis of apoptosis by multi-parameter flow cytometry.  Proceedings of the workshop on Advancements in Applications of Flow Cytometry (2002) 24-32.
6. Seema Gupta, B. S. Dwarakanath, K. Muralidhar and Viney Jain. Role of apoptosis in photodynamic sensitivity of human tumor cell lines.
Ind. J. Exp. Biol., 41 (2003) 33-40.
7. Seema Gupta, B. S. Dwarakanath, K. Muralidhar and Viney Jain. Cellular uptake, localization and photodynamic effects of haematoporphyrin derivative in human glioma and squamous carcinoma cell line. J. Photochem. Photobiol. B: Biol.  69 (2003) 107-120.
8. Seema Gupta, A. K. Mishra, K. Muralidhar and Viney Jain. Improved targeting of photosensitizers by intratumoral administration of immunoconjugates. Technol Cancer Res Treat. Jun 3 (3) (2004) 295-301.

9. Seema Gupta, Rohit Mathur, B. S. Dwarakanath. Modification of etoposide induced toxicity by 2- deoxy-D-glucose in murine tumors. Biomedicine, Oct. (2004) 31-43.
10. Seema Gupta, Rajiv Varshney and B. S. Dwarakanath. Radiosensitization of Ehrlich ascites tumors by 2-deoxy-D-glucose and 6-aminonicotinamide. Technol Cancer Res. Treatment, 3 (2004) 659-63.
11. Seema Gupta and Mansoor M. Ahmed.  A global perspective of radiation-induced signal transduction pathways in cancer therapeutics (Review), Ind. J. Exp. Biol., 42 (2004) 1153-76.

12. Seema Gupta, Rohit Mathur, B. S. Dwarakanath.  The glycolytic inhibitor 2-deoxy-D-glucose enhances the efficacy of etoposide in Ehrlich ascites tumor bearing mice.  Cancer Biology and Therapy, 4 (2005) 78-85.

Ongoing Research Support:
Post-doctoral traineeship award: Department of Defense Prostate Cancer Research Program ?Radio-sensitizing SaveCanceleffects of novel histone de-acetylase inhibitors in prostate cancer?, 11/01/04-11/30/06. This study involves novel histone-deacetylase inhibitors and tries to investigate their radiosensitizing effects in various prostate cancer cell lines as well as in prostate xenografts and TRAMP mice bearing in situ tumors.  The understanding of mechanisms underlying this radiosensitization effect will help in developing better therapeutic strategies for the treatment of prostate cancer. Role: PI










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Last updated on 11/27/2005

02 Jan 2006 19:14:21 -0800