Radiosensitizing effects of histone de-acetylase
inhibitors in prostate cancer
One of the most
problems in prostate cancer research is the need to identify a
radiation resistant prostate cancer. Radiation resistance in prostate
may be implicated to induction of pro-survival factors by radiation
pro-survival factors may provide anti-apoptotic signal to evade from
killing effects of radiation. It may be
possible to inhibit the functions of radiation-induced pro-survival
enhance radiation-induced apoptosis by the use of several drugs like
de-acetylase (HDAC) inhibitors.Acetylation status of
chromatin, modulated by histone acetylases (HATs) and HDACs, is
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
transcriptional activation. HDACs on
the other hand, remove acetyl groups from acetylated histones leading
chromatin compaction and transcriptional repression. HDACs have
been shown to target not only histones but
other transcription factors like RB, p53, NFkB,
ATM and MEF2 for deacetylation. Since,
aberrant activity of HDACs leads to the transcriptional repression of
suppressor genes contributing to tumor formation, targeting of HDACs
inhibitors would not only disrupt normal transcriptional regulation of
genes through the relaxation of chromatin conformation but also can be
a cancer therapy approach. Thus, HDAC
inhibitors can be used in combination with radiation to augment
and/or to reduce toxicity. Indeed, several
types of HDAC inhibitors have been shown to have anti-tumor activities
radiosensitizing effects in both tumor cells and xenografted models but
limited efficacy and side effects. In
addition, the mechanisms of radio-sensitization by these inhibitors
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
inhibitors. We are investigating the
effects of two of these novel inhibitors (VAD-18 and VAD-20) as well as
optically active a-branched
phenylbutyryl derivative, (S)-11 ((S)-HDAC-42. novel
inhibitor, (S)-HDAC-42 in various prostate cancer cell lines in
with radiation. Also, we are comparing
the effects of these novel inhibitors with SAHA and trying to
mechanisms behind radio-sensitization by elucidating the induced
pathways in prostate cancer cell lines. Further, we will
investigate the combined effects of HDAC
plus ionizing radiation on the regression of prostate cancer xenografts
in nude mice and (in-situ prostate
tumor in TRAMP mice.
Chemopotentiating effects of low dose
radiation therapy in lung and ovarian cancers. Historically, the
of treatment for patients with advanced solid tumors has been surgery,
radiotherapy and chemotherapy. Chemo-resistance is one of the possible
of the poor response to treatment in advanced stage tumors. Extensive
pre-clinical research has demonstrated that chemotherapy eliminates
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)
significant potentiation of cell killing with chemotherapeutic drugs:
cisplatin, paclitaxel and docetaxel in various lung, head and neck and
cancer cell lines. In particular, with taxanes, LDFRT was able to
anti-apoptotic and pro-survival effects of Bcl-2 and NFkappaB. LDFRT
with chemotherapy abrogates the "induced chemo-radiation resistance"
found in locally advanced solid tumors and enhances cell killing
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
adjuvant LDFRT and to determine the effect of chemotherapeutic drugs
by adjuvant LDFRT on regression of nude mice xenografts and tumor
delay. The induction of transcription
factors and gene expression signaling events will be correlated with
survival profile to elucidate the molecular mechanism of LDFRT mediated
1. Viney Jain and Seema Gupta.
therapy-A novel concept in Biomedicine. Indian Photobiology
Society Newsletter, No. 39
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)
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)
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.
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.
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.
traineeship award: Department
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
prostate cancer cell lines as well as in prostate xenografts and TRAMP
bearing in situ tumors. The
understanding of mechanisms underlying
this radiosensitization effect will help in developing better
strategies for the treatment of prostate cancer. Role: PI