Page 255 - 2014 Printable Abstract Book
P. 255
strongly suggest that the selected polyphenols in addition to their anti-pancreatic effect, they also
comprehensively inhibit tumor relapse process that may develop after therapy by targeting tumor
invasion and metastasis signal transduction pathways in tumor cells that could survive after treatment.
(PS4-33) Nitric oxide mediated inhibition of NFkB arbitrates EF24-induced radio-sensitization in
2
1
3
neuroblastoma tumor model. Vijayabaskar Pandian ; Mohan Natarajan, PhD ; Sheeja Aravindan, M.Phil. ;
1
1
1
Faizan H. Khan, PhD ; Satish K. Ramraj, PhD ; Terence S. Herman, MD ; and Natarajan Aravindan, PhD, 1
1
The Oklahoma University Health Science Center,, Oklahoma City, OK ; University of Texas Health Sciences
2
3
Center, San Antonio, TX ; and Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK
Recently we have demonstrated the sequential signal transduction flow through in
neuroblastoma (NB) cell radio-resistance. In parallel, we also have demonstrated the clinical efficacy of
novel synthetic monoketone EF24 in surviving neuroblastoma cells and tumor regression, by selectively
targeting radiation-induced NFκB signaling pathway. Those data clearly set a stage and warranted the
investigation of the upstream molecular signaling that are responsible for driving EF24-dependent
inhibition of NFκB and maintain for an extended period. EF24 treatment significantly increased
intracellular nitric oxide (NO) bioavailability in radio-resistant NB (SHSY5Y, MC-IXC and SK-PN-DW) cells.
Inhibiting intracellular NO with NO-specific inhibitor, L-NAME profoundly induced NFκB-DNA binding
activity (determined by EMSA). Conversely, increasing NO levels (by exogenous addition of NO donors,
GSNO) completely attenuated radiation-induced NFκB activity in these cells. Evidently, EF24 treatment
significantly inhibited L-NAME induced NFκB. Transcriptional analysis (examined by QPCR) further
confirmed that NO induction inhibited NFκB upstream IKK and downstream ERK and MMP9 mRNA levels
in NB cell lines. Immunoflurosence analysis corroborated this transcription data with NO dependent
inhibition of MMP9. In vivo using NB xenografts that were exposed to clinically relevant FIR (2Gy/day for
20 days to a total dose of 40Gy) with or without daily dose of intra peritoneal EF24 (at a final concen-
tration of 50, 100 or 200 μg/kg) and intravenous administration of EF24 loaded liposomes clearly
demonstrated robust levels of phospho eNOS expression (assayed by immunobloting) and cellular
localization (TMA coupled with automated IHC), which correlates with tumor regression. Together, these
data strongly suggested that EF24 associated eNOS phosphorylation dependent induction of intracellular
NO regulates radiation-induced NFκB and mediates radio-sensitizationin surviving NB cells.
(PS4-34) Targets sensitizing lung cancer to chemotherapy and radiation therapy by exploiting synthetic
1
2
lethal relationships in an RNAi high-throughput screen. Kunal Chaudhary ; Haiying Cheng ; Balazs
1
1
1
3
Halmos ; K. S. Clifford Chao ; Tom K Hei ; and Simon Cheng, Center for Radiological Research & Radiation
1
Oncology, Columbia University Medical Center, New York, NY ; Department of Medical Oncology, Albert
2
Einstein Medical Center, New York, NY ; and Department of Medical Oncology, Columbia University
3
Medical Center, New York, NY
Platinum-based concurrent chemoradiation therapy is the mainstay of treatment for locally
advanced lung cancer. However patient outcomes remain dismal and overall survival at 5 years is only
15%. The resistance mechanisms for concurrent chemoradiation therapy are poorly studied. We sought
therefore to identify therapy resistance pathways in lung cancer by using small interfering RNAs (siRNAs)
to increase the sensitivity of tumor cells to therapeutic challenge. To identify novel genes that modulate
253 | P a g e
comprehensively inhibit tumor relapse process that may develop after therapy by targeting tumor
invasion and metastasis signal transduction pathways in tumor cells that could survive after treatment.
(PS4-33) Nitric oxide mediated inhibition of NFkB arbitrates EF24-induced radio-sensitization in
2
1
3
neuroblastoma tumor model. Vijayabaskar Pandian ; Mohan Natarajan, PhD ; Sheeja Aravindan, M.Phil. ;
1
1
1
Faizan H. Khan, PhD ; Satish K. Ramraj, PhD ; Terence S. Herman, MD ; and Natarajan Aravindan, PhD, 1
1
The Oklahoma University Health Science Center,, Oklahoma City, OK ; University of Texas Health Sciences
2
3
Center, San Antonio, TX ; and Peggy and Charles Stephenson Cancer Center, Oklahoma City, OK
Recently we have demonstrated the sequential signal transduction flow through in
neuroblastoma (NB) cell radio-resistance. In parallel, we also have demonstrated the clinical efficacy of
novel synthetic monoketone EF24 in surviving neuroblastoma cells and tumor regression, by selectively
targeting radiation-induced NFκB signaling pathway. Those data clearly set a stage and warranted the
investigation of the upstream molecular signaling that are responsible for driving EF24-dependent
inhibition of NFκB and maintain for an extended period. EF24 treatment significantly increased
intracellular nitric oxide (NO) bioavailability in radio-resistant NB (SHSY5Y, MC-IXC and SK-PN-DW) cells.
Inhibiting intracellular NO with NO-specific inhibitor, L-NAME profoundly induced NFκB-DNA binding
activity (determined by EMSA). Conversely, increasing NO levels (by exogenous addition of NO donors,
GSNO) completely attenuated radiation-induced NFκB activity in these cells. Evidently, EF24 treatment
significantly inhibited L-NAME induced NFκB. Transcriptional analysis (examined by QPCR) further
confirmed that NO induction inhibited NFκB upstream IKK and downstream ERK and MMP9 mRNA levels
in NB cell lines. Immunoflurosence analysis corroborated this transcription data with NO dependent
inhibition of MMP9. In vivo using NB xenografts that were exposed to clinically relevant FIR (2Gy/day for
20 days to a total dose of 40Gy) with or without daily dose of intra peritoneal EF24 (at a final concen-
tration of 50, 100 or 200 μg/kg) and intravenous administration of EF24 loaded liposomes clearly
demonstrated robust levels of phospho eNOS expression (assayed by immunobloting) and cellular
localization (TMA coupled with automated IHC), which correlates with tumor regression. Together, these
data strongly suggested that EF24 associated eNOS phosphorylation dependent induction of intracellular
NO regulates radiation-induced NFκB and mediates radio-sensitizationin surviving NB cells.
(PS4-34) Targets sensitizing lung cancer to chemotherapy and radiation therapy by exploiting synthetic
1
2
lethal relationships in an RNAi high-throughput screen. Kunal Chaudhary ; Haiying Cheng ; Balazs
1
1
1
3
Halmos ; K. S. Clifford Chao ; Tom K Hei ; and Simon Cheng, Center for Radiological Research & Radiation
1
Oncology, Columbia University Medical Center, New York, NY ; Department of Medical Oncology, Albert
2
Einstein Medical Center, New York, NY ; and Department of Medical Oncology, Columbia University
3
Medical Center, New York, NY
Platinum-based concurrent chemoradiation therapy is the mainstay of treatment for locally
advanced lung cancer. However patient outcomes remain dismal and overall survival at 5 years is only
15%. The resistance mechanisms for concurrent chemoradiation therapy are poorly studied. We sought
therefore to identify therapy resistance pathways in lung cancer by using small interfering RNAs (siRNAs)
to increase the sensitivity of tumor cells to therapeutic challenge. To identify novel genes that modulate
253 | P a g e
