Abstract
Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 μg/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 μg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ∼40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin.
| Original language | English |
|---|---|
| Pages (from-to) | 2781-2789 |
| Number of pages | 9 |
| Journal | Tumor Biology |
| Volume | 34 |
| Issue number | 5 |
| DOIs | |
| State | Published - 20 May 2013 |
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Keywords
- Medulloblastoma
- NSAID
- Pediatric brain tumors
- Sp1
- Survivin
- Transcription factors
Cite this
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Anticancer activity of tolfenamic acid in medulloblastoma : A preclinical study. / Eslin, Don; Lee, Chris; Sankpal, Umesh Tanaji; Maliakal, Pius; Sutphin, Robert M.; Abraham, Liz; Basha, Riyaz Mahammad.
In: Tumor Biology, Vol. 34, No. 5, 20.05.2013, p. 2781-2789.Research output: Contribution to journal › Article
TY - JOUR
T1 - Anticancer activity of tolfenamic acid in medulloblastoma
T2 - A preclinical study
AU - Eslin, Don
AU - Lee, Chris
AU - Sankpal, Umesh Tanaji
AU - Maliakal, Pius
AU - Sutphin, Robert M.
AU - Abraham, Liz
AU - Basha, Riyaz Mahammad
PY - 2013/5/20
Y1 - 2013/5/20
N2 - Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 μg/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 μg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ∼40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin.
AB - Medulloblastoma (MB) is the most common malignancy in children arising in the brain. Morbidities associated with intensive therapy are serious concerns in treating MB. Our aim was to identify novel targets and agents with less toxicity for treating MB. Specificity protein 1 (Sp1) transcription factor regulates several genes involved in cell proliferation and cell survival including survivin, an inhibitor of apoptosis protein. We previously showed that tolfenamic acid (TA), a nonsteroidal anti-inflammatory drug, inhibits neuroblastoma cell growth by targeting Sp1. We investigated the anticancer activity of TA using human MB cell lines and a mouse xenograft model. DAOY and D283 cells were treated with vehicle (dimethyl sulfoxide) or TA (5-50 μg/ml), and cell viability was measured at 1-3 days posttreatment. TA inhibited MB cell growth in a time- and dose-dependent manner. MB cells were treated with vehicle or TA (10 μg/ml), and the effect on cell apoptosis was measured. Apoptosis was analyzed by flow cytometry (annexin V staining), and caspase 3/7 activity was determined using Caspase-Glo kit. The expression of Sp1, cleaved poly(ADP-ribose) polymerase (c-PARP), and survivin was determined by Western blot analysis. TA inhibited the expression of Sp1 and survivin and upregulated c-PARP. Athymic nude mice were subcutaneously injected with D283 cells and treated with TA (50 mg/kg, three times per week) for 4 weeks. TA caused a decrease of ∼40 % in tumor weight and volume. The tumor growth inhibition was accompanied by a decrease in Sp1 and survivin expression in tumor tissue. These preclinical data demonstrate that TA acts as an anticancer agent in MB potentially targeting Sp1 and survivin.
KW - Medulloblastoma
KW - NSAID
KW - Pediatric brain tumors
KW - Sp1
KW - Survivin
KW - Transcription factors
UR - http://www.scopus.com/inward/record.url?scp=84885418318&partnerID=8YFLogxK
U2 - 10.1007/s13277-013-0836-6
DO - 10.1007/s13277-013-0836-6
M3 - Article
C2 - 23686785
AN - SCOPUS:84885418318
VL - 34
SP - 2781
EP - 2789
JO - Tumor Biology
JF - Tumor Biology
SN - 1010-4283
IS - 5
ER -