Anticancer activity of tolfenamic acid in medulloblastoma: A preclinical study

Don Eslin, Chris Lee, Umesh Tanaji Sankpal, Pius Maliakal, Robert M. Sutphin, Liz Abraham, Riyaz Mahammad Basha

Research output: Contribution to journalArticle

14 Citations (Scopus)

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 languageEnglish
Pages (from-to)2781-2789
Number of pages9
JournalTumor Biology
Volume34
Issue number5
DOIs
StatePublished - 20 May 2013

Fingerprint

Medulloblastoma
Protein Transport
Tumor Burden
Nude Mice
Cell Survival
Growth
Sp1 Transcription Factor
Apoptosis
Inhibitor of Apoptosis Proteins
Caspase 7
tolfenamic acid
Neoplasms
Proteins
Poly(ADP-ribose) Polymerases
Annexin A5
Caspases
Dimethyl Sulfoxide
Neuroblastoma
Heterografts
Caspase 3

Keywords

  • Medulloblastoma
  • NSAID
  • Pediatric brain tumors
  • Sp1
  • Survivin
  • Transcription factors

Cite this

Eslin, Don ; Lee, Chris ; Sankpal, Umesh Tanaji ; Maliakal, Pius ; Sutphin, Robert M. ; Abraham, Liz ; Basha, Riyaz Mahammad. / Anticancer activity of tolfenamic acid in medulloblastoma : A preclinical study. In: Tumor Biology. 2013 ; Vol. 34, No. 5. pp. 2781-2789.
@article{0c19dddedb2249229586f9bffd74d390,
title = "Anticancer activity of tolfenamic acid in medulloblastoma: A preclinical study",
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.",
keywords = "Medulloblastoma, NSAID, Pediatric brain tumors, Sp1, Survivin, Transcription factors",
author = "Don Eslin and Chris Lee and Sankpal, {Umesh Tanaji} and Pius Maliakal and Sutphin, {Robert M.} and Liz Abraham and Basha, {Riyaz Mahammad}",
year = "2013",
month = "5",
day = "20",
doi = "10.1007/s13277-013-0836-6",
language = "English",
volume = "34",
pages = "2781--2789",
journal = "Tumor Biology",
issn = "1010-4283",
publisher = "SAGE Publications Inc.",
number = "5",

}

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 journalArticle

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 -