Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer

Umesh Tanaji Sankpal, Maen Abdelrahim, Sarah F. Connelly, Chris M. Lee, Rafael Madero-Visbal, Jimmie Colon, Joshua Smith, Stephen Safe, Pius Maliakal, Riyaz Mahammad Basha

Research output: Contribution to journalArticle

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Abstract

BACKGROUND Specificity protein (Sp) transcription factors are implicated in critical cellular and molecular processes associated with cancer that impact tumor growth and metastasis. The non-steroidal anti-inflammatory drug, tolfenamic acid (TA) is known to inhibit Sp proteins in some human cancer cells and laboratory animal models. We evaluated the anti-cancer activity of TA using in vitro and in vivo models for prostate cancer. METHODS The anti-proliferative efficacy of TA was evaluated using DU-145, PC-3, and LNCaP cells. PC-3 cells were treated with DMSO or 50 μM TA for 48 hr. Whole cell lysates were evaluated for the expression of Sp1, survivin, c-PARP, Akt/p-Akt, c-Met, cdk4, cdc2, cyclin D3, and E2F1 by Western blot analysis. Cell invasion was assessed by Boyden-chamber assay and flow cytometry analysis was used to study apoptosis and cell cycle distribution. An orthotopic mouse model for prostate cancer with PC-3-Luc cells was used to study the in vivo effect of TA. RESULTS TA inhibited the expression of Sp1, c-Met, p-Akt, and survivin; increased c-PARP expression and caspases activity in PC-3 cells. TA caused cell arrest at G 0/G1 phase accompanied by a decrease in cdk4, cdc2, cyclin D3, and E2F1 and an increase in critical apoptotic markers. TA augmented annexin-V staining, caspase activity, and c-PARP expression indicating the activation of apoptotic pathways. TA also decreased PC-3 cell invasion. TA significantly decreased the tumor weight and volume which was associated with low expression of Sp1 and survivin in tumor sections. CONCLUSION TA targets critical pathways associated with tumorigenesis and invasion. These pre-clinical data strongly demonstrated the anti-cancer activity of TA in prostate cancer.

Original languageEnglish
Pages (from-to)1648-1658
Number of pages11
JournalProstate
Volume72
Issue number15
DOIs
StatePublished - 1 Nov 2012

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Prostatic Neoplasms
Cell Proliferation
Growth
Neoplasms
Cyclin D3
Caspases
Tumor Burden
In Vitro Techniques
tolfenamic acid
Sp Transcription Factors
Critical Pathways
Annexin A5
G1 Phase
Dimethyl Sulfoxide
Cell Cycle
Flow Cytometry
Carcinogenesis
Proteins
Anti-Inflammatory Agents
Animal Models

Keywords

  • Sp1
  • cell invasion
  • survivin
  • tolfenamic acid
  • transcription factors

Cite this

Sankpal, Umesh Tanaji ; Abdelrahim, Maen ; Connelly, Sarah F. ; Lee, Chris M. ; Madero-Visbal, Rafael ; Colon, Jimmie ; Smith, Joshua ; Safe, Stephen ; Maliakal, Pius ; Basha, Riyaz Mahammad. / Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer. In: Prostate. 2012 ; Vol. 72, No. 15. pp. 1648-1658.
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title = "Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer",
abstract = "BACKGROUND Specificity protein (Sp) transcription factors are implicated in critical cellular and molecular processes associated with cancer that impact tumor growth and metastasis. The non-steroidal anti-inflammatory drug, tolfenamic acid (TA) is known to inhibit Sp proteins in some human cancer cells and laboratory animal models. We evaluated the anti-cancer activity of TA using in vitro and in vivo models for prostate cancer. METHODS The anti-proliferative efficacy of TA was evaluated using DU-145, PC-3, and LNCaP cells. PC-3 cells were treated with DMSO or 50 μM TA for 48 hr. Whole cell lysates were evaluated for the expression of Sp1, survivin, c-PARP, Akt/p-Akt, c-Met, cdk4, cdc2, cyclin D3, and E2F1 by Western blot analysis. Cell invasion was assessed by Boyden-chamber assay and flow cytometry analysis was used to study apoptosis and cell cycle distribution. An orthotopic mouse model for prostate cancer with PC-3-Luc cells was used to study the in vivo effect of TA. RESULTS TA inhibited the expression of Sp1, c-Met, p-Akt, and survivin; increased c-PARP expression and caspases activity in PC-3 cells. TA caused cell arrest at G 0/G1 phase accompanied by a decrease in cdk4, cdc2, cyclin D3, and E2F1 and an increase in critical apoptotic markers. TA augmented annexin-V staining, caspase activity, and c-PARP expression indicating the activation of apoptotic pathways. TA also decreased PC-3 cell invasion. TA significantly decreased the tumor weight and volume which was associated with low expression of Sp1 and survivin in tumor sections. CONCLUSION TA targets critical pathways associated with tumorigenesis and invasion. These pre-clinical data strongly demonstrated the anti-cancer activity of TA in prostate cancer.",
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author = "Sankpal, {Umesh Tanaji} and Maen Abdelrahim and Connelly, {Sarah F.} and Lee, {Chris M.} and Rafael Madero-Visbal and Jimmie Colon and Joshua Smith and Stephen Safe and Pius Maliakal and Basha, {Riyaz Mahammad}",
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Sankpal, UT, Abdelrahim, M, Connelly, SF, Lee, CM, Madero-Visbal, R, Colon, J, Smith, J, Safe, S, Maliakal, P & Basha, RM 2012, 'Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer', Prostate, vol. 72, no. 15, pp. 1648-1658. https://doi.org/10.1002/pros.22518

Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer. / Sankpal, Umesh Tanaji; Abdelrahim, Maen; Connelly, Sarah F.; Lee, Chris M.; Madero-Visbal, Rafael; Colon, Jimmie; Smith, Joshua; Safe, Stephen; Maliakal, Pius; Basha, Riyaz Mahammad.

In: Prostate, Vol. 72, No. 15, 01.11.2012, p. 1648-1658.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Small molecule tolfenamic acid inhibits PC-3 cell proliferation and invasion in vitro, and tumor growth in orthotopic mouse model for prostate cancer

AU - Sankpal, Umesh Tanaji

AU - Abdelrahim, Maen

AU - Connelly, Sarah F.

AU - Lee, Chris M.

AU - Madero-Visbal, Rafael

AU - Colon, Jimmie

AU - Smith, Joshua

AU - Safe, Stephen

AU - Maliakal, Pius

AU - Basha, Riyaz Mahammad

PY - 2012/11/1

Y1 - 2012/11/1

N2 - BACKGROUND Specificity protein (Sp) transcription factors are implicated in critical cellular and molecular processes associated with cancer that impact tumor growth and metastasis. The non-steroidal anti-inflammatory drug, tolfenamic acid (TA) is known to inhibit Sp proteins in some human cancer cells and laboratory animal models. We evaluated the anti-cancer activity of TA using in vitro and in vivo models for prostate cancer. METHODS The anti-proliferative efficacy of TA was evaluated using DU-145, PC-3, and LNCaP cells. PC-3 cells were treated with DMSO or 50 μM TA for 48 hr. Whole cell lysates were evaluated for the expression of Sp1, survivin, c-PARP, Akt/p-Akt, c-Met, cdk4, cdc2, cyclin D3, and E2F1 by Western blot analysis. Cell invasion was assessed by Boyden-chamber assay and flow cytometry analysis was used to study apoptosis and cell cycle distribution. An orthotopic mouse model for prostate cancer with PC-3-Luc cells was used to study the in vivo effect of TA. RESULTS TA inhibited the expression of Sp1, c-Met, p-Akt, and survivin; increased c-PARP expression and caspases activity in PC-3 cells. TA caused cell arrest at G 0/G1 phase accompanied by a decrease in cdk4, cdc2, cyclin D3, and E2F1 and an increase in critical apoptotic markers. TA augmented annexin-V staining, caspase activity, and c-PARP expression indicating the activation of apoptotic pathways. TA also decreased PC-3 cell invasion. TA significantly decreased the tumor weight and volume which was associated with low expression of Sp1 and survivin in tumor sections. CONCLUSION TA targets critical pathways associated with tumorigenesis and invasion. These pre-clinical data strongly demonstrated the anti-cancer activity of TA in prostate cancer.

AB - BACKGROUND Specificity protein (Sp) transcription factors are implicated in critical cellular and molecular processes associated with cancer that impact tumor growth and metastasis. The non-steroidal anti-inflammatory drug, tolfenamic acid (TA) is known to inhibit Sp proteins in some human cancer cells and laboratory animal models. We evaluated the anti-cancer activity of TA using in vitro and in vivo models for prostate cancer. METHODS The anti-proliferative efficacy of TA was evaluated using DU-145, PC-3, and LNCaP cells. PC-3 cells were treated with DMSO or 50 μM TA for 48 hr. Whole cell lysates were evaluated for the expression of Sp1, survivin, c-PARP, Akt/p-Akt, c-Met, cdk4, cdc2, cyclin D3, and E2F1 by Western blot analysis. Cell invasion was assessed by Boyden-chamber assay and flow cytometry analysis was used to study apoptosis and cell cycle distribution. An orthotopic mouse model for prostate cancer with PC-3-Luc cells was used to study the in vivo effect of TA. RESULTS TA inhibited the expression of Sp1, c-Met, p-Akt, and survivin; increased c-PARP expression and caspases activity in PC-3 cells. TA caused cell arrest at G 0/G1 phase accompanied by a decrease in cdk4, cdc2, cyclin D3, and E2F1 and an increase in critical apoptotic markers. TA augmented annexin-V staining, caspase activity, and c-PARP expression indicating the activation of apoptotic pathways. TA also decreased PC-3 cell invasion. TA significantly decreased the tumor weight and volume which was associated with low expression of Sp1 and survivin in tumor sections. CONCLUSION TA targets critical pathways associated with tumorigenesis and invasion. These pre-clinical data strongly demonstrated the anti-cancer activity of TA in prostate cancer.

KW - Sp1

KW - cell invasion

KW - survivin

KW - tolfenamic acid

KW - transcription factors

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U2 - 10.1002/pros.22518

DO - 10.1002/pros.22518

M3 - Article

C2 - 22473873

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VL - 72

SP - 1648

EP - 1658

JO - Prostate

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SN - 0270-4137

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