Novel survivin inhibitor for suppressing pancreatic cancer cells growth via downregulating Sp1 and Sp3 transcription factors

Myrna Hurtado, Umesh Tanaji Sankpal, Aboubacar Kaba, Shahela Mahammad, Jaya Chhabra, Deondra T. Brown, Raj K. Gurung, Alvin A. Holder, Jamboor K. Vishwanatha, Riyaz Mahammad Basha

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background/Aims: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Methods: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. Results: The IC 50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G 2 /M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. Conclusion: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.

Original languageEnglish
Pages (from-to)1894-1907
Number of pages14
JournalCellular Physiology and Biochemistry
Volume51
Issue number4
DOIs
StatePublished - 1 Dec 2018

Fingerprint

Sp3 Transcription Factor
Sp1 Transcription Factor
Pancreatic Neoplasms
Down-Regulation
Growth
Heterografts
Nude Mice
tolfenamic acid
Cell Cycle
Apoptosis Regulatory Proteins
Tumor Cell Line

Keywords

  • Copper-tolfenamic acid
  • Pancreatic cancer
  • Sp1
  • Sp3
  • Survivin

Cite this

Hurtado, Myrna ; Sankpal, Umesh Tanaji ; Kaba, Aboubacar ; Mahammad, Shahela ; Chhabra, Jaya ; Brown, Deondra T. ; Gurung, Raj K. ; Holder, Alvin A. ; Vishwanatha, Jamboor K. ; Basha, Riyaz Mahammad. / Novel survivin inhibitor for suppressing pancreatic cancer cells growth via downregulating Sp1 and Sp3 transcription factors. In: Cellular Physiology and Biochemistry. 2018 ; Vol. 51, No. 4. pp. 1894-1907.
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abstract = "Background/Aims: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Methods: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. Results: The IC 50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G 2 /M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48{\%}; 50 mg/kg: 68{\%}). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. Conclusion: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.",
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author = "Myrna Hurtado and Sankpal, {Umesh Tanaji} and Aboubacar Kaba and Shahela Mahammad and Jaya Chhabra and Brown, {Deondra T.} and Gurung, {Raj K.} and Holder, {Alvin A.} and Vishwanatha, {Jamboor K.} and Basha, {Riyaz Mahammad}",
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Novel survivin inhibitor for suppressing pancreatic cancer cells growth via downregulating Sp1 and Sp3 transcription factors. / Hurtado, Myrna; Sankpal, Umesh Tanaji; Kaba, Aboubacar; Mahammad, Shahela; Chhabra, Jaya; Brown, Deondra T.; Gurung, Raj K.; Holder, Alvin A.; Vishwanatha, Jamboor K.; Basha, Riyaz Mahammad.

In: Cellular Physiology and Biochemistry, Vol. 51, No. 4, 01.12.2018, p. 1894-1907.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Novel survivin inhibitor for suppressing pancreatic cancer cells growth via downregulating Sp1 and Sp3 transcription factors

AU - Hurtado, Myrna

AU - Sankpal, Umesh Tanaji

AU - Kaba, Aboubacar

AU - Mahammad, Shahela

AU - Chhabra, Jaya

AU - Brown, Deondra T.

AU - Gurung, Raj K.

AU - Holder, Alvin A.

AU - Vishwanatha, Jamboor K.

AU - Basha, Riyaz Mahammad

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Background/Aims: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Methods: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. Results: The IC 50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G 2 /M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. Conclusion: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.

AB - Background/Aims: Targeting survivin, an anti-apoptotic protein and mitotic regulator, is considered as an effective therapeutic option for pancreatic cancer (PaCa). Tolfenamic acid (TA) showed anti-cancer activity in pre-clinical studies. A recent discovery demonstrated a copper(II) complex of TA (Cu-TA) can result in higher activity. In this study, the ability of Cu-TA to inhibit survivin and its transcription factors, Specificity protein (Sp) 1 and 3 in PaCa cell lines and tumor growth in mouse xenograft model were evaluated. Methods: Cell growth inhibition was measured in MIA PaCa-2 and Panc1 cells for 2 days using CellTiter-Glo kit. Sp1, Sp3 and survivin expression (by Western blot and qPCR), apoptotic cells and cell cycle phase distribution (by flow cytometry) were evaluated. A pilot study was performed using athymic nude mice [treated with vehicle/Cu-TA (25 or 50 mg/kg) 3 times/week for 4 weeks. Results: The IC 50 value for Cu-TA was about half than TA.Both agents repressed the protein expression of Sp1/Sp3/survivin, Cu-TA was more effective than TA. Especially effect on survivin inhibition was 5.2 (MIA PaCa-2) or 6.4 (Panc1) fold higher and mRNA expression of only survivin was decreased. Apoptotic cells increased with Cu-TA treatment in both cell lines, while Panc1 showed both effect on apoptosis and cell cycle (G 2 /M) arrest. Cu-TA decreased the tumor growth in mouse xenografts (25 mg/kg: 48%; 50 mg/kg: 68%). Additionally, there was no change observed in mice body weights, indicating no overt toxicity was occurring. Conclusion: These results show that Cu-TA can serve as an effective survivin inhibitor for inhibiting PaCa cell growth.

KW - Copper-tolfenamic acid

KW - Pancreatic cancer

KW - Sp1

KW - Sp3

KW - Survivin

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