Novel Survivin Inhibitor for Suppressing Pancreatic Cancer Cells Growth via Downregulating Sp1 and Sp3 Transcription Factors.

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 IC50 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 (G2/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.

• Authors: Myrna Hurtado, Umesh T Sankpal, Aboubacar Kaba, Shahela Mahammad, Jaya Chhabra, Deondra T Brown, Raj K Gurung, Alvin A Holder, Jamboor K Vishwanatha, Riyaz Basha
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 51 Issue 4 Pg. 1894-1907 ( 2018) ISSN: 1421-9778 [Electronic] Germany
• PMID: 30504717 (Publication Type: Journal Article)
• Copyright: © 2018 The Author(s). Published by S. Karger AG, Basel.

Chemical References

• Antineoplastic Agents
• Coordination Complexes
• Sp1 Transcription Factor
• Survivin
• ortho-Aminobenzoates
• Sp3 Transcription Factor
• tolfenamic acid
• Copper

Topics

• Animals
• Antineoplastic Agents (chemistry, therapeutic use)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Coordination Complexes (chemistry, therapeutic use)
• Copper (chemistry, therapeutic use)
• Down-Regulation (drug effects)
• Female
• Humans
• Male
• Mice
• Mice, Nude
• Pancreatic Neoplasms (drug therapy, genetics, pathology)
• Sp1 Transcription Factor (genetics)
• Sp3 Transcription Factor (genetics)
• Survivin (antagonists & inhibitors)
• ortho-Aminobenzoates (chemistry, therapeutic use)