Cellular Physiology and Biochemistry
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.
Original Publication Citation
Hurtado, M., Sankpal, U. T., Kaba, A., Mahammad, S., Chhabra, J., Brown, D. T., . . . Basha, R. (2018). Novel survivin inhibitor for suppressing pancreatic cancer cells growth via downregulating sp1 and sp3 transcription factors. Cellular Physiology and Biochemistry, 51(4), 1894-1907. doi:10.1159/000495715
Hurtado, Myrna; Sankpal, Umesh T.; Kaba, Aboubacar; Mahammad, Shahela; Chhabra, Jaya; Brown, Deondra T.; Gurung, Raj K.; Holder, Alvin A.; Vishwanatha, Jamboor K.; and Basha, Riyaz, "Novel Survivin Inhibitor for Suppressing Pancreatic Cancer Cells Growth via Downregulating Sp1 and Sp3 Transciption Factors" (2018). Chemistry & Biochemistry Faculty Publications. 159.