Tolfenamic Acid and Curcumin Analogs Effectively Inhibits Pancreatic Cancer Cell Growth

Tolfenamic Acid and Curcumin Analogs Effectively Inhibits Pancreatic Cancer Cell Growth Background: Curcumin (Cur) is a natural phenol of the plant Curcuma longa that has been tested for anti-cancer activity in pre-clinical and clinical studies. The therapeutic efficacy of Cur is greatly impacted by its low bioavailability. Synthetic analogs of Cur are under testing to overcome this limitation. Cur analogs, EF31 and UBS109 have shown anti-cancer activity in colon and pancreatic cancers. Small molecule Tolfenamic acid (TA) is known to inhibit human cancer cells and tumor growth in mouse models for some human cancers. TA is known to target Specificity protein 1 (Sp1) transcription factor that mediates the expression of several genes associated with cancer including survivin, a key member of inhibitor of apoptosis proteins family. Purpose: Combination treatments have been tested to address the issues related to efficacy and drug resistance. In this project, the anti-cancer activity of EF31 and UBS109 was tested in combination with TA. Method: Human pancreatic cancer cells, L3.6pl and MIA PaCa-2 were grown in DMEM media with 5% fetal bovine serum. Cells were treated with DMSO (control) or EF31 or UBS109 or TA or EF31+TA or UBS109+TA and cell viability was measured at 48 hour post treatment using CellTiter-Glo (Promega) kit. The effect on apoptosis was assessed by determining the activity of caspase 3/7 (Caspase-Glo kit) and the expression of cleaved PARP (Western blot). The effect of individual and combination treatment(s) on the expression of Sp1 and survivin was evaluated by Western blot analysis. Results: TA in combination with EF31 or UBS109 resulted in an induction of cell growth inhibition which is accompanied by increased caspase 3/7 activity and upregulation of PARP cleavage. The combination treatment(s) also showed a modulation in the expression of Sp1 and survivin. Conclusions: TA combination with EF31 or UBS109 increases pancreatic cancer cell growth inhibition potentially by inducing the apoptotic pathways. When compared to TA, TA and Cur analog(s) is more effective in pancreatic cancer cells. These new combinations of anti-cancer molecules provide preliminary evidence for the therapeutic efficacy in treating pancreatic cancer.