Combination of Tolfenamic acid and curcumin induces colon cancer cell growth inhibition through modulating specific transcription factors and reactive oxygen species
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Umesh T. Sankpal1,2, Ganji Purnachandra Nagaraju3, Sriharika R. Gottipolu2, Myrna Hurtado2, Christopher G. Jordan1,4, Jerry W. Simecka5,6, Mamoru Shoji3, Bassel El-Rayes3, Riyaz Basha1,2,5
1Institute for Cancer Research, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
2Texas College of Osteopathic Medicine, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
3Department of Hematology Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA 30322, USA
4JPS Center for Cancer Care, Fort Worth, TX 76104, USA
5Preclinical Services, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
6College of Pharmacy, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Keywords: colon cancer, tolfenamic acid, curcumin, Sp1, NF-kB
Received: August 21, 2015 Accepted: November 21, 2015 Published: December 10, 2015
Curcumin (Cur) has been extensively studied in several types of malignancies including colorectal cancer (CRC); however its clinical application is greatly affected by low bioavailability. Several strategies to improve the therapeutic response of Cur are being pursued, including its combination with small molecules and drugs. We investigated the therapeutic efficacy of Cur in combination with the small molecule tolfenamic acid (TA) in CRC cell lines. TA has been shown to inhibit the growth of human cancer cells in vitro and in vivo, via targeting the transcription factor specificity protein1 (Sp1) and suppressing survivin expression. CRC cell lines HCT116 and HT29 were treated with TA and/or Cur and cell viability was measured 24–72 hours post-treatment. While both agents caused a steady reduction in cell viability, following a clear dose/ time-dependent response, the combination of TA+Cur showed higher growth inhibition when compared to either single agent. Effects on apoptosis were determined using flow cytometry (JC-1 staining to measure mitochondrial membrane potential), Western blot analysis (c-PARP expression) and caspase 3/7 activity. Reactive oxygen species (ROS) levels were measured by flow cytometry and the translocation of NF-kB into the nucleus was determined using immunofluorescence. Results showed that apoptotic markers and ROS activity were significantly upregulated following combination treatment, when compared to the individual agents. This was accompanied by decreased expression of Sp1, survivin and NF-kB translocation. The combination of TA+Cur was more effective in HCT116 cells than HT29 cells. These results demonstrate that TA may enhance the anti-proliferative efficacy of Cur in CRC cells.
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