Abstract A03: Tolfenamic acid induces the response of chemotherapy in pancreatic cancer: Preclinical study
Authors: Sankpal Umesh T. , Goodison Steven , Kayaleh Omar , Basha Riyaz 
Published: May 2015

Cancer treatment is complicated when patients develop resistance to standard therapies. Hence, developing strategies to address resistance to chemo therapy and improving therapeutic efficiency is of great importance in treating cancer successfully. Results from various preclinical studies showed that specificity protein (Sp) transcription factors regulate key genes associated with tumorigenesis, angiogenesis, and metastasis in several cancer models. Sp1 and Sp3 modulate the expression of survivin, an inhibitor of apoptosis protein (IAP) and we previously showed that targeting Sp transcription factors induced the response to radiation in pancreatic cancer cells and mice tumors. Research from our laboratory and others demonstrated the anti-cancer activity of a small molecule Tolfenamic Acid (TA) in some preclinical models of cancer including pancreatic cancer. It has been proposed that the anti-cancer activity of TA is associated with modulation of Sp proteins; however the precise underlying mechanisms are not extensively known.

In this investigation, we have conducted a molecular profiling analysis in three pancreatic cancer cell lines, Panc1, L3.6 pl and MiaPaCa2 to elucidate the mechanisms involved in the anti-cancer activity of TA. We also evaluated the potential of TA for improving the therapeutic efficacy of chemotherapeutic agents in pancreatic cancer cell lines and mice xenografts using two standard chemotherapeutic agents, 5-Flurouracil (5FU) and gemcitabine (GEM). Human pancreatic cancer cells, Panc1, L3.6pl and MiaPaCa2 were treated with 5FU or GEM or TA for 24-72 h to establish the dose curves. After monitoring the time/dose-response curves, optimized doses were used for the combination treatment. Cells were treated 5FU or GEM or TA or combinations (5FU+TA or GEM+TA) and the cell viability was measured at 48 h post-treatment. The tumor growth inhibitory response of individual and combination treatment was determined in mice xenografts. Nude mice were treated with 5FU (40 mg/kg, 3 times/wk for 2 wk) or GEM (50 mg/kg, 2 times/wk for 2 wk) or TA (50 mg/kg, 3 times/wk for 4 wk) or TA+5FU or TA+GEM as per the established methods. After the termination of the experiment, animals were euthanized; tumors were harvested and measured to determine the changes in tumor weight and volume.

Analysis of molecular profiling revealed that Sp1 and survivin are among the top candidates modulated by TA treatment; however TA modulates many genes associated with cancer and cell survival. The combination treatment experiments showed a significant increase in the anti-proliferative response of 5FU or GEM when used along with TA. Mice xenograft experiments also confirmed that TA enhanced the tumor growth inhibitory response of 5FU or GEM. Experiments using drug-resistant cell lines and functional studies to understand the underlying mechanisms of these combination therapies are ongoing.

These preclinical studies support the potential of TA for chemo sensitization and induction of the therapeutic response of standard chemotherapeutic agents in pancreatic cancer. Since enhancing the responses of standard therapeutic options is highly beneficial in treating cancer, these findings may lead to advances in developing novel strategies for treating aggressive malignancies like pancreatic cancer.

Financial Support: Shirley E. Noland Foundation; UFHCC, Orlando Health, Orlando, FL and Institute for Cancer Research, UNT Health Science Center, Fort Worth, TX.

Citation Format: Umesh T. Sankpal, Steven Goodison, Omar Kayaleh, Riyaz Basha. Tolfenamic acid induces the response of chemotherapy in pancreatic cancer: Preclinical study. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr A03.