Cellular and Organismal Toxicity of the Anti-Cancer Small Molecule, Tolfenamic Acid: a Pre-Clinical Evaluation

• Published in: Cellular physiology and biochemistry Vol. 32; no. 3; pp. 675 - 686
• Main Authors: Sankpal, Umesh T., Lee, Chris M., Connelly, Sarah F., Kayaleh, Omer, Eslin, Don, Sutphin, Robert, Goodison, Steven, Adwan, Lina, Zawia, Nasser H., Lichtenberger, Lenard M., Basha, Riyaz
• Format: Journal Article
• Language: English
• Published: Basel, Switzerland Cell Physiol Biochem Press GmbH & Co KG 01.01.2013
• Subjects: Animals; Antineoplastic Agents - toxicity; Body Weight - drug effects; Cell Differentiation - drug effects; Cell Line; Cell Survival - drug effects; Drug Evaluation, Preclinical; Hematocrit; Inhibitor of Apoptosis Proteins - metabolism; Intestines - pathology; Liver - pathology; Mice; Mice, Nude; Original Paper; ortho-Aminobenzoates - toxicity; Repressor Proteins - metabolism; Small molecule; Sp1; Sp1 Transcription Factor - metabolism; Stomach - pathology; Survivin; Tolfenamic acid; Toxicity; Small molecule; Survivin; Tolfenamic acid; Sp1; Toxicity
• DOI: 10.1159/000354471
• ISSN: 1015-8987

Background/Aims: The small molecule, Tolfenamic acid (TA) has shown anti-cancer activity in pre-clinical models and is currently in Phase I clinical trials at MD Anderson Cancer Center Orlando. Since specificity and toxicity are major concerns for investigational agents, we tested the effect of TA on specific targets, and assessed the cellular and organismal toxicity representing pre-clinical studies in cancer. Methods: Panc1, L3.6pl, and MiaPaCa-2 (pancreatic cancer), hTERT-HPNE(normal), and differentiated/un-differentiated SH-SY5Y (neuroblastoma) cells were treated with increasing concentrations of TA. Cell viability and effect on specific molecular targets, Sp1 and survivin were determined. Athymic nude mice were treated with vehicle or TA (50mg/kg, 3times/week for 6 weeks) and alterations in the growth pattern, hematocrit, and histopathology of gut, liver, and stomach were monitored. Results: TA treatment decreased cell proliferation and inhibited the expression of Sp1 and survivin in cancer cells while only subtle response was observed in normal (hTERT-HPNE) and differentiated SH-SY5Y cells. Mice studies revealed no effect on body weight and hematocrit. Furthermore, TA regimen did not cause signs of internal-bleeding or damage to vital tissues in mice. Conclusion: These results demonstrate that TA selectively inhibits malignant cell growth acting on specific targets and its chronic treatment did not cause apparent toxicity in nude mice.