Chemopreventive effects of tolfenamic acid against esophageal tumorigenesis in rats

Abstract

The primary objective of this study is to identify small molecules that target critical transcription factors for potential application in the chemoprevention of esophageal cancer. Specificity proteins (Sp) play a critical role in the growth and metastasis of several malignancies including esophageal cancer. Researchers at the M. D. Anderson Cancer Center Orlando Cancer Research Institute have reported previously that tolfenamic acid (TA) inhibits cancer cell proliferation and tumor growth through the degradation of Sp1, Sp3, and Sp4. We evaluated the chemopreventive properties of TA against esophageal tumorigenesis in N-nitrosomethylbenzylamine (NMBA)-induced murine tumor model. Fischer-344 rats were treated with NMBA (0.5 mg/kg s.c. 3 times a week) for 5 weeks to initiate the tumor formation, and then treated with 50 mg/kg TA from week 6 through week 25. Tumor incidence, tumor multiplicity (number of papilloma per rat), and tumor volume were evaluated after 25 weeks. All rats in the control group that received only NMBA developed lesions (100% incidence), while the TA-treated group showed significantly lower (33%) tumor incidence and tumor multiplicity. Furthermore, the tumor volume was significantly diminished in the TA-treated group when compared with the control group. Using small molecules such as TA to target key transcription factors associated with tumorigenesis for the prevention of esophageal malignancies is a new and promising strategy. Results of the current study provide evidence that TA, when given orally after tumor initiation, can significantly suppress tumorigenesis induced by carcinogenic nitrosamines in rats. These appealing results demonstrate that TA may potentially serve as an effective chemopreventive agent in patient populations vulnerable to esophageal cancer.

Small molecule tolfenamic acid and dietary spice curcumin treatment enhances antiproliferative effect in pancreatic cancer cells via suppressing Sp1, disrupting NF-kB translocation to nucleus and cell cycle phase distribution

“…This therapeutic strategy provides promising activity and better tolerance than standard cytotoxic therapies currently being used in pancreatic cancer. Cur [48] and TA [52] have been tested (individually) for their chemopreventive properties and both of these agents showed a positive response in animal models. Cur exhibited cancer prevention in a clinical study.…”

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

“…Even though our previous studies using rats showed limited toxicity of TA [38], this is the first study assessing the toxicity in detail, achieved through putting together the results of animal growth patterns, blood chemistry and organ histopathology. All these results showed limited cytotoxicity and GI effects.…”

“…TA has been studied in pre-clinical models for adult (pancreatic [26,27], lung [28], esophageal [14,29], ovarian [30], prostate [31,32], and colon [33,34]) cancers and pediatric (leukemia [35], neuroblastoma [36], and medulloblastoma [37]) malignancies. Experimental results from our laboratory also showed a chemopreventive effect by this drug in an animal model of esophageal cancer [29,38]. TA exhibits anticancer and chemopreventive activities primarily via inhibiting specificity protein (Sp) transcription factors.…”

Expression of Specificity Protein Transcription Factors in Pancreatic Cancer and their Association in Prognosis and Therapy

“…Tolfenamic acid when combined with mithramycin A, another Sp1 inhibitor, results in synergistic anticancer effect [93]. Tolfenamic acid has been successfully shown both in vitro and in vivo mouse models to inhibit growth of several different cancers including esophageal, oral, lung, breast, neuroblastoma, cervical, ovarian, colorectal, and prostate cancer [97][98][99][100][101][102][103][104][105].…”