tolfenamic-acid and Esophageal-Neoplasms

Specificity protein (Sp) transcription factors regulate the expression of genes associated with several cellular processes and play a critical role in early development. Typically, Sp protein expression decreases with age in healthy adults. Research has shown that Sp proteins can impact the development and transformation of cancer cells and other oncogenic processes, including survival, proliferation, spread, and metastasis. Among the Sp proteins, Sp1, Sp3, and Sp4 have been the main targets of study as they are shown to be highly expressed in cancer cells compared to healthy cells. Increased levels of Sp1 are correlated with poor prognosis in some malignancies, including gastrointestinal cancers. In this review, we discuss the role of Sp transcription factors and examine their activities as pro-oncogenic factors in esophageal cancer (EC). Other aspects presented in this review are potential therapeutic options for EC that target Sp1. We summarize the published information on preclinical results using mithramycin and tolfenamic acid.

Topics: Carcinogenesis; Esophageal Neoplasms; Humans; ortho-Aminobenzoates; Plicamycin; Prognosis; Risk Factors; Sp Transcription Factors

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.

Topics: Animals; Anticarcinogenic Agents; Carcinogens; Cell Line; Cell Survival; Dimethylnitrosamine; Disease Models, Animal; Esophageal Neoplasms; Humans; ortho-Aminobenzoates; Proto-Oncogene Proteins c-met; Rats; Rats, Inbred F344; Sp Transcription Factors; Tumor Burden

The non-steroidal anti-inflammatory drug tolfenamic acid (TA) inhibits proliferation of SEG-1 and BIC-1 esophageal cancer cells with half-maximal growth inhibitory concentration values of 36 and 48 muM, respectively. TA also increased Annexin V staining in both cell lines, indicative of proapoptotic activity. Treatment of SEG-1 and BIC-1 cells with TA for up to 72 h decreased expression of specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 and this was accompanied by decreased expression of the well-characterized Sp-regulated genes cyclin D1, vascular endothelial growth factor and survivin. TA also decreased hepatocyte growth factor receptor, (c-Met), a receptor tyrosine kinase that is overexpressed in esophageal cancer cells and tumors and is an important drug target. Knockdown of Sp1, Sp3 and Sp4 by RNA interference in SEG-1 and BIC-1 cells also decreased c-Met expression, demonstrating that c-Met is an Sp-regulated gene in esophageal cancer cells. Sp1 was overexpressed in esophageal cancer cells and tumors and increased Sp1 staining was observed in esophageal tumors from patients. TA (20 mg/kg/day) also decreased tumor growth and weight in athymic nude mice bearing SEG-1 cells as xenografts and this was accompanied by increased apoptosis and decreased Sp1 and c-Met staining in tumors from treated mice. Thus, TA-dependent downregulation of Sp transcription factors and c-Met defines a novel chemotherapeutic approach for treatment of esophageal cancer.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line, Tumor; Down-Regulation; Esophageal Neoplasms; Humans; Mice; Mice, Nude; Neoplasm Transplantation; ortho-Aminobenzoates; Proto-Oncogene Proteins c-met; Sp Transcription Factors; Transplantation, Heterologous