Researchers at the National Sun Yat-Sen University and Kaohsiung Medical University, Kaohsiung, Taiwan have revealed a new mechanism by which nonsteroidal anti-inflammatory drugs (NSAIDs) attenuate tumor invasion and metastasis. The research, to be published in the April 2008 issue of Experimental Biology and Medicine, provides new insights for the understanding of the anti-cancer effects of NSAIDs.
NSAIDs have been used for the suppression of pain and inflammation in the clinic for many years. The main targets of these drugs are cyclooxygenases (COXs) which play critical roles in maintaining physiological homeostasis, mediating inflammatory reactions and promoting tumorigenesis. However, COX-independent effects are also important for the inhibition of cancer development by NSAIDs. Indeed, NSAIDs are considered as a novel class of effective chemopreventive drugs.
The research team, led by Wen-Chun Hung, Dean of College of Science, National Sun Yat-Sen University, and a recent doctorial graduate Mei-Ren Pan and two collaborators Hui-Chiu Chang and Lea-Yea Chuang of Kaohsiung Medical University found that NSAIDs up-regulated several anti-metastatic genes including secreted protein acidic and rich in cysteine (SPARC), thrombospindin-1 (TSP-1), TSP-3 and tissue inhibitors of metalloproteinase-2 (TIMP-2) in human lung cancer cells. Our functional assay suggested that increases of SPARC and other anti-metastatic genes were important for NSAIDs to inhibit tumor invasion and metastasis said Wen-Chun Hung. More importantly, we elucidated the underlying mechanism and demonstrated that up-regulation of SPARC in human lung cancer cells was mediated via inhibition of DNA methyltransferases (DNMTs) expression and promoter de-methylation. This is the first report to show that NSAIDs may inhibit the expression of DNMTs to reverse promoter methylation and to reactivate gene transcription.
The researchers say that hypermethylation of tumor suppressor genes is frequently found in many types of human cancer and is a crucial step for tumorigenesis. Recently, a number of de-methylating agents have been reported to exhibit potent anti-cancer effects in vitro and in vivo. Therefore, these agents are considered to be useful for cancer therapy. As a matter of fact, two de-methylating drugs 5-Azacitidine and 5-Aza-2-deoxycytidine (decitabine) have been approved for the treatment of myelodysplastic syndromes, a heterogenous group of hematopoietic stem cell disorders that are multifactorial in their etiology. Hung says our results indicate that NSAIDs may function as de-methylating agents via inhibition of DNMTs and may provide a new strategy for the treatment or prevention of cancer. Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, agrees and said These unique findings by Dr. Hung and colleagues suggest an entirely new function for non-steroidal anti-inflamatory drugs in cancer therapy. This is an exciting advance for the field of Cancer biology.
|Contact: Dr. Wen-Chung Hung|
Society for Experimental Biology and Medicine