WHEN IT COMES TO CANCER DRUGS, SOMETIMES LESS IS MORE
The chemotherapeutic drug decitabine (DAC) and its analog azacitidine (AZA) are FDA approved to treat cancers of the blood, such as myelodysplastic syndromes and certain types of leukemias. In high concentrations, DAC and AZA cause acute DNA damage followed by cell death. Currently, both drugs are limited to treatment of blood cancers, since the high doses required for the treatment of solid tumors are toxic and too often associated with severe side effects. DAC and AZA also possess the ability to reduce DNA methylation levels by directly inhibiting the activity of DNA methyltransferases. Because these drugs inhibit DNA methylation, it seems likely that their anti-cancer activity may at least partially be the result of reversing cancer-specific epigenetic changes, which is an attractive new approach to cancer therapy.
In a recent article published in Cancer Cell, Tsai et al. investigated the ability of DAC and AZA to treat cancer at the epigenetic level by reversing DNA hypermethylation-induced silencing of critical tumor suppressor genes. The authors found that low doses of DAC treatment did not cause significant DNA damage yet were sufficient to decrease the tumorigenicity of leukemic cell lines and primary leukemia cells tested both in vitro and when implanted into mice. Importantly, DAC treatment did not inhibit the growth potential or cause toxicity in primary normal (non-cancer) bone marrow cells. The authors expanded their study to the treatment of solid tumors. DAC or AZA treatment of cancer cell lines derived from breast, colon, and lung tumors, and primary breast cancer cells, followed by transplantation of these cells into mice, significantly inhibited tumor formation, relative to mock treatment. The authors then investigated changes occurring at the molecular level that might explain the DAC/AZA anti-cancer effects. Using a DNA methylation array, Tsai et al. found that promoter methylation decreases throughout the genome and was accompanied by widespread increases in gene expression. Notably, the authors found that key tumor suppressors that are hypermethylated in cancer saw a substantial increase in their transcription following treatment. The increased expression is followed by sustained downregulation of cancer cell signaling pathways in both breast cancer as well as leukemia cells.
This study provides mechanistic insight as to how DNA methylation inhibitors halt cancer progression in blood and solid tissues. Their findings indicate that epigenetic changes relieving the high levels of DNA methylation that silence tumor suppressors are a promising area for therapeutic exploration. Importantly, the low drug doses effecting those epigenetic changes should have minimal patient side effects, demonstrating that sometimes less truly is more. The compelling findings put forth by Tsai et al. give notice that epigenetic therapy is poised to revolutionize cancer treatment.
Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV, Shin JJ, Harbom KM, Beaty R, Pappou E, Harris J, Yen RW, Ahuja N, Brock MV, Stearns V, Feller-Kopman D, Yarmus LB, Lin YC, Welm AL, Issa JP, Minn I, Matsui W, Jang YY, Sharkis SJ, Baylin SB, & Zahnow CA (2012). Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer cell, 21 (3), 430-46 PMID: 22439938