Delivery of 5-Azacytidine to Human Cancer Cells by Elaidic Acid Esterification Increases Therapeutic Drug Efficacy

Abstract

Azacytidine is an established nucleoside drug that is well known for its ability to modulate epigenetic gene regulation by inhibition of DNA methylation. Despite recent advances in the clinical development of azacytidine, the use of the drug is limited by its low bioavailability and dependen cy on variably expressed nucleoside transporters for cellular uptake. We show here that CP-4200, an elaidic acid derivative of azacytidine, has strong epigenetic modulatory potency in human cancer cell lines, as evidenced by efficient depletion of DNA methyltransferase protein, genome-wide DNA demethylation, and robust reactivation of epigenetically silenced tumor suppressor genes. Importantly, however, the cellular uptake of CP-4200 was substantially less dependent on the nucleoside transporters that are known to be involved in azacytidine uptake. In agreement with this notion, CP-4200 showed a significantly higher antitumoral activity than azacytidine in an orthotopic mouse tumor model for acute lymphocytic leukemia. Together, these data represent a detailed characterization of the CP-4200 mode of action and suggest that elaidic acid modification improves the therapeutic efficacy of azacytidine. Mol Cancer Ther; 9(5); 1256-64. ©2010 AACR.

Epigenetic cancer therapy: rationales, targets and drugs

“…In addition, CP-4200 also causes widespread DNA demethylation and reactivation of tumor suppressor genes under conditions where inhibition of hENTdependent drug transport completely blocked the demethylating effects of 5-azacytidine (MR and FL, unpublished data). Both CP-4200 and S110 have shown significant in vivo activity in mouse tumor models (Brueckner et al, 2010;Chuang et al, 2010), which further illustrates the potential of the azacytosine scaffold for continued preclinical development. Importantly, the development of chemically modified azacytosine derivatives might also allow the targeting of tumor entities that are insensitive to 5-azacytidine and decitabine.…”

“…S110 is a dinucleotide of decitabine and deoxyguanidine, and is highly resistant to cytidine deaminase (Yoo et al, 2007). CP-4200 is an elaidic acid ester of 5-azacytidine, which utilizes a modified and potentially less selective transport uptake mechanism (Brueckner et al, 2010). Importantly, both drugs have retained robust demethylating activity, despite their extensive chemical modifications (Yoo et al, 2007;Brueckner et al, 2010).…”

“…CP-4200 is an elaidic acid ester of 5-azacytidine, which utilizes a modified and potentially less selective transport uptake mechanism (Brueckner et al, 2010). Importantly, both drugs have retained robust demethylating activity, despite their extensive chemical modifications (Yoo et al, 2007;Brueckner et al, 2010). In addition, CP-4200 also causes widespread DNA demethylation and reactivation of tumor suppressor genes under conditions where inhibition of hENTdependent drug transport completely blocked the demethylating effects of 5-azacytidine (MR and FL, unpublished data).…”

Enhanced in Vitro Anti-Tumor Activity of 5-Azacytidine by Entrapment into Solid Lipid Nanoparticles

“…The first is to change the drug structure by chemical reactions like esterification. 15 Although this strategy shows good results, the drug approving procedure for new drugs is time-and cost-consuming. The second strategy is to encapsulate 5-azacytidine in nanoparticles to protect it from enzymatic deamination.…”

Hypomethylation effects of curcumin, demethoxycurcumin and bisdemethoxycurcumin on WIF-1 promoter in non-small cell lung cancer cell lines

“…Several categories of DnMT1 inhibitors have been identified in previous studies. Among these, nucleoside analogs such as decitabine or 5-azacytidine appear to be most effective in inducing global DNA hypomethylation and the reactivation of epigenetically silenced tumor suppressor genes in malignant cells (16)(17)(18). However, toxicity (e.g., myelosuppression) inherent to the cell cycle phase specificity of nucleoside analogs significantly limits the use of these drugs, particularly in patients with solid tumors (19).…”