Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™

Sun, Feng; Lee, Lawrence; Zhang, Zhiwei; Wang, Xiaochong; Q, Yu; Duan, Xiaoqun; Chan, Eli

doi:10.1016/j.ejps.2015.06.021

Cited by 31 publications

(26 citation statements)

References 58 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A recent detailed pharmacokinetic study in rats showed that intravenous administration of 3-DZNeP to rats at a dose of #10 mg/kg body wt did not cause any obvious signs of toxicity, and the kidney was the major organ for its clearance. 74 Additionally, a stimulated human whole-body, physiologically based pharmacokinetic model identified that the intravenous administration of 3-DZNeP could be developed for human cancer therapy. 74 Because it is predominantly cleared by the kidney, 3-DZNeP at 2 mg/kg was selected for assessing its therapeutic effect on renal fibrosis in our UUO model.…”

Section: Discussionmentioning

confidence: 99%

“…74 Additionally, a stimulated human whole-body, physiologically based pharmacokinetic model identified that the intravenous administration of 3-DZNeP could be developed for human cancer therapy. 74 Because it is predominantly cleared by the kidney, 3-DZNeP at 2 mg/kg was selected for assessing its therapeutic effect on renal fibrosis in our UUO model. With this low-dose regiment, 3-DZNeP showed a strong inhibitory effect on renal myofibroblast activation and renal fibrogenesis, suggesting the perspective for development of it as an antifibrosis drug.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression

Zhou

Zang

Ponnusamy

et al. 2015

JASN

146

158

View full text Add to dashboard Cite

Enhancer of zeste homolog 2 (EZH2) is a methyltransferase that induces histone H3 lysine 27 trimethylation (H3K27me3) and functions as an oncogenic factor in many cancer types. However, the role of EZH2 in renal fibrogenesis remains unexplored. In this study, we found high expression of EZH2 and H3K27me3 in cultured renal fibroblasts and fibrotic kidneys from mice with unilateral ureteral obstruction and humans with CKD. Pharmacologic inhibition of EZH2 with 3-deazaneplanocin A (3-DZNeP) or GSK126 or siRNAmediated silencing of EZH2 inhibited serum-and TGFb1-induced activation of renal interstitial fibroblasts in vitro, and 3-DZNeP administration abrogated deposition of extracellular matrix proteins and expression of a-smooth muscle actin in the obstructed kidney. Injury to the kidney enhanced Smad7 degradation, Smad3 phosphorylation, and TGFb receptor 1 expression, and 3-DZNeP administration prevented these effects. 3-DZNeP also suppressed phosphorylation of the renal EGF and PDGFb receptors and downstream signaling molecules signal transducer and activator of transcription 3 and extracellular signal-regulated kinase 1/2 after injury. Moreover, EZH2 inhibition increased the expression of phosphatase and tensin homolog (PTEN), a protein previously associated with dephosphorylation of tyrosine kinase receptors in the injured kidney and serum-stimulated renal interstitial fibroblasts. Finally, blocking PTEN with SF1670 largely diminished the inhibitory effect of 3-DZNeP on renal myofibroblast activation. These results uncovered the important role of EZH2 in mediating the development of renal fibrosis by downregulating expression of Smad7 and PTEN, thus activating profibrotic signaling pathways. Targeted inhibition of EZH2, therefore, could be a novel therapy for treating CKD.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression

Zhou

Zang

Ponnusamy

et al. 2015

JASN

146

158

View full text Add to dashboard Cite

show abstract

“…Identification of more favorable DZNep analogs exploiting desirably reprogrammed miRNAs or direct delivery of reprogrammed miRNAs into tumors offers two potential avenues for therapeutic development. The recent preclinical pharmacokinetic studies optimizing intravenous administration of DZNep for utilities in advanced-stage solid tumors are also very encouraging (49). …”

Section: Discussionmentioning

confidence: 99%

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

Mody

Hung

Alsaggar

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

Identification of epigenetic reversal agents for use in combination chemotherapies to treat human pancreatic ductal adenocarcinomas (PDAC) remains an unmet clinical need. Pharmacological inhibitors of Enhancer of Zeste Homolog 2 (EZH2) are emerging as potential histone methylation reversal agents for the treatment of various solid tumors and leukemia; however, the surprisingly small set of mRNA targets identified with EZH2 knockdown suggests novel mechanisms contribute to their anti-tumorigenic effects. Here, 3-deazaneplanocin-A (DZNep), an inhibitor of S-adenosyl-L-homocysteine hydrolase and EZH2 histone lysine-N-methyltransferase, significantly reprograms noncoding miRNA (miR) expression and dampens TGFβ1-induced epithelial-to-mesenchymal (EMT) signals in pancreatic cancer. In particular, miR-663a and miR-4787-5p were identified as PDAC-downregulated miRs that were reactivated by DZNep to directly target TGFβ1 for RNA interference. Lentiviral overexpression of miR-663a and miR-4787-5p reduced TGFβ1 synthesis and secretion in PDAC cells and partially phenocopied DZNep’s EMT-resisting effects, whereas locked nucleic acid (LNA) antagomiRs counteracted them. DZNep, miR-663a, and miR-4787-5p reduced tumor burden in vivo and metastases in an orthotopic mouse pancreatic tumor model. Taken together, these findings suggest the epigenetic reprogramming of miRs by synthetic histone methylation reversal agents as a viable approach to attenuate TGFβ1-induced EMT features in human PDAC and uncover putative miR targets involved in the process.

show abstract

“…Overall, these findings are consistent with our previous work which demonstrated DZNep to induce chemosensitizing properties in pancreatic cancer (19). Nonetheless, DZNep is a non-specific, global histone methylation inhibitor reported to cause several unintended toxicities (e.g., nephrotoxicity) in mice that halted the clinical development of the compound (30). Hence, by understanding the mechanistic aspects of DZNep, further efforts were made in this study to identify the molecular targets of DZNep responsible for its beneficial therapeutic actions.…”

Section: Discussionmentioning

confidence: 99%

miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer

Mody

Hung

Pathak

et al. 2017

Molecular Cancer Research

View full text Add to dashboard Cite

Previous studies in our laboratory identified that 3-deazaneplanocin A (DZNep), a carbocyclic adenosine analog and histone methyl transferase inhibitor, suppresses TGFβ-induced epithelial-to-mesenchymal (EMT) characteristics. In addition, DZNep epigenetically reprograms miRNAs (miRs) to regulate endogenous TGFβ1 levels via miR-663/4787 mediated RNA interference (Mol Cancer Res. 2016 Sep 13. pii: molcanres.0083.2016) (1). While DZNep also attenuates exogenous TGFβ-induced EMT response, the mechanism of this inhibition was unclear. Here, DZNep induced miR-202-5p to target both TGFβ receptors, TGFBR1 and TGFBR2, for RNA interference and thereby contribute to the suppression of exogenous TGFβ-induced EMT in pancreatic cancer cells. Lentiviral overexpression of miR-202 significantly reduced the protein levels of both TGFβ receptors and suppressed TGFβ signaling and EMT phenotypic characteristics of cultured parenchymal pancreatic cancer cells. Consistently, transfection of anti-miRs against miR-202-5p resulted in increased TGFBR1 and TGFBR2 protein expressions and induced EMT characteristics in these cells. In stellate pancreatic cells, miR-202 overexpression slowed growth as well as reduced stromal extracellular membrane matrix (ECM) protein expression. In orthotopic pancreatic cancer mouse models, both immunodeficient and immunocompetent, miR-202 reduced tumor burden and metastasis. Together, these findings demonstrate an alternative mechanism of DZNep in suppressing TGFβ signaling at the receptor level and uncover the EMT suppressing role of miR-202 in pancreatic cancer. Implications These findings support the possibility of combining small molecule- (e.g., DZNep analogs) or large molecule- (e.g., miRs) based epigenetic modifiers with conventional nucleoside analogs (e.g., gemcitabine, capecitabine) to improve the anti-metastatic potential of current pancreatic cancer therapy.

show abstract

Preclinical pharmacokinetic studies of 3-deazaneplanocin A, a potent epigenetic anticancer agent, and its human pharmacokinetic prediction using GastroPlus™

Cited by 31 publications

References 58 publications

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression

Enhancer of Zeste Homolog 2 Inhibition Attenuates Renal Fibrosis by Maintaining Smad7 and Phosphatase and Tensin Homolog Expression

Inhibition of S-Adenosylmethionine-Dependent Methyltransferase Attenuates TGFβ1-Induced EMT and Metastasis in Pancreatic Cancer: Putative Roles of miR-663a and miR-4787-5p

miR-202 Diminishes TGFβ Receptors and Attenuates TGFβ1-Induced EMT in Pancreatic Cancer

Contact Info

Product

Resources

About