Dual inhibition of HDAC and tyrosine kinase signaling pathways with CUDC-907 attenuates TGFβ1 induced lung and tumor fibrosis

Abstract

TGFβ1 signaling is a critical driver of collagen accumulation in pulmonary fibrotic diseases and a well-characterized regulator of cancer associated fibroblasts (CAF) activation in lung cancer. Myofibroblasts induced by TGFβ1 and other factors are key players in the pathogenesis of lung fibrosis and tumor. Tremendous attention has been gained to targeting myofibroblasts in order to inhibit the progression of fibrosis and myofibroblast-induced tumor progression and metastasis. Here we determined the therapeutic efficacy of simultaneously targeting PI3K and HDAC pathways in lung myofibroblasts and CAF with a single agent and to evaluate biomarkers of treatment response. CUDC-907 is a first-in-class compound, functioning as a dual inhibitor of HDACs and PI3K/AKT pathway. We investigated its effects in counteracting the activity of TGFβ1-induced myofibroblasts/CAF in regard to cell proliferation, migration, invasion, apoptosis in vitro antifibrosis efficiency in vivo. We found that CUDC-907 inhibited myofibroblasts/CAF cell proliferation, migration and apoptosis in a dose-dependent manner and caused cell cycle arrest at G1-S phase. CUDC-907 not only inhibited myofibroblasts markers expression, but also significantly inhibited the phosphorylation level of AKT, mTOR, Smad2/3, and promoted acetylation of histones. Furthermore, the observed inhibitory effect was also confirmed in bleomycin-induced mice lung fibrosis and nude mouse transplanted tumor model. Overall, these data suggest that dual inhibition of HDAC and the tyrosine kinase signaling pathways with CUDC-907 is a promising treatment strategy for TGFβ1-induced lung and tumor fibrosis.

Dual Targeting of PI3K and HDAC by CUDC-907 Inhibits Pediatric Neuroblastoma Growth

“…Our results demonstrated the effect of CUDC-907 in inhibiting the PI3K/AKT, HDACs, and enhancing the H3K9Ac levels in NB. Numerous reports in different cancers have shown similar results of the CUDC-907-mediated inhibition of PI3K, HDACs, and related proteins [ 20 , 21 , 32 , 35 , 37 , 38 ]. MYCN is one of the most important prognostic factors for the NB progression [ 46 ].…”

“…Similar results of the CUDC-907-mediated blockage of the S and G2/M phases were shown for pancreatic and thyroid cancers via the downregulation of the cell cycle regulators cyclin B1, AURKA, and PLK1 [ 33 , 35 ]. In glioblastoma, CUDC-907 induces G1 cell cycle arrest through CDKN1A promoter hyperacetylation-driven transcriptional activation and downregulation of CDK1 [ 36 ], while in lung fibroblast cells, CUDC-907 blocks G1 and S phase [ 37 ]. In breast cancer, CUDC-907 enhances TRAIL-induced apoptosis through the upregulation of cell survival proteins, including XIAP, Bcl-xL, and Bcl-2 [ 38 ].…”

Fibrosis: Sirtuins at the checkpoints of myofibroblast differentiation and profibrotic activity

“…As result, CUDC-907 exerted beneficial effects against lung fibrosis and cancer. 167 The use of Sirt1 activators for the treatment of kidney fibrosis has been also demonstrated by Ren and colleagues. 168 Indeed, the authors halted the profibrotic TGF-β1/CTGF signalling pathway in mice with UUO-induced tubulointerstitial fibrosis by administering SRT1720, a Sirt1 activator.…”

Therapeutic and diagnostic targeting of fibrosis in metabolic, proliferative and viral disorders

“…Inhibition of proteins related to homeostatic mechanisms, e.g., H + /K + -ATPase [183], GPR43 and GPR109A sensing receptors [184,185], intestinal fatty acid-binding protein (FABP2) [186], has also been shown to confer promising anti fibrotic efficacy in disease models related to chronic pancreatitis, diabetic nephropathy, and atherosclerosis. Finally, promising anti-fibrotic activity profiles have been published for inhibition of other proteins, such as PI3Kα and HDAC proteins in lung adenocarcinoma [187], CXCR4 in lung metastasis [188], the proteasome and the RNA-binding protein HuR in diabetic nephropathy [189,190], the pyruvate kinase M2, MCL1, and ACVR1 in liver diseases [191][192][193], and PI4KIIIβ, CFTR and IL-1R in viral infections [194][195][196].…”