CG200745, an HDAC inhibitor, induces anti-tumour effects in cholangiocarcinoma cell lines via miRNAs targeting the Hippo pathway

Abstract

Cholangiocarcinoma is a devastating malignancy with fatal complications that exhibits low response and resistance to chemotherapy. Here, we evaluated the anticancer effects of CG200745, a novel histone deacetylase inhibitor, either alone or in combination with standard chemotherapy drugs in cholangiocarcinoma cells. CG200745 dose-dependently reduced the viability of cholangiocarcinoma cells in vitro and decreased tumour volume and weight in a xenograft model. Administering CG200745 along with other chemotherapeutic agents including gemcitabine, 5-fluorouracil (5-FU), cisplatin, oxaliplatin, or gemcitabine plus cisplatin further decreased cholangiocarcinoma cell viability, with a combination index < 1 that indicated synergistic action. CG200745 also enhanced the sensitivity of gemcitabine-resistant cells to gemcitabine and 5-FU, thereby decreasing cell viability and inducing apoptosis. This was accompanied by downregulation of YAP, TEAD4, TGF-β2, SMAD3, NOTCH3, HES5, Axl, and Gas6 and upregulation of the miRNAs miR-22-3p, miR-22-5p, miR-194-5p, miR-194-3p, miR-194-5p, miR-210-3p, and miR-509-3p. The Ingenuity Pathway Analysis revealed that CG200745 mainly targets the Hippo signalling pathway by inducing miR-509-3p expression. Thus, CG200745 inhibits cholangiocarcinoma growth in vitro and in vivo, and acts synergistically when administered in combination with standard chemotherapeutic agents, enabling dose reduction. CG200745 is therefore expected to improve the outcome of cholangiocarcinoma patients who exhibit resistance to conventional therapies.

HDAC Inhibitor, CG-745, Enhances the Anti-Cancer Effect of Anti-PD-1 Immune Checkpoint Inhibitor by Modulation of the Immune Microenvironment

“…These contradictory effects might reflect the distinct roles of individual HDACs in the immune responses. Therefore, the novel discovery of CG-745 in anti-cancer immunity suggests an excellent combination partner of various cancer immunotherapy and supports the reason why CG-745 shows the excellent synergistic efficacy in the combination treatment of various mouse tumor models such as in cholangiocarcinoma, pancreatic cancer, prostate cancer, and non-small cell lung cancer [30][31][32][33].…”

“…While HDACis in anti-cancer therapy are commonly known as apoptosis inducers through anti-cancer gene expression and cell cycle arrest, recent studies have shown anti-tumor efficacy of HDACis in certain cancer types [26][27][28][29]. CG-745 is a HDAC inhibitor, and it has been reported as a potent anti-cancer agent in cholangiocarcinoma, pancreatic cancer, prostate cancer, and non-small cell lung cancer [30][31][32][33]. In cholangiocarcinoma, CG-745 is known to target the Hippo pathway via upregulation of miR-509-3p expression [33].…”

“…CG-745 is a HDAC inhibitor, and it has been reported as a potent anti-cancer agent in cholangiocarcinoma, pancreatic cancer, prostate cancer, and non-small cell lung cancer [30][31][32][33]. In cholangiocarcinoma, CG-745 is known to target the Hippo pathway via upregulation of miR-509-3p expression [33]. Also, reduction of the ATP-binding cassette-transporter genes, especially multi-drug resistance protein 3 and 4 which also resist CG-745, induce pancreatic cancer cells to sensitively respond to gemcitabine.…”

Histone deacetylase inhibitor CG200745 ameliorates high-fat diet-induced hypertension via inhibition of angiotensin II production

“…We presume that CG200745 may not cause renal insufficiency because CG200745 works by inhibiting over-production of angiotensinogen or Ang II in response to HFD not by random inhibition of existing angiotensinogen or Ang II. Of course the side effects of CG200745 should be studied thoroughly but good thing is that the dose we used in this study (200 μg/ kg) is greatly lower than the dose of clinical trial (1.275-6.25 mg/kg) (Kim et al 2015) or other researches at 5 mg/kg (Lee et al 2016;Bae et al 2019) or 35-45 mg/kg (Hwang et al 2012;Jung et al 2017) reducing the possibility of side effects. In this study, even combined with HFD, 200 μg/kg i.p.…”

Distinct Subsets of Noncoding RNAs Are Strongly Associated With BMD and Fracture, Studied in Weight-Bearing and Non–Weight-Bearing Human Bone

“…Still, we acknowledge that detection methodologies (microarrays with detection of biotin labeled ncRNAs versus TaqMan assays involving detection of PCR products after cleavage of quenching hybridizing probes) and quantification analyses (eg, different types of sample normalization, software, and thresholds) could have an influence on the results. However, several papers show that in general there is a very good concurrence in studies where miRNA levels was measured by both GeneChip miRNA 4.0 Array and TaqMan PCR analysis …”