Identification of a 3,3-difluorinated tetrahydropyridinol compound as a novel antitumor agent for hepatocellular carcinoma acting via cell cycle arrest through disturbing CDK7-mediated phosphorylation of Cdc2

SummaryTetrahydropyridinol derivatives were recently reported to exhibit good biological activities, and the incorporation of fluorine into organic molecules may have profound effects on their physical and biological properties. Therefore, we investigated the anticancer activities of six fluorinated tetrahydropyridinol derivatives that we synthesized previously. We found that only one compound, 3,3-difluoro-2,2-dimethyl-1,6-diphenyl-5-tosyl-1,2,3,6-tetrahydropyridin-4-ol, showed significant antiproliferative activity on human hepatocellular carcinoma HepG2 and HMCCLM3 cells (the IC50 values were 21.25 and 29.07  μM, respectively). We also found that this compound mediated cell cycle arrest in the G0/G1 phase at 30–40 μM. Western blot analysis demonstrated that the cell cycle arrest induced by this compound in HepG2 and HMCCLM3 cells was associated with a significant decrease in Cdc2 and cyclin B1, wh ich led to the accumulation of the phosphorylated-Tyr15 (inactive) form of Cdc2 and low expression of M phase-promoting factor (cyclin B1/Cdc2). Moreover, cells treated with this compound exhibited decreased expression of cyclin-dependent kinase (CDK)-activating kinase (CDK7/cyclin H). This compound also induced cell apoptosis via activation of caspase-3. A xenograft model in nude mice demonstrated anti-liver cancer activity and the mechanism of action of this compound. These findings indicated that the anticancer effect of this compound was partially due to...
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research

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Glycosylation of immune receptors and ligands, such as T cell receptor and coinhibitory molecules, regulates immune signaling activation and immune surveillance. However, how oncogenic signaling initiates glycosylation of coinhibitory molecules to induce immunosuppression remains unclear. Here we show that IL-6–activated JAK1 phosphorylates programmed death-ligand 1 (PD-L1) Tyr112, which recruits the endoplasmic reticulum–associated N-glycosyltransferase STT3A to catalyze PD-L1 glycosylation and maintain PD-L1 stability. Targeting of IL-6 by IL-6 antibody induced synergistic T cell killing effects when combined...
Source: Journal of Clinical Investigation - Category: Biomedical Science Authors: Source Type: research
(University of Texas M. D. Anderson Cancer Center) A study at The University of Texas MD Anderson Cancer Center discovered a cellular pathway tied to cancer that may be beneficial in reducing side effects and extending duration of immunotherapy in some patients with hepatocellular carcinoma, the most common form of liver cancer.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
Conclusion: In this retrospective study involving well-selected HCC patients, high ORR and long TTTF and OS are observed after TACE using idarubicin-loaded TANDEM. A randomized trial is needed.
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
In this study, we investigated therapeutic potential of a natural flavonoid Morin hydrate against cisplatin-induced toxicity using the HepG2DR multi-drug resistant cell line, which is derived from the HepG2 human hepatocellular carcinoma cell line. HepG2DR cells were exposed to cisplatin and Morin hydrate alone or together after which autophagy and apoptotic signaling pathways were monitored by fluorometric assay and Western blot analysis. Xenograft mouse models were performed to confirm the in vitro effect of Morin hydrate. PARP1 was hyper activated in cisplatin-resistant HepG2DR cells. Cisplatin-induced PARP1 activation ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Go J. Yoshida We hypothesized that sorafenib plus transarterial chemoembolization (TACE) would confer survival benefits over sorafenib alone for advanced hepatocellular carcinoma (aHCC). We investigated this while using the population-based All-Cancer Dataset to assemble a cohort (n = 3674; median age, 60; 83% men) of patients receiving sorafenib for aHCC (Child-Pugh A) with macro-vascular invasion or nodal/distant metastases. The patients were classified into the sorafenib-TACE group (n = 426) or the propensity score-matched sorafenib-alone group (n = 1686). All of the participants were followed up until death or the ...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Authors: Mo Y, He L, Lai Z, Wan Z, Chen Q, Pan S, Li L, Li D, Huang J, Xue F, Che S Abstract Abnormal expression of microRNAs (miRNAs) contributes to tumour growth and invasion. MiR-326 expression often down-regulates in several kinds of cancer and low expression of miR-326 is linked with poor prognosis in cancer patients. In the present study, we aimed to explore the modulatory mechanism of miR-326 in hepatocellular carcinoma (HCC). miR-326 expression was significantly decreased in HCC cell lines and tissues. miR-326 decreased HCC cell growth by affecting cell-cycle progression and by promoting apoptosis. In addit...
Source: Artificial Cells, Nanomedicine and Biotechnology - Category: Biotechnology Tags: Artif Cells Nanomed Biotechnol Source Type: research
Authors: Elshaarawy O, Alkhatib A, Elhelbawy M, Gomaa A, Allam N, Alsebaey A, Rewisha E, Waked I Abstract BACKGROUND: An ideal staging system for hepatocellular carcinoma (HCC) should rely on the hepatic reserve function and tumor burden. With the improvement in diagnostic and treatment strategies for HCC, in addition to recent treatment of viral hepatitis, finding a suitable assessment tool for hepatic reserve has become mandatory. AIM: To validate a recently proposed modified albumin-bilirubin-TNM (mALBI-T) grade as a prognostic model for patients with HCC in Egypt. METHODS: For patients diagnosed with HC...
Source: World Journal of Hepatology - Category: Gastroenterology Tags: World J Hepatol Source Type: research
Contributor : Shimin ShuaiSeries Type : Expression profiling by high throughput sequencingOrganism : Homo sapiensDespite an intensive search for non-coding cancer drivers, only a few have been discovered to date and none have been found among the RNAs contributing to the spliceosome. Here we report a highly recurrent A>C somatic mutation at the third base of U1 spliceosomal RNA in several tumour types. This mutation changes the preferential A-U base-pairing between U1 and 5 ′ splice site to C-G base-pairing, thereby creating novel splice junctions and altering the splice pattern of multiple genes, including those ...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
Abstract Alternative splicing events (ASEs) play a role in cancer development and progression. We investigated whether ASEs are prognostic for overall survival (OS) in hepatocellular carcinoma (HCC). RNA sequencing data was obtained for 343 patients included in The Cancer Genome Atlas. Matched splicing event data for these patients was then obtained from the TCGASpliceSeq database, which includes data for seven types of ASEs. Univariate and multivariate Cox regression analysis demonstrated that 3,814 OS-associated splicing events (OS-SEs) were correlated with OS. Prognostic indices were developed based on the most...
Source: Aging - Category: Biomedical Science Authors: Tags: Aging (Albany NY) Source Type: research
Conclusions: Majority of hepatocellular carcinomas show high levels of PSMA expression on tumor vessels and on canalicular membrane of the tumor cells. Putative diagnostic, prognostic and therapeutic value of PSMA in HCC warrants further clinically oriented investigations. PMID: 31289613 [PubMed]
Source: Oncotarget - Category: Cancer & Oncology Tags: Oncotarget Source Type: research
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