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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CONCLUSIONS In this study, a novel approach was proposed for evaluating HCC prognosis, which may be useful in evaluatingthe intensity of the immune response in the HCC microenvironment. PMID: 32945289 [PubMed - in process]
Source: Medical Science Monitor - Category: Research Tags: Med Sci Monit Source Type: research
Source: Cancer Management and Research - Category: Cancer & Oncology Tags: Cancer Management and Research Source Type: research
Authors: Wu CH, Yeh CT, Lin KH Abstract Thyroid hormones (TH) are multifunctional mediators that fine‑tune several physiological processes, including metabolic rate, digestive function and tissue development via interactions with type II nuclear thyroid hormone receptors (TR). Upon binding of TH, TRs interact specifically with thyroid hormone response elements of target gene promoter regions to regulate their transcription. Earlier studies suggested a correlation between aberrant TR regulation and hepatocellular carcinoma (HCC). THs are involved in a crosstalk between hepatoma and stromal cells, and disruption of...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
ASTN1 is associated with immune infiltrates in hepatocellular carcinoma, and inhibits the migratory and invasive capacity of liver cancer via the Wnt/β‑catenin signaling pathway. Oncol Rep. 2020 Jul 24;: Authors: Chen QF, Shi F, Huang T, Huang C, Shen L, Wu P, Li W Abstract Astrotactin 1 (ASTN1) is known to serve a physiological role in neuronal migration; however its role in liver cancer remains to be determined. In the present study, ASTN1 levels were lower in liver cancer tissues compared with those in matching normal tissue. ASTN1 levels were negatively associated with microscopic vascular i...
Source: Oncology Reports - Category: Cancer & Oncology Tags: Oncol Rep Source Type: research
Source: Cancer Management and Research - Category: Cancer & Oncology Tags: Cancer Management and Research Source Type: research
Authors: Chen C, Gu C, Ren Q, Ding F, Pan Q, Niu Y, Ma D, Wu L Abstract Long non‑coding RNA high expression in hepatocellular carcinoma (lncRNA HEIH) acts as an oncogene in multiple tumors, including hepatocellular carcinoma, colorectal cancer, melanoma and non‑small cell lung cancer. However, the role of HEIH in breast cancer remains unknown. The present study focused on the clinical significance and biological function of HEIH in breast cancer. Specifically, the expression levels of HEIH in breast cancer tissues and breast cancer cell lines were investigated. The results indicated high expression levels of HE...
Source: Molecular Medicine Reports - Category: Molecular Biology Tags: Mol Med Rep Source Type: research
ConclusionIn the real-life clinical setting, TARE is largely considered to be a part of a palliative treatment strategy across indications and provides an excellent safety profile.Level of evidenceLevel 3.Trial registrationClinicalTrials.gov NCT02305459.
Source: CardioVascular and Interventional Radiology - Category: Radiology Source Type: research
Taesung Park Aberrations of the human microbiome are associated with diverse liver diseases, including hepatocellular carcinoma (HCC). Even if we can associate specific microbes with particular diseases, it is difficult to know mechanistically how the microbe contributes to the pathophysiology. Here, we sought to reveal the functional potential of the HCC-associated microbiome with the human metabolome which is known to play a role in connecting host phenotype to microbiome function. To utilize both microbiome and metabolomic data sets, we propose an innovative, pathway-based analysis, Hierarchical structural Componen...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Authors: Liu X, Zhang T, Li Y, Zhang Y, Zhang H, Wang X, Li L Abstract Hypermethylation can downregulate many tumor suppressor gene expressions. Aplasia Ras homologue member I (ARHI, DIRAS3) is one of the maternally imprinted tumor suppressors in the RAS superfamily. This chapter overviewed the importance of ARHI methylation and expression phenomes in various types of cancers, although the exact mechanisms remain unclear. As an imprinted gene, aberrant DNA methylation of the paternal allele of ARHI was identified as a primary inhibitor of ARHI expression. The role of methylation in the CpG islands of the ARHI promo...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
To evaluate the predictive value of preoperative biochemical marker [platelet-to-lymphocyte ratio (PLR)] in patients with advanced hepatocellular cancer receiving transarterial chemoembolization (TACE) plus targeted molecular therapy (apatinib) treatment. Clinical records of 134 patients receiving the treatment of TACE + apatinib (TACE-A) and the treatment of TACE alone were compared in a single-center study. Time to progression (TTP) and overall survival (OS) were compared between TACE-A and TACE alone groups in patients with PLR > 150 and PLR ≤ 150, respectively. The area under the recei...
Source: Anti-Cancer Drugs - Category: Cancer & Oncology Tags: Clinical Reports Source Type: research
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