Inhibitory Effect of Histone Deacetylase Inhibitor on the Proliferation of Leukemia Cells and Its Anti-Tumor Pharmacology

The aim of this study was to explore the inhibitory effect of histone deacetylase inhibitor (HDACI) on the proliferation of leukemia cells. The two kinds of leukemia cells (human promyelocytic leukemia cell (HL-60) and human acute myelogenous leukemia cell (KG-1)) were selected for in vitro research. Besides, Chidamide, a kind of benzamide HDACI, was applied to induce and culture the HL-60 and KG-1 cells, and the anti-tumor cell proliferation activity of Chidamide on HL-60 and KG-1 was detected by the methyl thiazolyl tetrazolium (MTT) assay, which was 5.6 and 6.1 in turn. The cell scratch experiment verified that Chidamide had the metastasis inhibitory effect on HL-60 and KG-1 cells. Flow cytometry was employed to measure the percentage of apoptotic cells, and it was found that the percentage of apoptotic cells was 55.6% ± 1% and 48.6% ± 1% in sequence after HL-60 and KG-1 cells were treated with Chidamide for 36 hours. The number of auto-phagosomes was determined by transmission electron microscopy showing that the number of auto-phagosomes in HL-60 and KG-1 cells was 12 ± 1 and 10 ± 1, respectively after the induction process of Chidamide. The phosphorylated histone H2AX protein (γ-H2AX) recognition antibody immunofluorescence method was adopted to determine the deoxyribonucleic acid (DNA) damage, and the positive rates of HL-60 and KG-1 cells reached 28.41% and 26.35%, respectively after Chidamide treatment. Therefore, Chidamide, as a kind of HDACI, could effectively inhibit the proliferation of leukemia cells, so that the results of this experiment had a good guiding meaning for the clinical diagnosis and treatment of leukemia.

Antitumor activity of miR-188-3p in gastric cancer is achieved by targeting CBL expression and inactivating the AKT/mTOR signaling

BACKGROUND Altered miR-188-3p expression has been observed in various human cancers.AIM To investigate the miR-188-3p expression,its roles,and underlying molecular events in gastric cancer.METHODS Fifty gastric cancer and paired normal tissues were collected to analyze miR-188-3p and CBL expression.Normal and gastric cancer cells were used to manipulate miR-188-3p and CBL expression through different assays.The relationship between miR-188-3p and CBL was predicted bioinformatically and confirmed using a luciferase gene reporter assay.A Kaplan-Meier analysis was used to associate miR-188-3p or CBL expression with patient survival.A nude mouse tumor cell xenograft assay was used to confirm the in vitro data.RESULTS MiR-188-3p was found to be lower in the plasma of gastric cancer patients,tissues,and cell lines compared to their healthy counterparts.It was associated with overall survival of gastric cancer patients(P<0.001),tumor differentiation(P<0.001),lymph node metastasis(P=0.033),tumor node metastasis stage(I/II vs III/IV,P=0.024),and American Joint Committee on Cancer stage(I/II vs III/IV,P=0.03).Transfection with miR-188-3p mimics reduced tumor cell growth and invasion while inducing apoptosis and autophagy.CBL was identified as a direct target of miR-188-3p,with its expression antagonizing the effects of miR-188-3p on gastric cancer(GC)cell proliferation by inducing tumor cell apoptosis and autophagy through the inactivation of the Akt/mTOR signaling pathway.The in vivo data confirmed antitumor activity via CBL downregulation in gastric cancer.CONCLUSION The current data provides ex vivo,in vitro,and in vivo evidence that miR-188-3p acts as a tumor suppressor gene or possesses antitumor activity in GC.

Characterizing gastrointestinal stromal tumors and evaluating neoadjuvant imatinib by sequencing of endoscopic ultrasound-biopsies

AIM To evaluate endoscopic ultrasound(EUS)-guided biopsies for the pretreatment characterization of gastrointestinal stromal tumors(GIST) to personalize the management of patients.METHODS All patients with lesions suspected to be GIST who were referred for EUS-sampling at a tertiary Swedish center were eligible for inclusion 2006-2015. During the observational study phase(2006-2011), routine fine-needle-aspiration(EUS-FNA) was performed.In 2012-2015, we converted to an interventional, randomized protocol with dual sampling EUS-FNA and fine-needle-biopsy-sampling(EUS-FNB) for all lesions. c-KIT-and DOG-1-immunostaining was attempted in all samples and a manual count of the Ki-67-index was performed. FNB-sampled tissue and the resected specimens were subjected to Sanger sequencing of the KIT and platelet-derived growth factor alpha(PDGFRA) genes. RESULTS In all, 64 unique patients with GIST were included, and of these, 38 were subjected to pretreatment dual sampling. EUS-FNB had a higher diagnostic sensitivity when compared head-to-head with EUS-FNA(98% vs 58%, P < 0.001) and was more adequate for Ki-67-indexing(Ki-67EUS)(92% vs 40%, P < 0.001). Sequencing of EUS-biopsies was successful in 43/44(98%) patients, and the mutation profiles(KIT-mutation 73%, PDGFRA-mutation 18%, wild-type 7%) were fully congruent with those detected in the corresponding resected specimens. In imatinib-na?ve patients, the Ki-67_(EUS) was comparable with the Ki-67-index in the corresponding surgical specimens(Ki-67_(SURG))(2.7% vs 2.9%, P = 0.68). In patients treated with neoadjuvant imatinib who also carried mutations indicating sensitivity, the Ki-67 EUS was higher than the Ki-67_(SURG)(2.5% vs 0.2%, P = 0.005), with a significant reduction in the Ki-67-index of-91.5%(95%CI:-82.4 to-96.0, P = 0.005). CONCLUSION EUS-guided biopsy sampling is accurate for the pretreatment diagnosis and characterization of GISTs and allows the prediction and evaluation of tumor response to neoadjuvant imatinib therapy.

Role of Oxidative Stress in Non-genotoxic Carcinogenesis with Special Reference to Liver Tumors Induced by Peroxisome Proliferators

Peroxisome proliferators (POPs), such as hypolipidemic drugs or industrial phthalate ester plasticizers, are widely known as non-genotoxic hepatocarcinogens in rodents. As one of the possible mechanisms of POP-induced carcinogenesis, the 'Oxidative Stress' theory has been postulated. In this review, in order to reconsider the significance of 'Oxidative Stress' to POP-induced carcinogenesis, we focus on in vivo studies examining formation of 8-hydroxydeoxyguanosine (8-OH -dG), a marker of oxidative DNA damage with mutagenic potential, after treatment of rodents with POPs. Some studies clearly demonstrated that 8-OH-dG levels in the liver DNA were increased by POP-treatments. These findings suggest that 'Oxidative Stress' could contribute as one factor to POP-induced carcinogenesis. Furthermore, we refer to other multiple biological changes caused by POP-treatment presumably contributing to the carcinogenic mechanisms, and consider possible roles of 'Oxidative Stress' in the carcinogenesis process

Roles of THEM4 in the Akt pathway:a double-edged sword

The protein kinase B(Akt)pathway can regulate the growth,proliferation,and metabolism of tumor cells and stem cells through the activation of multiple downstream target genes,thus affecting the development and treatment of a range of diseases.thioesterase superfamily member 4(THEM4),a member of the thioesterase superfamily,is one of the Akt kinase-binding proteins.Some studies on the mechanism of cancers and other diseases have shown that THEM4 binds to Akt to regulate its phosphorylation.Initially,THEM4 was considered an endogenous inhibitor of Akt,which can inhibit the phosphorylation of Akt in diseases such as lung cancer,pancreatic cancer,and liver cancer,but subsequently,THEM4 was shown to promote the proliferation of tumor cells by positively regulating Akt activity in breast cancer and nasopharyngeal carcinoma,which contradicts previous findings.Considering these two distinct views,this review summarizes the important roles of THEM4 in the Akt pathway,focusing on THEM4 as an Akt-binding protein and its regulatory relationship with Akt phosphorylation in various diseases,especially cancer.This work provides a better understanding of the roles of THEM4 combined with Akt in the treatment of diseases.