A Novel Isaindigotone Derivative Displays Better Anti-Proliferation Activities and Induces Apoptosis in Gastric Cancer Cells
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ABSTRACT:
SUBMITTER: Du K
PROVIDER: S-EPMC9324172 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Aberrant activation of Wnt/?-catenin signaling pathways is closely involved in the occurrence and progression of several types of human malignancies. However, as a fundamental component in this cascade, Wnt3 has not been well understood for the expression level and pathogenic mechanism in gastric carcinogenesis. Here, this research was undertaken to elucidate the important role of Wnt3 in gastric cancer. Wnt3 expression in gastric carcinomas and their respective normal tissues was examined by immunoblotting and immunohistochemistry. In all cases, Wnt3 expression was significantly elevated in gastric carcinomas compared with normal tissues. Knocking down Wnt3 in MGC-803 gastric cancer cells by small interfering RNAs transfection led to an obvious decrease in both transcript and protein levels. Silence of Wnt3 expression in gastric cancer cells inhibited the expression of ?-catenin and cyclin D1 genes in Wnt/?-catenin pathway, significantly blocked cellular proliferation, delayed cell cycle, suppressed cell invasion and metastasis, accompanied by a higher apoptosis rate. Together, we conclude that upregulation of Wnt3 plays a crucial role in gastric tumorigenesis by inducing proliferation, migration, and invasion and inhibiting apoptosis of cancer cells, and Wnt3 might be a potential target for the treatment of gastric cancer.
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Project description:Homeobox A10 (HOXA10) has been implicated critical for the promotion of carcinogenesis, but the underlying mechanism between HOXA10 and malignant gastric cancer (GC) phenotype remains elusive. In the present study, we analyzed and validated that HOXA10 and BCL2 expressions were elevated both at the mRNA and protein levels in GC tissues. Upregulated HOXA10 promoted GC cell proliferation with reduced apoptosis in vitro and accelerated GC tumor growth in vivo. Bioinformatics analysis and quantitative real-time polymerase chain reaction (qRT-PCR) experiment inferred that HOXA10 might upregulate the expression of BCL2. By performing western blot, chromatin immunoprecipitation and quantitative PCR (ChIP-qPCR), and rescue experiment, we found that HOXA10 might bind to BCL2 promoter region, induce its expression, and thus inhibit intrinsic apoptosis pathway. Moreover, higher expression of HOXA10 and BCL2 predicted poor overall survival (OS) in GC patients. In summary, our study indicated that HOXA10 was upregulated in GC, and that HOXA10 might promote cell proliferation by elevating BCL2 expression and inhibiting apoptosis.
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Project description:Chronic myeloid leukemia (CML) is a malignant blood disease with a particular chromosomal aberration that is known as a common form of leukemia. The chromene family exhibits strong anti-cancer effects. Therefore, the effects of six members of the dihydropyrano [2,3-g] chromene family on cell toxicity and apoptosis induction in K562 cancer cells were investigated and compared with those of normal peripheral blood mononuclear cells (PBMCs). The K562 cells were cultured in the presence of the aforementioned chromene derivatives at concentrations of 40 to 200 ?M for 24 to 72 h. The effects of these compounds on the growth and viability of the K562 cell line and PBMCs were studied through MTT assay. Furthermore, apoptosis induction was investigated using flow cytometry. Real-time PCR was used for relative quantification of BCL2, Bax, TP53 and BCR- ABL genes after 48 h of exposing K562 cells and PBMCs to 4-Clpgc. Based on the results, these chromene derivatives inhibited the growth of K562 cells. According to the obtained data, 4-Clpgc was the strongest compound with IC50 values of 102?±?1.6 ?M and 143?±?9.41 ?M in K562 cells and PBMCs, while pgc was the weakest one with IC50 levels of 278?±?2.7 ?M and 366?±?47 ?M in K562 cells and PBMCs (after 72 h), respectively. The results demonstrated that the apoptotic cell percentage in the control group increased from 6.09% to 84.10% and 17.2% to 20.06% in K562 cells and PBMCs after 48 h of treatment, respectively. Moreover, 4-Clpgc treatment increased the expression of Bax and TP53 genes by 42.74 and 35.88 folds in K562 cells and 9.60 and 7.75 folds in PBMCs, respectively. On the other hand, the expression of BCL2 was reduced by 1.47 and 1.38 folds in K562 cells and PBMCs, respectively. These compounds were associated with less toxic effects on normal cells, compared to the cancer cells. In conclusion, these derivatives can be considered as appropriate candidates for leukemia treatment.
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Project description:Indolizine derivatives are a class of compounds with excellent biological activity. In this study, a series of indolizine derivatives, compound 1 (C1), compound 2 (C2), compound 3 (C3), and compound 4 (C4), were synthesized. 3-(4,5-dimethylthiazole)-2,5-diphenyltetraazolium bromide (MTT) assay was used to evaluate their cytotoxicity against HepG2 (p53-wild), A549, and HeLa cell lines. HepG2 cells apoptosis induced by C3 was determined using Hoechst staining and acridine orange/ethidium bromide staining. Cells' apoptotic ratio was measured by Annexin V-FITC/PI double staining. Changes in mitochondrial membrane potential and intracellular reactive oxygen species (ROS) in HepG2 cells after C3 treatment were determined. Immunofluorescence staining and Western blot analysis were carried out to detect p53 levels and analyze the apoptosis-associated proteins, respectively. Moreover, the cytotoxic activity of C3 was examined in two other hepatocellular carcinoma (HCC) cell lines with different p53 status including Huh-7 cells (p53-mutant) and Hep3B cells (p53-null). The results indicated that C3 showed stronger inhibition towards HepG2 cells than other cell lines. Fluorescent staining and flow cytometry analysis confirmed that C3 induced apoptosis of HepG2 cells. C3 could also increase intracellular ROS and cause a decrease in the mitochondrial membrane potential. C3 promoted p53 activation and increased p53 accumulation in nuclei. The expression of p53 and Bax was increased with the down-regulation of Bcl-2, which promoted the release of cytochrome c and caspase-3 activation. Collectively, the study demonstrated that C3 caused HepG2 cell apoptosis via the mitochondria p53 pathway. These results inspired us to further develop indolizine derivatives as potential potent inhibitors against liver cancer.
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Project description:BackgroundGamma glutamylcyclotransferase (GGCT) has been proved to be involved in various cancers, but the biological function of GGCT in gastric cancer is still largely unknown.MethodsThe expression level of GGCT was evaluated by informatics analyses based on the Oncomine database. GGCT gene was then effectively knocked down via lentivirus mediated short hairpin RNA (shRNA) system. Then a series of functional assays, including MTT, colony formation and flow cytometry analysis were conducted on gastric cancer cells following GGCT knockdown.ResultsWe found GGCT is commonly up-regulated in gastric cancer tissues. Furthermore, MTT analysis showed that GGCT depletion significantly inhibited cell proliferation in MGC80-3 and AGS cells. Colony formation assay revealed that depletion of GGCT reduced the colony formation ability in gastric cancer cells. What's more, cell cycle analysis showed that depletion of GGCT induced gastric cancer cell cycle arrested G2/M phase. More importantly, cell apoptosis analysis further revealed that GGCT inhibition induced early and late cell apoptosis in gastric cancer.ConclusionThis study suggests GGCT is essential for gastric cancer proliferation and its downregulation may provide a potential anticancer therapy for gastric cancer.
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Project description:To investigate the effects of S-allylcysteine (SAC), a water-soluble garlic derivative, on human ovarian cancer cells in vitro.Human epithelial ovarian cancer cell line A2780 was tested. Cell proliferation was examined with CCK-8 and colony formation assays. Cell cycle was analyzed with flow cytometry. Cell apoptosis was studied using Hoechst 33258 staining and Annexin V/PI staining with flow cytometry. The migration and invasion of A2780 cells were examined with transwell and wound healing assays. The expression of relevant proteins was detected with Western blot assays.SAC (1-100 mmol/L) inhibited the proliferation of A2780 cells in dose- and time-dependent manners (the IC50 value was approximately 25 mmol/L at 48 h, and less than 6.25 mmol/L at 96 h). Furthermore, SAC dose-dependently inhibited the colony formation of A2780 cells. Treatment of A2780 cells with SAC resulted in G1/S phase arrest and induced apoptosis, accompanied by decreased expression of pro-caspase-3, Parp-1 and Bcl-2, and increased expression of active caspase-3 and Bax. SAC treatment significantly reduced the migration of A2780 cells, and markedly decreased the protein expression of Wnt5a, p-AKT and c-Jun, which were the key proteins involved in proliferation and metastasis.SAC suppresses proliferation and induces apoptosis in A2780 ovarian cancer cells in vitro.
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Project description:Aberration of PI3K signaling pathway has been confirmed to be associated with several hematological malignancies including acute myeloid leukemia (AML). FD268, a pyridinesulfonamide derivative characterized by the conjugation of 7-azaindole group, is a newly identified PI3K inhibitor showing high potent enzyme activity at nanomole concentration. In this study, we demonstrated that FD268 dose-dependently inhibits survival of AML cells with the efficacy superior to that of PI-103 (pan-PI3K inhibitor) and CAL-101 (selective PI3Kδ inhibitor) in the tested HL-60, MOLM-16, Mv-4-11, EOL-1 and KG-1 cell lines. Further mechanistic studies focused on HL-60 revealed that FD268 significantly inhibits the PI3K/Akt/mTOR signaling pathway, promotes the activation of pro-apoptotic protein Bad and downregulates the expression of anti-apoptotic protein Mcl-1, thus suppressing the cell proliferation and inducing caspase-3-dependent apoptosis. The bioinformatics analysis of the transcriptome sequencing data also indicated a potential involvement of the PI3K/Akt/mTOR pathway. These studies indicated that FD268 possesses high potent activity toward AML cells via inhibition of PI3K/Akt/mTOR signaling pathway, which sheds some light on the pyridinesulfonamide scaffold for further optimization and investigation.
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Project description:Splicing dysregulation, which leads to apoptosis resistance, has been recognized as a major hallmark for tumorigenesis and cancer progression. Targeting alternative splicing by either increasing pro-apoptotic proteins or inhibiting anti-apoptotic proteins in tumor cells may be an effective approach for gastric cancer (GC) therapy. However, the role of modulation of alternative splicing in GC remains poorly understood. In this study, to the best of our knowledge, the unbalanced expression of the myeloid cell leukemia-1 (Mcl-1) splicing variants, Mcl-1L and Mcl-1S, was identified in GC patients for the first time. Increasing anti-apoptotic Mcl-1L and decreasing pro-apoptotic Mcl-1S expression levels were correlated with tumor proliferation and poor survival. In vitro data showed that a shift in splicing from Mcl-1L to Mcl-1S induced by treatment with Mcl-1-specific steric-blocking oligonucleotides (SBOs) efficiently decreased Mcl-1L expression, increased Mcl-1S expression, and accelerated tumor cell apoptosis in a dose-dependent manner. Additionally, mouse xenotransplant models confirmed that modification of Mcl-1 alternative splicing increased tumor cell death and suppressed tumor proliferation. This study demonstrated that the modification of Mcl-1 splicing might stimulate the pro-apoptotic factor and inhibit the anti-apoptotic protein to induce significant apoptosis. Thus, this finding provided a strategy for cancer therapy, according to which SBOs could be used to change the Mcl-1 splicing pattern, thereby inducing apoptosis.
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Project description:There is no clinically available biomarker for efficiently indicating the overall survival or therapy response of gastric cancer (GC). The autoantibodies (Abs) in the sera of anti-far-upstream element-binding protein-interacting repressor-lacking exon2 (FIRΔexon2), anti-sorting nexin 15, and anti-spermatogenesis and oogenesis-specific basic helix-loop-helix 1 were markedly higher in GC patients than in healthy donors (HDs). These Abs were identified by large-scale serological identification of antigens by recombinant cDNA expression cloning screenings and their expression levels were evaluated by amplified luminescence proximity homogeneous assay. In particular, compared with age-matched HDs, the level of anti-FIRΔexon2 Abs in GC patients was significantly higher (P < .001). The Spearman's rank correlation analysis between anti-FIRΔexon2 Abs and clinically available tumor markers such as carcinoembryonic antigen (CEA) was statistically insignificant, indicating that FIRΔexon2 Abs is an independent biomarker. We performed receiver-operating curve analysis to evaluate the anti-FIRΔexon2 Ab as a candidate biomarker with CEA and carbohydrate antigen 19-9 (CA19-9). The overall survival of GC patients with high anti-FIRΔexon2 Abs titer was significantly favorable (P = .04) than that of GC patients who were below detection level of anti-FIRΔexon2 Abs. However, clinical stages were not apparently correlated with the levels of anti-FIRΔexon2 Ab, CEA, and CA19-9. In conclusion, anti-FIRΔexon2 Abs detected in GC patients is a potential biomarker for monitoring a better prognosis. Hence, anti-FIRΔexon2 Abs is a promising biomarker for indicating better overall survival of gastric cancer patients.
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