Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer.
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ABSTRACT:
SUBMITTER: Wei TT
PROVIDER: S-EPMC4494952 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients. Cells from human lung carcinoma cell line H661 with wildtype scrambled controls or Sall4 knockdown were used for RNA extraction and hybridization on Affymetrix microarrays.
2015-05-16 | E-GEOD-68959 | biostudies-arrayexpress
Project description:The overall survival of lung cancer patients remains dismal despite the availability of targeted therapies. Oncofetal protein SALL4 is a novel cancer target. We herein report that SALL4 was aberrantly expressed in a subset of lung cancer patients with poor survival. SALL4 silencing by RNA interference or SALL4 peptide inhibitor treatment led to impaired lung cancer cell growth. Expression profiling on SALL4-knockdown cells demonstrated that both the EGFR and IGF1R signaling pathways were affected. Further studies revealed that SALL4 suppresses these pathways indirectly by repressing CBL-B. Connectivity Map analysis revealed HDAC inhibitor MS-275 as a potential drug in treating SALL4-expressing cancers and this was confirmed using 17 lung cancer cell lines. In summary, we report for the first time that MS-275 can target the novel SALL4/CBL-B pathway in lung cancer. This lays the foundation for future clinical studies to evaluate the therapeutic efficacy of MS-275 in SALL4-positive lung cancer patients.
2015-05-16 | GSE68959 | GEO
Project description:Histone modification plays a pivotal role on gene regulation, as regarded as global epigenetic markers, especially in tumor related genes. Hence, chemical approaches targeting histone-modifying enzymes have emerged onto the main stage of anticancer drug discovery. Here, we investigated the therapeutic potentials and mechanistic roles of the recently developed histone deacetylase inhibitor, CG200745, in non-small cell lung cancer cells. Treatment with CG200745 increased the global level of histone acetylation, resulting in the inhibition of cell proliferation. ChIP-on-chip analysis with an H4K16ac antibody showed altered H4K16 acetylation on genes critical for cell growth inhibition, although decreased at the transcription start site of a subset of genes. Altered H4K16ac was associated with changes in mRNA expression of the corresponding genes, which were further validated in quantitative RT-PCR and western blotting assays. Our results demonstrated that CG200745 causes NSCLC cell growth inhibition through epigenetic modification of critical genes in cancer cell survival, providing pivotal clues as a promising chemotherapeutics against lung cancer.
| S-EPMC4363698 | biostudies-literature
Project description:AimSulfotransferase-catalyzed sulfation is the most important pathway for inactivating estrogens. Thus, activation of estrogen sulfotransferase (EST) may be an alternative approach for the treatment of estrogen-dependent breast cancer. In this study we investigated the involvement of EST in anti-breast cancer effects of the dithiocarbamate derivative TM208 in vitro and in vivo.MethodsThe viability of human breast cancer MCF-7 cells was determined using a SBB assay. Nude mice bearing MCF-7 cells were orally administered TM208 (50 and 150 mg·kg(-1)·d(-1)) for 18 days. The xenograft tumors and uteri were collected. The mRNA expression of EST was examined with real-time PCR. EST protein was detected with Western blot, ELISA or immunohistochemical staining assays. A radioactive assay was used to measure the EST activity. Uterotropic bioassay was used to examine the uterine estrogen responses.ResultsTreatment with TM208 (10, 15 and 20 μmol/L) concentration-dependently increased EST expression in MCF-7 cells in vitro. Co-treatment with triclosan, an inhibitor of sulfonation, abolished TM208-induced cytotoxicity in MCF-7 cells. TM208 exhibited an apparent anti-estrogenic property: it exerted more potent cytotoxicity in E2-treated MCF-7 cells. In the nude mice bearing MCF-7 cells, TM208 administration time-dependently increased the expression and activity of EST, and blocked the gradual increase of E2 concentration in the xenograft tumors. Furthermore, TM208 administration blocked the estrogens-stimulated uterine enlargement. Tamoxifen, a positive control drug, produced similar effects on the expression and activity of EST in vitro and in vivo.ConclusionThe induction of EST and reduction of estrogen concentration contribute to the anti-breast cancer action of TM208 and tamoxifen. TM208 may be developed as anticancer drug for the treatment of estrogen receptor-positive breast cancer.
| S-EPMC4814201 | biostudies-literature
Project description:Histone deacetylase inhibitors (HDACis) - based therapeutic drug tolerance is one of the principal factors of poor prognosis of patients with nasopharyngeal cancer (NPC). Mechanisms of tolerance to HDACis are not well understood. Nowadays, dysregulation of long non-coding RNAs (LncRNAs) and microRNAs (miRNAs) has been reported to provide beneficial or inhibitory effects in drug-tolerance in various cancers. Herein, we established the HDAC inhibitor (SAHA)-tolerant NPC cell sublines, which had decreased apoptosis in response to SAHA treatment. We observed that the expression of miR-129 was significantly reduced in SAHA-tolerant NPC cells. Manipulating the expression of miR-129 overcame SAHA tolerance, and enhanced the SAHA-induced apoptosis. In terms of miR-129 downregulation, we identified that NEAT1 suppresses miR-129 expression. NEAT1 was found to be upregulated in SAHA tolerance cells. The depletion of NEAT1 phenocopied the effect of miR-129 overexpression, which also enhanced SAHA-induced apoptosis. Bcl-2 was the downstream target of miR-129 and contributed to SAHA tolerance in NPC. Our in vivo xenograft experiment confirmed that the administration of miR-129 or inhibition of Bcl-2 overcame the SAHA tolerance in NPC. In conclusion, NEAT1 increases in NPC tissues and manages to facilitate SAHA tolerance by modulating the miR-129/Bcl-2 axis, providing novel therapeutic targets for NPC treatment.
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Project description:BackgroundPI3K-Akt pathway activation and the expression of histone deacetylases (HDACs) are highly increased in esophageal cancer, suggesting that inhibition of such targets may be a viable therapeutic strategy. Herein, we aimed to evaluate the anti-tumor effect of CUDC-907, a dual PI3K-HDAC inhibitor, in esophageal squamous cell carcinoma (ESCC).MethodsThe anti-tumor effects of CUDC-907 in ESCC were evaluated using cell counting kit-8, flow cytometry, and western blot. mRNA-sequencing was used to explore the mechanism underlying CUDC-907 anti-tumor effects. The relations of reactive oxygen species (ROS), lipocalin 2 (LCN2), and CUDC-907 were determined by flow cytometry, rescue experiments, and western blot. The activation of the IRE1α-JNK-CHOP signal cascade was confirmed by western blot. The in vivo inhibitory effects of CUDC-907 were examined by a subcutaneous xenograft model in nude mice.ResultsCUDC-907 displayed effective inhibition in the proliferation, migration, and invasion of ESCC cells. Through an mRNA-sequencing and functional enrichment analysis, autophagy was found to be associated with cancer cells death. CUDC-907 not only inhibited the PI3K-Akt-mTOR pathways to result in autophagy, but also induced ROS accumulation to activate IRE1α-JNK-CHOP-mediated cytotoxic autophagy by downregulating LCN2 expression. Consistently, the in vivo anti-tumor effects of CUDC-907 accompanied by the downregulated expression of p-mTOR and LCN2 and upregulated expression of p-IRE1α and LC3B-II were evaluated in a xenograft mouse model.ConclusionOur findings suggested the clinical development and administration of CUDC-907 might act as a novel treatment strategy for ESCC. A more in-depth understanding of the anti-tumor effect of CUDC-907 in ESCC will benefit the clinically targeted treatment of ESCC.
| S-EPMC9394063 | biostudies-literature
Project description:Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with poor prognosis and progression to lung fibrosis related to genetic factors as well as environmental factors. In fact, it was discovered that in South Korea many people who used humidifier disinfectants containing polyhexamethylene guanidine (PHMG), died of lung fibrosis. Currently two anti-fibrotic drugs, pirfenidone and nintedanib, have been approved by the FDA, but unfortunately, do not cure the disease. Since the histone deacetylase (HDAC) activity is associated with progression to chronic diseases and with fibrotic phenomena in the kidney, heart and lung tissues, we investigated the anti-fibrotic effects of CG-745, an HDAC inhibitor. After lung fibrosis was induced in two animal models by bleomycin and PHMG instillation, the regulation of fibrosis and epithelial mesenchymal transition (EMT)-related markers was assessed. CG-745 exhibited potent prevention of collagen production, inflammatory cell accumulation, and cytokines release in both models. Additionally, N-cadherin and vimentin expression were lowered significantly by the treatment of CG-745. The anti-fibrotic effects of CG-745 proven by the EMT regulation may suggest a potential therapeutic effect of CG-745 on lung fibrosis.
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Project description: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.
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Project description:Intrahepatic cholangiocarcinoma (iCCA), the second most common primary liver cancer, has high mortality rates because of its limited treatment options and acquired resistance to chemotherapy. Sulforaphane (SFN), a naturally occurring organosulfur compound found in cruciferous vegetables, exhibits multiple therapeutic properties, such as histone deacetylase (HDAC) inhibition and anti-cancer effects. This study assessed the effects of the combination of SFN and gemcitabine (GEM) on human iCCA cell growth. HuCCT-1 and HuH28 cells, representing moderately differentiated and undifferentiated iCCA, respectively, were treated with SFN and/or GEM. SFN concentration dependently reduced total HDAC activity and promoted total histone H3 acetylation in both iCCA cell lines. SFN synergistically augmented the GEM-mediated attenuation of cell viability and proliferation by inducing G2/M cell cycle arrest and apoptosis in both cell lines, as indicated by the cleavage of caspase-3. SFN also inhibited cancer cell invasion and decreased the expression of pro-angiogenic markers (VEGFA, VEGFR2, HIF-1α, and eNOS) in both iCCA cell lines. Notably, SFN effectively inhibited the GEM-mediated induction of epithelial-mesenchymal transition (EMT). A xenograft assay demonstrated that SFN and GEM substantially attenuated human iCCA cell-derived tumor growth with decreased Ki67+ proliferative cells and increased TUNEL+ apoptotic cells. The anti-cancer effects of every single agent were markedly augmented by concomitant use. Consistent with the results of in vitro cell cycle analysis, G2/M arrest was indicated by increased p21 and p-Chk2 expression and decreased p-Cdc25C expression in the tumors of SFN- and GEM-treated mice. Moreover, treatment with SFN inhibited CD34-positive neovascularization with decreased VEGF expression and GEM-induced EMT in iCCA-derived xenografted tumors. In conclusion, these results suggest that combination therapy with SFN with GEM is a potential novel option for iCCA treatment.
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Project description:Previous research reported that the curcumin derivative (CU17) inhibited several cancer cell growths in vitro. However, its anticancer potential against human lung cancer cells (A549 cell lines) has not yet been evaluated. The purpose of this research was to examine the HDAC inhibitory and anti-cancer activities of CU17 compared to curcumin (CU) in A549 cells. An in vitro study showed that CU17 had greater HDAC inhibitory activity than CU. CU17 inhibited HDAC activity in a dose dependent manner with the half-maximal inhibitory concentration (IC50) value of 0.30 ± 0.086 µg/mL against HDAC enzymes from HeLa nuclear extract. In addition, CU17 could bind at the active pockets of both human class I HDACs (HDAC1, 2, 3, and 8) and class II HDACs (HDAC4, 6, and 7) demonstrated by molecular docking studies, and caused hyperacetylation of histone H3 (Ac-H3) in A549 cells shown by Western blot analysis. MTT assay indicated that both CU and CU17 suppressed A549 cell growth in a dose- and time-dependent manner. Besides, CU and CU17 induced G2/M phase cell cycle arrest and p53-independent apoptosis in A549 cells. Both CU and CU17 down-regulated the expression of p53, p21, Bcl-2, and pERK1/2, but up-regulated Bax expression in this cell line. Although CU17 inhibited the growth of lung cancer cells less effectively than CU, it showed less toxicity than CU for non-cancer cells. Accordingly, CU17 is a promising agent for lung cancer treatment. Additionally, CU17 synergized the antiproliferative activity of Gem in A549 cells, indicating the possibility of employing CU17 as an adjuvant treatment to enhance the chemotherapeutic effect of Gem in lung cancer.
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