Dataset Information

The in vitro and vivo anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) and MG132 on the aggressive phenotypes of gastric cancer cells.

ABSTRACT: Here, we found that both SAHA and MG132 synergistically inhibited proliferation, glycolysis and mitochondrial oxidization, induced cell cycle arrest and apoptosis in MGC-803 and MKN28 cells. SAHA increased cell migration and invasionat a low concentration. SAHA induced the overexpression of acetyl histone 3 and 4, which were recruited to p21, p27, Cyclin D1, c-myc and nanog promoters to transcriptionally up-regulate the former two and down-regulate the latter three. The expression of acetyl-histone 3 and 4 was increased during gastric carcinogenesis and positively correlated with cancer differentiation. SAHA and MG132 exposure suppressed tumor growth by inhibiting proliferation and inducing apoptosis in nude mice, increased serum ALT and AST levels and decreased hemaglobin level, white blood cell and neutrophil numbers. These data indicated that SAHA and MG132 in vivo and vitro synergistically induced cytotoxicity and apoptosis, suppressed proliferation, growth, migration and invasion of gastric cancer cells. Therefore, they might potentially be employed as chemotherapeutic agents if the hepatic injury and the killing effects of peripheral blood cells are avoided or ameliorated.

SUBMITTER: Lu H

PROVIDER: S-EPMC5302865 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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The in vitro and vivo anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) and MG132 on the aggressive phenotypes of gastric cancer cells.

Lu Hang H Yang Xue-Feng XF Tian Xiao-Qing XQ Tang Shou-Long SL Li Lian-Qian LQ Zhao Shuang S Zheng Hua-Chuan HC

Oncotarget 20160801 35

Here, we found that both SAHA and MG132 synergistically inhibited proliferation, glycolysis and mitochondrial oxidization, induced cell cycle arrest and apoptosis in MGC-803 and MKN28 cells. SAHA increased cell migration and invasionat a low concentration. SAHA induced the overexpression of acetyl histone 3 and 4, which were recruited to p21, p27, Cyclin D1, c-myc and nanog promoters to transcriptionally up-regulate the former two and down-regulate the latter three. The expression of acetyl-hist ...[more]

PMID: 27447743

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Project description:Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or Zolinza(TM)) affects bone mass and remodeling in vivo. Male C57BL/6J mice received daily SAHA (100mg/kg) or vehicle injections for 3 to 4weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for 4weeks after 4weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that clinical use of SAHA and other Hdac inhibitors to treat cancer, epilepsy or other conditions may potentially compromise skeletal structure and function.

Dataset Information

The in vitro and vivo anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) and MG132 on the aggressive phenotypes of gastric cancer cells.

Publications

The in vitro and vivo anti-tumor effects and molecular mechanisms of suberoylanilide hydroxamic acid (SAHA) and MG132 on the aggressive phenotypes of gastric cancer cells.

Similar Datasets

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