Effect of DNA damage response by quinazolinone analogue HMJ-38 on human umbilical vein endothelial cells

Chiang, Jen‐Huai; Yang, Jai Sing; Lu, Chi‐Cheng; Hour, Mann‐Jen; Liu, K. C.; Lin, Jan‐Yi; Lee, Tsung‐Han; Chung, Jing‐Gung

doi:10.1177/0960327113504791

Cited by 4 publications

(5 citation statements)

References 55 publications

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“…There has been evidence that quinazolinone derivatives have antitumor effects on a variety of cancer cell lines [ 2 , 9 – 11 , 42 – 44 ]. HMJ-38 is a quinazolinone derivative that inhibits the polymerization of tubulin.…”

Section: Discussionmentioning

confidence: 99%

“…Dr. Mann-Jen Hour synthesized a version of HMJ-38 (School of Pharmacy, China Medical University, Taichung, Taiwan) [ 2 , 9 – 11 ]. The following products were obtained from Sigma–Aldrich: acridine orange (AO), chloroquine (CQ), 3-methyladenine (3 MA), monodansylcadaverine (MDC), and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT).…”

Section: Methodsmentioning

confidence: 99%

“…Quinazolinone derivatives possess pharmacological actions including antibacterial activities [ 1 ], anti-angiogenesis activity [ 2 ], anti-microbial and anti-fungal activities [ 3 ], anti-malarial activity [ 4 ], analgesic activity [ 5 ], anti-tubercular activity [ 6 ], anticonvulsant activity [ 7 ], hypoglycemic activity [ 8 ] and anti-cancer activity [ 9 , 10 ]. New quinazolinone derivatives have been developed that have anti-cancer and anti-angiogenesis properties [ 2 , 9 – 11 ]. In vitro and in vivo studies have shown that HMJ-38 (2-(3′-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone) increases CDK1 activity and alters Bcl-2 phosphorylation in CAL 27 oral cancer cells and HL-60 leukemia cells [ 9 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of HMJ-38, a new quinazolinone analogue, against the gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cells

Hour,

Tsai,

Lai

et al. 2023

BioMedicine

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Gemcitabine is frequently utilized to treat pancreatic cancer. The purpose of our study was to create a gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cell line (MIA-GR100) and to evaluate the anti-pancreatic cancer efficacy of HMJ-38, a new quinazolinone analogue. Compared to their parental counterparts, MIA-PaCa-2, established MIA-GR100 cells were less sensitive to gemcitabine. MIA-GR100 cell viability was not affected by 10, 50 and 100 nM gemcitabine concentrations. HMJ-38 reduced MIA-GR100 cell growth and induced autophagy and apoptosis. When stained with monodansylcadaverine (MDC), acridine orange (AO), and terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL), MIA-GR100 cells shrunk, punctured their membranes, and produced autophagy vacuoles and apoptotic bodies. Combining chloroquine (CQ) and 3-methyladenine (3-MA) with HMJ-38 dramatically reduced cell viability, indicating that autophagy function as a cytoprotective mechanism. MIA-GR100 cells treated with both z-VAD-FMK and HMJ-38 were much more viable than those treated with HMJ-38 alone. HMJ-38 promotes apoptosis in MIA-GR100 cells by activating caspases. Epidermal growth factor receptor (EGFR) is one of HMJ-38’s principal targets, as determined via in silico target screening with network prediction. HMJ-38 also inhibited EGFR kinase activity and EGFR-associated signaling in MIA-GR100 cells. HMJ-38 may be an effective chemotherapeutic adjuvant for gemcitabine-resistant pancreatic cancer cells, in which it induces an antitumor response.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Efficacy of HMJ-38, a new quinazolinone analogue, against the gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cells

Hour,

Tsai,

Lai

et al. 2023

BioMedicine

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“…Comet assay and DAPI staining. C6 cells (2x10 5 cells/well) were treated with 0, 50, 100, 150 and 200 µM of GdCl 3 for 24 h. Comet assay was applied according to the vendor's instructions and a previous study (15). Additionally, chromatin undergoes a phase change from loose to condensed during apoptosis.…”

Section: Methodsmentioning

confidence: 99%

Caspase‑dependent apoptotic death by gadolinium chloride (GdCl3) via reactive oxygen species production and MAPK signaling in rat C6 glioma cells

Tsai¹,

Chen

Hsiao³

et al. 2018

Oncol Rep

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Gadolinium (Gd) compounds serve as magnetic resonance imaging contrast agents and exert certain anticancer activities. Yet, the molecular signaling underlying the antitumor effect of Gd chloride (GdCl 3) on glioma remains unclear. In the present study, we aimed to ascertain the apoptotic mechanisms of GdCl 3 on rat glioma C6 cells. Our results demonstrated that GdCl 3 significantly reduced cell viability and shrunk cell morphology of C6 cells in a concentration-dependent manner. GdCl 3 led to apoptotic C6 cell death as detected by TUNEL staining. An increase in cleaved caspase-3, cleaved caspase-8 and cleaved caspase-9 occurred in GdCl 3-treated C6 cells as detected by immunoblotting analysis. The activities of caspase-3, caspase-8 and caspase-9 were increased, and the specific inhibitors of caspase-3/-8/-9 individually reversed cell viability, which caused apoptotic death in C6 cells prior to GdCl 3 exposure. GdCl 3 also caused an elevation in the cytoplasmic Ca 2+ level and reactive oxygen species (ROS) production, as well as the loss of mitochondrial membrane potential (ΔΨm) as shown by flow cytometric analysis in C6 cells. The results from the immunoblotting analysis demonstrated that there were upregulated protein levels of cytochrome c and Bax but a downregulated protein level of Bcl-2 in C6 cells after GdCl 3 treatment. Additionally, GdCl 3 decreased the protein levels of phosphorylated-extracellular signal-regulated kinases, phosphorylated-c-Jun N-terminal kinase and phosphorylated-p38 mitogen-activated protein kinases in C6 cells. In conclusion, ROS production and MAPKs signaling pathways contribute to GdCl 3-induced caspase cascade-mediated apoptosis in C6 cells. Our findings provide a better understanding of the molecular mechanisms underlying the role of GdCl 3 in rat glioma C6 cells.

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“…U-2 OS cells (2x10 5 cells/well) in 24-well plates were treated with 0, 50, 100, 150 and 200 µM of GdCl 3 for 24 h. Apoptotic DNA breaks were labeled with the In Situ Cell Death Detection kit, Fluorescein (Roche Diagnostics GmbH, Mannheim, Germany) according to the vendor's protocol, and the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick-end labeling (TUNEL) positive cells were monitored using a BD FACSCalibur flow cytometry (BD Biosciences, San Jose, CA, USA) and BD CellQuest Pro Software (BD Biosciences), as previously described (26). DAPI dye was used to countstain condensation nuclei (a characteristic of apoptosis) in U-2 OS cells with or without 200 µM GdCl 3 for 24 h, as detailed by previous studies (27,28). Determinations of intracellular Ca 2+ , ROS and ΔΨm levels by flow cytometry.…”

Section: Chemicals and Reagents Gadolinium Chloride (Gdclmentioning

confidence: 99%

Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

Tsai¹,

Huang²,

Chiang³

et al. 2016

Oncology Reports

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Gadolinium (Gd) compounds are important as magnetic resonance imaging (MRI) contrast agents, and are potential anticancer agents. However, no report has shown the effect of gadolinium chloride (GdCl3) on osteosarcoma in vitro. The present study investigated the apoptotic mechanism of GdCl3 on human osteosarcoma U-2 OS cells. Our results indicated that GdCl3 significantly reduced cell viability of U-2 OS cells in a concentration-dependent manner. GdCl3 led to apoptotic cell shrinkage and DNA fragmentation in U-2 OS cells as revealed by morphologic changes and TUNEL staining. Colorimetric assay analyses also showed that activities of caspase-3, caspase-8, caspase-9 and caspase-4 occurred in GdCl3-treated U-2 OS cells. Pretreatment of cells with pan-caspase inhibitor (Z-VAD-FMK) and specific inhibitors of caspase-3/-8/-9 significantly reduced cell death caused by GdCl3. The increase of cytoplasmic Ca2+ level, ROS production and the decrease of mitochondria membrane potential (ΔΨm) were observed by flow cytometric analysis in U-2 OS cells after GdCl3 exposure. Western blot analyses demonstrated that the levels of Fas, FasL, cytochrome c, Apaf-1, GADD153 and GRP78 were upregulated in GdCl3-treated U-2 OS cells. In conclusion, death receptor, mitochondria-dependent and endoplasmic reticulum (ER) stress pathways contribute to GdCl3-induced apoptosis in U-2 OS cells. GdCl3 might have potential to be used in treatment of osteosarcoma patients.

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Effect of DNA damage response by quinazolinone analogue HMJ-38 on human umbilical vein endothelial cells

Cited by 4 publications

References 55 publications

Efficacy of HMJ-38, a new quinazolinone analogue, against the gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cells

Efficacy of HMJ-38, a new quinazolinone analogue, against the gemcitabine-resistant MIA-PaCa-2 pancreatic cancer cells

Caspase‑dependent apoptotic death by gadolinium chloride (GdCl3) via reactive oxygen species production and MAPK signaling in rat C6 glioma cells

Gadolinium chloride elicits apoptosis in human osteosarcoma U-2 OS cells through extrinsic signaling, intrinsic pathway and endoplasmic reticulum stress

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