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Biochim Biophys Acta. 2014 Jul;1840(7):2310-20. doi: 10.1016/j.bbagen.2014.02.022. Epub 2014 Mar 1.

Cell death caused by quinazolinone HMJ-38 challenge in oral carcinoma CAL 27 cells: dissections of endoplasmic reticulum stress, mitochondrial dysfunction and tumor xenografts.

Author information

1
Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan.
2
Department of Pharmacology, China Medical University, Taichung 40402, Taiwan.
3
School of Pharmacy, China Medical University, Taichung 40402, Taiwan.
4
Department of Radiation Oncology, Chi Mei Medical Center, Tainan 71004, Taiwan.
5
Department of Life Sciences, National Chung Hsing University, Taichung 40227, Taiwan; Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan. Electronic address: thlee@email.nchu.edu.tw.
6
Department of Biological Science and Technology, China Medical University, Taichung 40402, Taiwan; Department of Biotechnology, Asia University, Taichung 41354, Taiwan. Electronic address: jgchung@mail.cmu.edu.tw.

Abstract

BACKGROUND:

This investigation clearly clarified the synthesized and antimitotic compound, 2-(3'-methoxyphenyl)-6-pyrrolidinyl-4-quinazolinone (HMJ-38), addressing its target and precise mechanism of action. We hypothesized that HMJ-38 might sensitize apoptotic death of human oral carcinoma CAL 27 cells in vitro and inhibit xenograft tumor growth in vivo.

METHODS:

Cell viability was assessed utilizing MTT assay. HMJ-38-treated cells represented DNA fragmentation using agarose gel electrophoresis as further evidenced using TUNEL staining. Flow cytometric analyses, immunoblotting and quantitative RT-PCR were applied for protein and gene expression. Antitumor xenograft study was employed.

RESULTS:

HMJ-38 concentration- and time-dependently reduced viability of CAL 27 cells. The effect of intrinsic molecules was signalized during HMJ-38 exposure with disruption of ΔΨm, MPT pore opening and the release of various events from mitochondria undergoing cell apoptosis. HMJ-38 also markedly facilitated G2/M phase arrest. HMJ-38 stimulated the activation of CDK1 activity that modulated phosphorylation on Ser70 of Bcl-2-mediated mitotic arrest and apoptosis. HMJ-38 triggered intracellular Ca(2+) release and activated related pivotal hallmarks of ER stress. HMJ-38 in nude mice bearing CAL 27 tumor xenografts decreased tumor growth. Furthermore, HMJ-38 enhanced caspase-3 gene expression and protein level in xenotransplanted tumors.

CONCLUSIONS:

Early roles of mitotic arrest, unfolded protein response and mitochondria-dependent signaling contributed to apoptotic CAL 27 cell demise induced by HMJ-38. In in vivo experiments, HMJ-38 also efficaciously suppressed tumor volume in a xenotransplantation model.

GENERAL SIGNIFICANCE:

This finding might fully support a critical event for HMJ-38 via induction of apoptotic machinery and ER stress against human oral cancer cells.

KEYWORDS:

Endoplasmic reticulum stress; HMJ-38; Human oral carcinoma cells; Mitochondrial dysfunction; Tumor xenografts

PMID:
24594224
DOI:
10.1016/j.bbagen.2014.02.022
[Indexed for MEDLINE]

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