کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
1947507 | 1054614 | 2014 | 11 صفحه PDF | دانلود رایگان |

• HMJ-38 induces mitochondrial death effector-mediated apoptosis.
• CDK1-regulated Bcl-2 phosphorylation is prompted by HMJ-38.
• Proapoptotic ER stress response occurs after HMJ-38 challenge.
• HMJ-38 inhibits tumor growth of oral cancer xenografts.
• Novel HMJ-38 shows oral anticancer effect in response to potential therapeutic value.
BackgroundThis 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.MethodsCell 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.ResultsHMJ-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 Ca2 + 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.ConclusionsEarly 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 significanceThis finding might fully support a critical event for HMJ-38 via induction of apoptotic machinery and ER stress against human oral cancer cells.
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Journal: Biochimica et Biophysica Acta (BBA) - General Subjects - Volume 1840, Issue 7, July 2014, Pages 2310–2320