title: MST-312 induces G2/M cell cycle arrest and apoptosis in APL cells through inhibition of telomerase activity and suppression of NF-κB pathway.
abstract: Telomerase-targeted therapy for cancer has received great attention because telomerase is expressed in almost all cancer cells but is inactive in most normal somatic cells. This study was aimed to investigate the effects of telomerase inhibitor MST-312, a chemically modified derivative of epigallocatechin gallate (EGCG), on acute promyelocytic leukemia (APL) cells. Our results showed that MST-312 exerted a dose-dependent short-term cytotoxic effect on APL cells, with G2/M cell cycle arrest. Moreover, MST-312 induced apoptosis of APL cells in caspase-mediated manner. Telomeric repeat amplification protocol (TRAP) assay revealed significant reduction in telomerase activity of APL cells following short-term exposure to MST-312. Interestingly, MST-312-induced telomerase inhibition was coupled with suppression of NF-κB activity as evidenced by inhibition of IκBα phosphorylation and its degradation and decreased NF-κB DNA binding activity. In addition, gene expression analysis showed downregulation of genes regulated by NF-κB, such as antiapoptotic (survivin, Bcl-2, Mcl-1), proliferative (c-Myc), and telomerase-related (hTERT) genes. Importantly, MST-312 did not show any apoptotic effect in normal human peripheral blood mononuclear cells (PBMCs). In conclusion, our data suggest that dual inhibition of telomerase activity and NF-κB pathway by MST-312 represents a novel treatment strategy for APL.
authors.affiliation: Department of Hematology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Fatemi
authors.affiliation: Department of Hematology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
authors.forename: Majid
authors.initials: M
authors.lastname: Safa
authors.affiliation: Department of Hematology, School of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran. a.kazemi@iums.ac.ir.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kazemi
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000008:administration & dosage* / Q000737:chemistry; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D045744:Cell Line, Tumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016328:NF-kappa B / Q000096:biosynthesis* / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects; D019098:Telomerase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*
chemical_list: D001549:Benzamides; C470197:MST 312; D016328:NF-kappa B; D002392:Catechin; C045651:epigallocatechin gallate; C509186:TERT protein, human; D019098:Telomerase
keywords: APL; MST-312; NF-κB; Telomerase