title: Antileukemia activity of MSFTZ-a novel flavanone analog.
abstract: A newly synthesized flavanone derivative, (+/-)-(3aRS,4SR)-2-(2-chloro-4-methyl- sulfonylphenyl)-4'-chloro-3a,4-diethoxy-flavane[4,3-d]-Delta-1,2,3-thiadiazoline (MSFTZ), was investigated for its antileukemia activity and molecular mechanisms. Cytotoxicity assay confirmed the high antiproliferative efficiency of MSFTZ in six leukemia cell lines (including two drug-resistant cell lines), with 50% inhibition of cell viability values ranging from 1.0 to 9.2 micromol/l. The results of flow cytometry assay showed that the percentage of apoptotic HL-60 cells was 68.3% after 48 h treatment with MSFTZ, suggesting that the activation of the apoptosis pathway was an anticancer property of MSFTZ. Furthermore, the protein changes related to apoptosis were investigated. Exposure of HL-60 cells to MSFTZ induced pro-caspase-9 and pro-caspase-3 cleavage, X-linked inhibitor of apoptosis protein and Bcl-X(L) downregulation, and poly(ADP-ribose) polymerase degradation. Treatment of cells with MSFTZ resulted in a time-dependent reduction in phosphorylation (activation) of extracellular signal-regulated kinase 1/2 and an increase in phosphorylation (activation) of Jun N-terminal kinase. Taken together, our results demonstrated that activation of mitogen-activated protein kinase and apoptotic cascade is involved in MSFTZ-induced antileukemia activity. All data suggest that MSFTZ is a promising chemotherapy drug.
authors.affiliation: Institute of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
authors.forename: Qiaojun
authors.initials: Q
authors.lastname: He
authors.forename: Runping
authors.initials: R
authors.lastname: Li
authors.forename: Liang
authors.initials: L
authors.lastname: Fang
authors.forename: Huazhou
authors.initials: H
authors.lastname: Ying
authors.forename: Yongzhou
authors.initials: Y
authors.lastname: Hu
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001578:Benzopyrans / Q000737:chemistry / Q000627:therapeutic use*; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D044950:Flavanones / Q000627:therapeutic use*; D005434:Flow Cytometry; D018922:HL-60 Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013830:Thiadiazoles / Q000737:chemistry / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: C516246:2-(2-chloro-4-methylsulfonylphenyl)-4'-chloro-3a,4-diethoxyflavane(4,3-d)-delta(1,9b)-1,2,3-thiadiazoline; D000970:Antineoplastic Agents; D001578:Benzopyrans; D044950:Flavanones; D019253:Proto-Oncogene Proteins c-bcl-2; D013830:Thiadiazoles; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D053148:Caspase 3; D053453:Caspase 9