title: Silibinin suppresses NPM-ALK, potently induces apoptosis and enhances chemosensitivity in ALK-positive anaplastic large cell lymphoma.
abstract: Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), an oncogenic fusion protein carrying constitutively active tyrosine kinase, is known to be central to the pathogenesis of ALK-positive anaplastic large cell lymphoma (ALK+ALCL). Here, it is reported that silibinin, a non-toxic naturally-occurring compound, potently suppressed NPM-ALK and effectively inhibited the growth and soft agar colony formation of ALK+ALCL cells. By western blots, it was found that silibinin efficiently suppressed the phosphorylation/activation of NPM-ALK and its key substrates/downstream mediators (including STAT3, MEK/ERK and Akt) in a time- and dose-dependent manner. Correlating with these observations, silibinin suppressed the expression of Bcl-2, survivin and JunB, all of which are found to be upregulated by NPM-ALK and pathogenetically important in ALK+ALCL. Lastly, silibinin augmented the chemosensitivity of ALK+ALCL cells to doxorubicin, particularly the small cell sub-set expressing the transcriptional activity of Sox2, an embryonic stem cell marker. To conclude, the findings suggest that silibinin might be useful in treating ALK+ALCL.
authors.affiliation: a Faculty of Pharmacy, Tabriz University of Medical Sciences , Tabriz , Iran.|b Department of Laboratory Medicine and Pathology , Faculty of Medicine and Dentistry, University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Ommoleila
authors.initials: O
authors.lastname: Molavi
authors.affiliation: c Department of Biochemistry , Faculty of Medicine, Tabriz University of Medicine , Tabriz , Iran.
authors.forename: Nasser
authors.initials: N
authors.lastname: Samadi
authors.affiliation: b Department of Laboratory Medicine and Pathology , Faculty of Medicine and Dentistry, University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Chengsheng
authors.initials: C
authors.lastname: Wu
authors.affiliation: d Faculty of Pharmacy and Pharmaceutical Science, University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Afsaneh
authors.initials: A
authors.lastname: Lavasanifar
authors.affiliation: b Department of Laboratory Medicine and Pathology , Faculty of Medicine and Dentistry, University of Alberta , Edmonton , Alberta , Canada.
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004357:Drug Synergism; D006801:Humans; D016130:Immunophenotyping; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*
chemical_list: D055748:SOXB1 Transcription Factors; D012838:Silymarin; D000077385:Silybin; D004317:Doxorubicin; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases
keywords: NPM-ALK; Silibinin; anaplastic large cell lymphoma; apoptosis; tumorigenicity