title: Wnt signaling inhibitor FH535 selectively inhibits cell proliferation and potentiates imatinib-induced apoptosis in myeloid leukemia cell lines.
abstract: Wnt signaling pathway plays a major role in leukemogenesis of myeloid leukemia. Aberrancy in its regulation results in hyperactivity of the pathway contributing to leukemia propagation and maintenance. To investigate effects of Wnt pathway inhibition in leukemia, we used human leukemia cell lines (i.e., K562, HL60, THP1, and Jurkat) and several Wnt inhibitors, including XAV939, IWP2 and FH535. Our results showed that leukemia cell lines (>95 % cells) had increased endogenous levels of β-catenin as compared to mononuclear cells from healthy donors (0 %). Among the tested inhibitors, FH535 demonstrated a markedly suppressive effect (IC50= 358 nM) on mRNA levels of β-catenin target genes (LEF1, CCND1, and cMYC). In addition, FH535 significantly potentiated imatinib-induced apoptosis. Evaluation of erythrocyte and megakaryocyte lineage using flow cytometry demonstrated that the potentiation mechanism is independent of the developmental stage, and is more likely due to crosstalk between other pathways and β-catenin. FH535 also displayed antiproliferative properties in other cell lines used in this study. In summary, FH535 showed significantly high antiproliferative effects at submicromolar dosages, and additionally enhanced imatinib-induced apoptosis in human leukemia cell lines. Our results highlight its potential antileukemic promise when used in conjunction with other conventional therapeutic regimens.
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand. suknuntha@uwalumni.com.
authors.forename: Kran
authors.identifier: http://orcid.org/0000-0002-6648-8235
authors.initials: K
authors.lastname: Suknuntha
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Thanyatip
authors.initials: T
authors.lastname: Thita
authors.affiliation: Cell Therapy Core, Blood Systems Research Institute, San Francisco, CA, 94118, USA.
authors.forename: Padma Priya
authors.initials: PP
authors.lastname: Togarrati
authors.affiliation: Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Piyanee
authors.initials: P
authors.lastname: Ratanachamnong
authors.affiliation: Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Patompon
authors.initials: P
authors.lastname: Wongtrakoongate
authors.affiliation: Department of Pharmacology, Faculty of Dentistry, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Sirada
authors.initials: S
authors.lastname: Srihirun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, 53792, USA.|Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI, 53715, USA.
authors.forename: Igor
authors.initials: I
authors.lastname: Slukvin
authors.affiliation: Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.
authors.forename: Suradej
authors.initials: S
authors.lastname: Hongeng
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology; D020239:Receptor Cross-Talk / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D051176:beta Catenin / Q000187:drug effects / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C575430:FH535; D013449:Sulfonamides; D051176:beta Catenin; D000068877:Imatinib Mesylate
keywords: Apoptosis; CML; FH535; HL60; Imatinib; Jurkat; K562; Leukemia; Myeloid; Proliferation; THP1; Wnt inhibitor