title: Paraptosis cell death induction by the thiamine analog benfotiamine in leukemia cells.
abstract: Benfotiamine is a synthetic thiamine analogue that stimulates transketolase, a cellular enzyme essential for glucose metabolism. Currently, benfotiamine is used to treat diabetic neuropathy. We recently reported that oral benfotiamine induced a temporary but remarkable recovery from acute myeloid leukemia in an elderly patient who was ineligible for standard chemotherapy due to dementia and renal failure. In the present study we present evidences that benfotiamine possess antitumor activity against leukemia cells. In a panel of nine myeloid leukemia cell lines benfotiamine impaired the viability of HL-60, NB4, K562 and KG1 cells and also inhibited the growing of primary leukemic blasts. The antitumor activity of benfotiamine is not mediated by apoptosis, necrosis or autophagy, but rather occurs though paraptosis cell death induction. Mechanistic studies revealed that benfotiamine inhibited the activity of constitutively active ERK1/2 and concomitantly increased the phosphorylation of JNK1/2 kinase in leukemic cells. In addition, benfotiamine induced the down regulation of the cell cycle regulator CDK3 which resulted in G1 cell cycle arrest in the sensitive leukemic cells. Moreover, combination index studies showed that benfotiamine enhanced the antiproliferative activities of cytarabine against leukemia cells. These findings suggest that benfotiamine has antitumor therapeutic potential.
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan.
authors: Naomi
authors: N
authors: Sugimori
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan.
authors: J Luis
authors: JL
authors: Espinoza
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan.
authors: Ly Quoc
authors: LQ
authors: Trung
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan; Department of Hematology Oncology, Aichi Medical University School of Medicine, Nagakute, Japan.
authors: Akiyoshi
authors: A
authors: Takami
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan.
authors: Yukio
authors: Y
authors: Kondo
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan.
authors: Dao Thi
authors: DT
authors: An
authors: Department of Pathology, Kanazawa University, Kanazawa, Japan.
authors: Motoko
authors: M
authors: Sasaki
authors: Department of Anatomy and Histology, Kanazawa University, Kanazawa, Japan.
authors: Tomohiko
authors: T
authors: Wakayama
authors: Department of Hematology Oncology, Kanazawa University Hospital, Kanazawa University, Kanazawa, Japan Takaramachi 13-1, Kanazawa, Japan.
authors: Shinji
authors: S
authors: Nakao
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D002614:Chelating Agents; D013831:Thiamine; C013835:benphothiamine