title: The antileukemia effect of metformin in the Philadelphia chromosome-positive leukemia cell line and patient primary leukemia cell.
abstract: In recent years, there have been considerable research advances on the antileukemic mechanisms of the antidiabetic drug metformin. Our current studies have shown that metformin suppresses cell viability, induces apoptosis, and downregulates the mTORC1 signaling pathway both in the Ph+ALL cell line and primary blasts from Ph+ ALL patients, as well as the CML cell lines K562 (imatinib-sensitive) and K562R (imatinib-resistance). We have also shown that metformin activates the ERK pathway in Ph+ALL cells, SUP-B15, a side effect that can be overcome by U0126 (MEK1/2 inhibitor) or imatinib. Moreover, this activation of ERK signaling in SUP-B15 induces autophagy. Inhibition of the autophagic process by 3-MA, promoting the death of these cells, suggests that autophagy may be a cytoprotective factor in cell survival after metformin treatment. Finally, metformin is shown to potentiate the anticancer efficacy of imatinib in Ph+ALL and CML cells, resensitizing the CML imatinib-resistance cells to imatinib. Overall, our data suggest that metformin represents a promising and attractive agent for Ph+ALL or CML therapy.
authors.affiliation: Department of Hematology, West China Hospital, Sichuan University, Chengdu, China.
authors.forename: Rui
authors.initials: R
authors.lastname: Shi
authors.forename: Juan
authors.initials: J
authors.lastname: Lin
authors.forename: Yuping
authors.initials: Y
authors.lastname: Gong
authors.forename: Tianyou
authors.initials: T
authors.lastname: Yan
authors.forename: Fangfang
authors.initials: F
authors.lastname: Shi
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.forename: Xuehua
authors.initials: X
authors.lastname: Liu
authors.forename: Duolan
authors.initials: D
authors.lastname: Naren
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D006801:Humans; D000068877:Imatinib Mesylate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000473:pathology*; D020935:MAP Kinase Signaling System; D008687:Metformin / Q000494:pharmacology*; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000494:pharmacology; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D008687:Metformin