title: Combination of tipifarnib and rapamycin synergistically inhibits the growth of leukemia cells and overcomes resistance to tipifarnib via alteration of cellular signaling pathways.
abstract: Small molecules are attractive agents for the treatment of leukemia. We found that a combination of a farnesyltransferase inhibitor, tipifarnib, and an mTOR inhibitor, rapamycin, synergistically inhibited the growth of myeloid leukemia cell lines and primary leukemia cells by inducing apoptosis and cell-cycle blockage. The combined agents reduced the level of phospho-ERK1/2, suggesting that they altered the network of signaling pathways. They also showed synergistic effects in tipifarnib-resistant K562/RR cells. The results support the utility of this combination as a potential therapy for leukemia. The combination might also be effective in overcoming resistance to tipifarnib.
authors.affiliation: Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan. t-nagai@jichi.ac.jp
authors.forename: Tadashi
authors.initials: T
authors.lastname: Nagai
authors.forename: Ken
authors.initials: K
authors.lastname: Ohmine
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Fujiwara
authors.forename: Mitsuyo
authors.initials: M
authors.lastname: Uesawa
authors.forename: Chihiro
authors.initials: C
authors.lastname: Sakurai
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005434:Flow Cytometry; D006801:Humans; D007938:Leukemia / Q000145:classification / Q000188:drug therapy* / Q000473:pathology; D015363:Quinolones / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage; D014407:Tumor Cells, Cultured
chemical_list: D015363:Quinolones; C402769:tipifarnib; D020123:Sirolimus