Combination of tipifarnib and rapamycin synergistically inhibits the growth of leukemia cells and overcomes resistance to tipifarnib via alteration of cellular signaling pathways.
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.
Nagai
Tadashi
T
Division of Hematology, Department of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke, Tochigi, Japan. t-nagai@jichi.ac.jp
Ohmine
Ken
K
Fujiwara
Shin-Ichiro
S
Uesawa
Mitsuyo
M
Sakurai
Chihiro
C
Ozawa
Keiya
K
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
D015363:Quinolones; C402769:tipifarnib; D020123:Sirolimus