Nitrogen-containing bisphosphonates induce S-phase cell cycle arrest and apoptosis of myeloma cells by activating MAPK pathway and inhibiting mevalonate pathway.
Bisphosphonates have been used for the treatment of hypercalcemia associated with malignancies and osteoporosis. It was previously reported that the mevalonate pathway is involved in nitrogen-containing bisphosphonate-induced apoptosis in osteoclasts and myeloma cells. The aim of this study was to determine the effects of two bisphosphonates, incadronate, and newly developed bisphosphonate YM529 on human myeloma cells, U266, RPMI-8226, and HS-Sultan. Both incadronate and YM529 induced S-phase cell cycle arrest and apoptosis in these myeloma cells. Treatment of the myeloma cells with cell-permeable substrates for mevalonate pathways, geranylgeraniol, and farnesol prevented bisphosphonate-mediated growth suppression. Checkpoint kinases, Chk1/2, and MAPK became phosphorylated after stimulation with bisphosphonates in the myeloma cells. Bisphosphonate-induced apoptosis was partially prevented by the pretreatment with MAPK inhibitor. These results demonstrate that incadronate and YM529 suppress the proliferation of myeloma cells through mevalonate pathway and MAPK pathway.
Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
Toyotaka
T
Iguchi
Yoshitaka
Y
Miyakawa
Kaori
K
Yamamoto
Masahiro
M
Kizaki
Yasuo
Y
Ikeda
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D000071877:Checkpoint Kinase 1; D004164:Diphosphonates / Q000494:pharmacology*; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005204:Farnesol / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008798:Mevalonic Acid / Q000378:metabolism*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D016196:S Phase / Q000187:drug effects* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism
D004164:Diphosphonates; D004224:Diterpenes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D015850:Interleukin-6; C087958:YM 529; C071542:cimadronate; D005204:Farnesol; C017338:geranylgeraniol; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D008798:Mevalonic Acid