title: Nitrogen-containing bisphosphonates induce apoptosis of hematopoietic tumor cells via inhibition of Ras signaling pathways and Bim-mediated activation of the intrinsic apoptotic pathway.
abstract: Nitrogen-containing bisphosphonates (N-BPs) induce apoptosis in tumor cells by inhibiting the prenylation of small G-proteins. However, the details of the apoptosis-inducing mechanism remain obscure. The present study showed that the induction of apoptosis by N-BPs in hematopoietic tumor cells is mediated by mitochondrial apoptotic signaling pathways, which are activated by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. Furthermore, N-BPs decreased the levels of phosphorylated extracellular signal-regulated kinase (ERK) and mTOR via suppression of Ras prenylation and enhanced Bim expression. The present results indicated that N-BPs induce apoptosis by decreasing the mitochondrial transmembrane potential, increasing the activation of caspase-9 and caspase-3, and enhancing Bim expression through inhibition of the Ras/MEK/ERK and Ras/mTOR pathways. The accumulation of N-BPs in bones suggests that they may act more effectively on tumors that have spread to bones or on Ras-variable tumors. This is the first study to show that the specific molecular pathways of N-BP-induced apoptosis.
authors.affiliation: Division of Pharmacotherapy, Kinki University School of Pharmacy, Kowakae, Higashi-Osaka 577-8502, Japan.
authors.forename: Masanobu
authors.initials: M
authors.lastname: Tsubaki
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Itoh
authors.forename: Takao
authors.initials: T
authors.lastname: Satou
authors.forename: Motohiro
authors.initials: M
authors.lastname: Imano
authors.forename: Makiko
authors.initials: M
authors.lastname: Komai
authors.forename: Naoki
authors.initials: N
authors.lastname: Ogawa
authors.forename: Junji
authors.initials: J
authors.lastname: Mukai
authors.forename: Shozo
authors.initials: S
authors.lastname: Nishida
mesh_terms: D019386:Alendronate / Q000009:adverse effects / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D050071:Bone Density Conservation Agents / Q000009:adverse effects / Q000494:pharmacology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D004164:Diphosphonates / Q000009:adverse effects / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000009:adverse effects / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017368:Protein Prenylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; C087958:YM 529; C071542:cimadronate; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D016283:Proto-Oncogene Proteins p21(ras); D019386:Alendronate