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: Masanobu Tsubaki, Tatsuki Itoh, Takao Satou, Motohiro Imano, Makiko Komai, Naoki Ogawa, Junji Mukai, Shozo Nishida
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 85 Issue 2 Pg. 163-72 (Jan 15 2013) ISSN: 1873-2968 [Electronic] England
• PMID: 23085435 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• Bcl-2-Like Protein 11
• Bone Density Conservation Agents
• Diphosphonates
• Imidazoles
• Membrane Proteins
• Neoplasm Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• YM 529
• cimadronate
• MTOR protein, human
• TOR Serine-Threonine Kinases
• Proto-Oncogene Proteins p21(ras)
• Alendronate

Topics

• Alendronate (adverse effects, pharmacology)
• Antineoplastic Agents (adverse effects, pharmacology)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (antagonists & inhibitors, genetics, metabolism)
• Bcl-2-Like Protein 11
• Bone Density Conservation Agents (adverse effects, pharmacology)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism, pathology)
• Cell Survival (drug effects)
• Diphosphonates (adverse effects, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Silencing
• Hematologic Neoplasms (drug therapy, metabolism, pathology)
• Humans
• Imidazoles (adverse effects, pharmacology)
• MAP Kinase Signaling System (drug effects)
• Membrane Proteins (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Proteins (antagonists & inhibitors, genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Protein Prenylation (drug effects)
• Proto-Oncogene Proteins (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (antagonists & inhibitors, metabolism)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)