The Possibility of Simvastatin as a Chemotherapeutic Agent for All-trans Retinoic Acid-Resistant Promyelocytic Leukemia

In this study, the authors evaluated the possible use of 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in anti-leukemic chemotherapy. Cytotoxic potency against HL-60 was as follows; simvastatin (SV)>atorvastatin>cerivastatin>fluvastatin. Interestingly, HL-60-R2...

Full description

Saved in:
Bibliographic Details
Published in:Biological & Pharmaceutical Bulletin 2008/03/01, Vol.31(3), pp.369-374
Main Authors: Tomiyama, Naoki, Matzno, Sumio, Kitada, Chihiro, Nishiguchi, Eri, Okamura, Noboru, Matsuyama, Kenji
Format: Article
Language:English
Subjects:
all-trans retinoic acid-resistant acute promyelocytic leukemia
Antineoplastic Agents - pharmacology
apoptosis
Apoptosis - drug effects
Caspase 9 - metabolism
Cell Survival - drug effects
Cytochromes c - metabolism
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm - drug effects
Electrophoresis, Agar Gel
HL-60 Cells
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors - pharmacology
Leukemia, Promyelocytic, Acute - drug therapy
Membrane Potential, Mitochondrial - drug effects
Mitochondria - drug effects
Reactive Oxygen Species - metabolism
Simvastatin - pharmacology
statin
Tretinoin - pharmacology
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In this study, the authors evaluated the possible use of 3-hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) in anti-leukemic chemotherapy. Cytotoxic potency against HL-60 was as follows; simvastatin (SV)>atorvastatin>cerivastatin>fluvastatin. Interestingly, HL-60-R2, an all-trans retinoic acid (ATRA)-resistant HL-60 variant, was twice as sensitive to SV than HL-60. Further studies revealed the particular mechanism of action of SV-induced apoptosis in leukemia. SV directly and rapidly disordered mitochondria with a loss of its membrane potential, reactive oxygen species (ROS) generation and subsequent irreversible damage with cytochrome c leakage and, finally, SV induced apoptosis through caspase-9 activation, whereas several studies have shown that other statins induced apoptosis to leukemia by the depletion of isoprenoids used for the prenylation of small GTPases, which are essential for cellular signal transduction. Our findings suggest that the mitochondrial pathway plays an important role in the higher potency of SV as a new class of agents for anti-leukemic therapy alone and/or in combination with agents.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.31.369