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, 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.
Tomiyama
Naoki
N
School of Pharmaceutical Sciences, Mukogawa Women's University, 11-68 Koshien Kyuban-cho, Nishinomiya, Hyogo 663-8179, Japan.
Matzno
Sumio
S
Kitada
Chihiro
C
Nishiguchi
Eri
E
Okamura
Noboru
N
Matsuyama
Kenji
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D053453:Caspase 9 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004587:Electrophoresis, Agar Gel; D018922:HL-60 Cells; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D019821:Simvastatin / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology*
D000970:Antineoplastic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D014212:Tretinoin; D045304:Cytochromes c; D019821:Simvastatin; D053453:Caspase 9