| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Published online before print May 30, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Departments of Pharmacology,
Gastroenterological Surgery, Transplant, and Surgical Oncology, and
Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan; and
Novartis Institutes for Biomedical Research, Basel, Switzerland
1Correspondence: Department of Pharmacology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama 700-8558, Japan. E-mail: mbori{at}md.okayama-u.ac.jp
ABSTRACT
Statins, which inhibit 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase, are thought to reduce the risk of cancer through the inhibition of Ras farnesylation and serum lipid level. A pleiotropic proinflammatory cytokine, interleukin-18 (IL-18), is reported to exhibit significant antitumor activities through the activation of cytotoxic T lymphocytes and natural killer cells and the inhibition of angiogenesis. Previously, we found that pravastatin, fluvastatin, and simvastatin induced the production of IL-18 in human monocytes. The addition of mevalonate abolished the IL-18 production induced by pravastatin, fluvastatin, and simvastatin, indicating that the IL-18 production might be a result of the inhibition of HMG-CoA reductase. We present a new hypothesis that the production of IL-18 might play roles in the action of statins on cancer.
Key Words: statin • cancer
It has been suggested that the anticancer effect of statins can be potentially exploited for the cancer therapy. Retrospective studies concluded that the long-term use of statins actually reduces the risk of pancreatic cancer by 59%, prostate cancer by 50%, and colorectal cancer by 49% [1 ]. In addition, several cancer trials have shown evidence supporting the use of statins as therapeutic anticancer agents [2 , 3 ]. However, the anticancer effect of statins is still incompletely characterized and controversial. In this report, we discuss the mechanism for the anticancer effect of statins introduced by the results of the clinical studies.
The mechanism responsible for action of statins is considered to be the inhibition of cholesterol biosynthesis through inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A (HMG-CoA) reductase. This results in depletion of mevalonate, which is a precursor of cholesterol. It is reported that the elevated serum lipid levels facilitate the development of distant metastasis in colorectal cancer patients [4 ]. The deprivation of dietary cholesterol reduces the incidence of colon cancer metastases [5 ]. Lovastatin or simvastatin has been shown to inhibit metastasis in colon, pancreatic, and melanoma cancer cells [6 7 8 ]. These findings suggested that the reduction in serum lipid level might help to prevent cancer metastases. Although the decrease in cancer risk among statin users is accentuated, the small number of users of nonstatin lipid-lowering drugs does not allow a thorough analysis of individual cancers. Therefore, the inhibition of cholesterol might not support all of the statin anticancer effects. Conversely, mevalonate is known as a precursor of farnesyl and geranylgeranyl moieties, which are essential for the activation of prenylation [9 ], involved in the activation of Ras protein, which plays roles in the regulation of cell differentiation and proliferation. Approximately 30% of the human tumors have a mutation of k-Ras oncogene, and the expression of this oncogene is related to aberrant cellular growth [10 ]. Then, the inhibition of Ras farnesylation is originally thought to be the mechanism that mediates statin-induced effects in cancer [11 ].
Interleukin (IL)-18 is produced during the acute immune response by monocytes, macrophages, and immature dendritic cells by activation of caspase-1 [12
]. IL-18 is known to exhibit significant antitumor activities [13
]. The antitumor effects of IL-18 are mediated by activation of cytotoxic T lymphocytes and natural killer (NK) cells [14
], by production of interferon (IFN)-
from T cells and NK cells [14
], and by inhibiting angiogenesis [15
]. Serum cholesterol level is reported to be elevated significantly in IL-18-deficient apolipoprotein E(–/–) mice [16
]. Fluvastatin is reported to lead the activation of caspase-1 and in a small secretion of IL-1ß, IL-18, and IFN- in human peripheral blood mononuclear cells (PBMC) [17
]. In a previous study, we found that pravastatin and simvastatin as well as fluvastatin induced the production of IL-18 in the medium of human monocytes isolated from human PBMC using the therapeutic concentrations of statins (submicromolar) [18
, 19
]. The effects of pravastatin, fluvastatin, and simvastatin on the production of IL-18 were abolished by the addition of mevalonate, indicating the involvement of HMG-CoA reductase in the action of pravastatin, fluvastatin, and simvastatin. Recently, it is reported that lymphocyte function-associated antigen (LFA)703 is a statin-derived LFA-1 inhibitor, which did not inhibit HMG-CoA reductase [20
]. In the previous study, we found that LFA703 did not induce IL-18 production [18
]. However, little is known about the effect of LFA703 on cancer, and further study should be continued. We suggest that the production of IL-18 may contribute partially to the anticancer effects of statins, although the direct evidence is scarce about the statin-induced IL-18 production in vivo in humans.
Received April 5, 2006; accepted April 25, 2006.
REFERENCES
-inducing factor and regulates LPS-induced IFN- production Nature 386,619-623[CrossRef][Medline]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
