Carcinogenesis Advance Access published online on June 3, 2004
Carcinogenesis, doi:10.1093/carcin/bgh201
© 2004 by Oxford University Press
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1 Department of Anatomy and Biology, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan; High-Tech Research Center, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
* To whom correspondence should be addressed. E-mail: an1014{at}art.osaka-med.ac.jp.
The effects of lovastatin, a potent inhibitor of HMG CoA reductase, were studied in a mouse model of metastatic mammary cancer carrying a p53 mutation. Mice bearing mammary tumors, induced by inoculation of syngeneic BALB/c mice with BJMC3879 cells, were treated with lovastatin at 0, 25, and 50 mg/kg three times a week. Tumor volumes were significantly reduced in a dose-dependent manner throughout the 6-week study and were associated with both a decrease in DNA synthesis and an increase in apoptosis; the high dose of lovastatin also inhibited lung metastasis. In a corollary in vitro study, flow cytometric analyses of lovastatin-treated mammary cancer cells additionally showed cell cycle arrest at G1 phase and decreases in S and G2/M phases. Laser scanning cytometric analyses further demonstrated that cancer cells in S and G2/M were particularly susceptible to the effects of lovastatin. Transmission electron microscopic evaluation of TUNEL-confirmed apoptotic bodies in lovastatin-treated mammary carcinoma cells revealed many free 3'-OH ends of DNA in condensed chromatin within fragmented nuclei that occasionally assumed a characteristic half-moon shape. Consistent with initiation of apoptosis, cellular caspase-8, -9 and -3 activities were elevated in lovastatin-treated cells; the mitochondrial membrane potential was also decreased with subsequent release of cytochrome c. However, lovastatin-induced cell death was significantly reduced by the broad-spectrum caspase inhibitor, z-VAD-fmk, as well as the caspase-9 inhibitor, z-LEHD-fmk, and the caspase-3 inhibitor, z-DEVD-fmk, but not by the specific caspase-8 inhibitor, z-IETD-fmk. Since immunoelectron microscopy showed translocation of Bax to the mitochondria in lovastatin-treated cells, lovastatin-induced apoptosis may, therefore, be ultimately dependent on Bax-induction of cytochrome c release. These results suggest that lovastatin may be useful as an adjuvant therapy in breast cancers containing p53 mutations due to its ability to both suppress DNA synthesis and induce p53-independent mitochondrial-mediated apoptosis. Key Words:
lovastatin, mammary cancer, anticancer drug, apoptosis, mitochondria
Revised April 19, 2004
Accepted May 27, 2004
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Lovastatin inhibits tumor growth and lung metastasis in mouse mammary carcinoma model: a p53-independent mitochondrial-mediated apoptotic mechanism
2 Department of Anatomy and Biology, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
3 Laboratory Animal Center, Osaka Medical College, 2-7, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan
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