The HMG-CoA reductase inhibitor, simvastatin, exhibits anti-metastatic and anti-tumorigenic effects in ovarian cancer.
Ovarian cancer is the 5th leading cause of cancer death among women in the United States. The mevalonate pathway is thought to be a potential oncogenic pathway in the pathogenesis of ovarian cancer. Simvastatin, a 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) inhibitor, is a widely used drug for inhibiting the synthesis of cholesterol and may also have anti-tumorigenic activity. Our goal was to evaluate the effects of simvastatin on ovarian cancer cell lines, primary cultures of ovarian cancer cells and in an orthotopic ovarian cancer mouse model. Simvastatin significantly inhibited cellular proliferation, induced cell cycle G1 arrest and apoptosis, and caused cellular stress via reduction in the enzymatic activity of HMGCR and inhibition of the MAPK and mTOR pathways in ovarian cancer cells. Furthermore, simvastatin induced DNA damage and reduced cell adhesion and invasion. Simvastatin also exerted anti-proliferative effects on primary cell cultures of ovarian cancer. Treatment with simvastatin in an orthotopic mouse model reduced ovarian tumor growth, coincident with decreased Ki-67, HMGCR, phosphorylated-Akt and phosphorylated-p42/44 protein expression. Our findings demonstrate that simvastatin may have therapeutic benefit for ovarian cancer treatment and be worthy of further exploration in clinical trials.
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
Jessica E
JE
Stine
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Department of Gynecologic Oncology, ShanDong Cancer Hospital & Institute, Jinan University, Jinan, P.R. China.
Hui
H
Guo
Department of Gynecologic Oncology, ShanDong Cancer Hospital & Institute, Jinan University, Jinan, P.R. China.
Xiugui
X
Sheng
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Department of Gynecologic Oncology, ShanDong Cancer Hospital & Institute, Jinan University, Jinan, P.R. China.
Xiaoyun
X
Han
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
Monica N
MN
Schointuch
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
Timothy P
TP
Gilliam
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Paola A
PA
Gehrig
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Chunxiao
C
Zhou
Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
Victoria L
VL
Bae-Jump
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D015151:Immunoblotting; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009362:Neoplasm Metastasis; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D019821:Simvastatin / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D017382:Reactive Oxygen Species; D019821:Simvastatin; D006903:Hydroxymethylglutaryl CoA Reductases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases
HMGCR; apoptosis; invasion; ovarian cancer; simvastatin