Atorvastatin induces apoptosis in vitro and slows growth of tumor xenografts but not polyp formation in MIN mice.
BACKGROUND
Despite the availability of effective surveillance for colorectal cancer with colonoscopy, relatively few at-risk individuals utilize this option. Colon cancer chemoprevention might be a more acceptable alternative. Some epidemiologic studies have suggested that statins may have chemopreventive effects without the risks of nonsteroidal anti-inflammatory drugs, but other epidemiologic studies have found no effect of statins.


METHODS
We aimed to evaluate the efficacy of atorvastatin in inducing apoptosis in vitro, in preventing polyp formation in the min mouse, and in preventing tumor growth in nude mice.


RESULTS
Atorvastatin rapidly induces apoptosis in the HCT116 colon cancer cell line in vitro, and this effect is reversible with mevalonate and geranylgeranyl pyrophosphate, but less so by farnesyl pyrophosphate. Atorvastatin chow was ineffective in reducing polyp formation in the min mouse model, with no significant effect on polyp number. Atorvastatin was effective in significantly slowing the growth of HCT116 colon cancer cell xenografts in nude mice (p = 0.008). Further, this reduction is due to increased levels of apoptosis.


CONCLUSIONS
Atorvastatin can induce apoptosis in vitro, through mevalonate and prenylation pathways. Atorvastatin, while not effective in preventing polyp formation in the min mouse model, was very effective in slowing tumor growth in a nude mouse model. Consistent with in vitro findings, increased apoptosis accounted for decreased tumor growth. Statins may have benefit in cancer by slowing tumor growth, rather than preventing tumor initiation.
Huang
Emina H
EH
Department of Surgery, University of Florida, Gainesville, FL, USA.
Johnson
Laura A
LA
Eaton
Kathryn
K
Hynes
Mark J
MJ
Carpentino
Joseph E
JE
Higgins
Peter D R
PD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000069059:Atorvastatin; D003110:Colonic Neoplasms / Q000517:prevention & control*; D003111:Colonic Polyps / Q000517:prevention & control*; D053938:DNA Fragmentation; D004195:Disease Models, Animal; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D000069059:Atorvastatin