Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac.
OBJECTIVE
3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (HRIs) were found incidentally to reduce new cases of colon cancer in 2 large clinical trials evaluating coronary events, although most patients in both treatment and control group were taking nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs are associated with reduced colon cancer incidence, predominantly by increasing apoptosis. We showed previously that lovastatin induces apoptosis in colon cancer cells. In the present study we evaluated the potential of combining lovastatin with sulindac for colon cancer chemoprevention.


RESULTS
Lovastatin, 10-30 micromol/L, augmented sulindac-induced apoptosis up to 5-fold in 3 colon cancer cell lines. This was prevented by mevalonate (100 micromol/L) or geranylgeranylpyrophosphate (10 micromol/L) but not farnesylpyrophosphate (100 micromol/L), suggesting inhibition of geranylgeranylation of target protein(s) as the predominant mechanism. In an azoxymethane rat model of chemical-induced carcinogenesis, the total number of colonic aberrant crypt foci per animal (control, 161 +/- 11) and the number of foci with 4+ crypts (control, 40 +/- 4.5) decreased to 142 +/- 14 (NS) and 43 +/- 2.9 (NS), respectively, with 50 ppm lovastatin alone; to 137 +/- 5.4 (P = 0.053) and 36 +/- 2.1 (NS) with 80 ppm sulindac alone; and to 116 +/- 8.1 (P = 0.004) and 28 +/- 3.4 (P = 0.02) when 50 ppm lovastatin and 80 ppm sulindac were combined.


CONCLUSIONS
Addition of an HRI such as lovastatin may augment chemopreventive effects of NSAIDs or/and may allow lower, less toxic doses of these drugs to be used.
Agarwal
B
B
Division of Gastroenterology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA.
Rao
C V
CV
Bhendwal
S
S
Ramey
W R
WR
Shirin
H
H
Reddy
B S
BS
Holt
P R
PR
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001397:Azoxymethane; D002273:Carcinogens; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004357:Drug Synergism; D007527:Isoenzymes / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology*; D008297:Male; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013467:Sulindac / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D002273:Carcinogens; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D013467:Sulindac; D008148:Lovastatin; D011451:Prostaglandin-Endoperoxide Synthases; D001397:Azoxymethane