Atorvastatin and celecoxib in combination inhibits the progression of androgen-dependent LNCaP xenograft prostate tumors to androgen independence.
Epidemiology studies suggest that statins and nonsteroidal anti-inflammatory drugs reduce the risk of prostate cancer. In the present study, LNCaP cells were cultured in regular medium containing fetal bovine serum or in medium supplemented with charcoal-stripped fetal bovine serum to mimic androgen deprivation treatment. We found that atorvastatin (Lipitor) or celecoxib (Celebrex) treatment of LNCaP cells cultured in regular or androgen-depleted medium inhibited growth and stimulated apoptosis. A combination of atorvastatin and celecoxib was more effective than either agent alone. In animal studies, severe combined immunodeficient mice were injected s.c. with LNCaP cells in Matrigel. After 4 to 6 weeks, mice with LNCaP tumors (about 0.6 cm wide and 0.6 cm long) were surgically castrated and received daily i.p. injections of vehicle, atorvastatin (10 microg/g body weight/d), celecoxib (10 microg/g/d), or a combination of atorvastatin (5 microg/g/d) and celecoxib (5 microg/g/d) for 42 days. In all groups, the androgen-dependent LNCaP tumors regressed initially in response to castration, but the tumors eventually progressed to androgen independence and started to grow. Treatment of the mice with atorvastatin or celecoxib alone suppressed the regrowth of LNCaP tumors after castration. A combination of low doses of atorvastatin and celecoxib had a more potent effect in inhibiting the growth and progression of LNCaP tumors to androgen independence than a higher dose of either agent alone. Our results indicate that administration of a combination of atorvastatin and celecoxib may be an effective strategy for the prevention of prostate cancer progression from androgen dependence to androgen independence.
Zheng
Xi
X
Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, 08854, USA. xizheng@rci.rutgers.edu
Cui
Xiao-Xing
XX
Gao
Zhi
Z
Zhao
Yang
Y
Lin
Yong
Y
Shih
Weichung Joe
WJ
Huang
Mou-Tuan
MT
Liu
Yue
Y
Rabson
Arnold
A
Reddy
Bandaru
B
Yang
Chung S
CS
Conney
Allan H
AH
D000728:Androgens / Q000378:metabolism; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D015153:Blotting, Western; D000068579:Celecoxib; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D015870:Gene Expression; D006538:Heptanoic Acids / Q000008:administration & dosage; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016328:NF-kappa B / Q000187:drug effects / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011720:Pyrazoles / Q000008:administration & dosage; D011758:Pyrroles / Q000008:administration & dosage; D013449:Sulfonamides / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000728:Androgens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018931:Antineoplastic Agents, Hormonal; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016328:NF-kappa B; D011720:Pyrazoles; D011758:Pyrroles; D013449:Sulfonamides; D000069059:Atorvastatin; D000068579:Celecoxib