title: Atorvastatin and celecoxib in combination inhibits the progression of androgen-dependent LNCaP xenograft prostate tumors to androgen independence.
abstract: 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.
authors.affiliation: Department of Chemical Biology, Rutgers, The State University of New Jersey, Piscataway, 08854, USA. xizheng@rci.rutgers.edu
authors.forename: Xi
authors.initials: X
authors.lastname: Zheng
authors.forename: Xiao-Xing
authors.initials: XX
authors.lastname: Cui
authors.forename: Zhi
authors.initials: Z
authors.lastname: Gao
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yong
authors.initials: Y
authors.lastname: Lin
authors.forename: Weichung Joe
authors.initials: WJ
authors.lastname: Shih
authors.forename: Mou-Tuan
authors.initials: MT
authors.lastname: Huang
authors.forename: Yue
authors.initials: Y
authors.lastname: Liu
authors.forename: Arnold
authors.initials: A
authors.lastname: Rabson
authors.forename: Bandaru
authors.initials: B
authors.lastname: Reddy
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.forename: Allan H
authors.initials: AH
authors.lastname: Conney
mesh_terms: 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
chemical_list: 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