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 μg/g body weight/d), celecoxib (10 μg/g/d), or a combination of atorvastatin (5 μg/g/d) and celecoxib (5 μg/g/d) for 42 days. In all groups, the androgendependent 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. Cancer Prev Res; 3(1); 114-24. ©2010 AACR.

Nonsteroidal Anti-Inflammatory Drugs and Prostatic Diseases

“…Similar results were also obtained in xenograft models [47]. NSAIDs have also been shown to delay the progression of prostate tumors from androgen-dependent to androgen-independent growth [48]. NSAIDs delayed the regrowth of LNCaP xenografts in castrated SCID mice.…”

Oral simvastatin administration delays castration-resistant progression and reduces intratumoral steroidogenesis of LNCaP prostate cancer xenografts

“…18 This previous study concluded that decreased tumor growth in statin-treated animals was a result of increased apoptosis. Our study goes on to report that time to BCR following castration was significantly increased in the simvastatin-treated group, indicative of repressed AR reactivation and delayed castration-resistant progression of the xenografts.…”

“…17 In addition, atorvastatin treatment of castrated SCID mice harboring LNCaP xenografts resulted in decreased tumor growth that was correlated to an apoptotic response. 18 Finally, castration-resistant progression of LNCaP xenografts has been linked to intratumoural de novo steroidogenesis as well as to increased expression of cholesterol uptake and synthesis proteins. 6,19 We therefore hypothesized that simvastatin treatment may delay castration-resistant prostate cancer (CRPC) progression by blocking cellular cholesterol synthesis and therefore reducing de novo steroidogenesis.…”

Mechanistic Study of Inhibitory Effects of Metformin and Atorvastatin in Combination on Prostate Cancer Cells <i>in Vitro</i> and <i>in Vivo</i>

“…This combination inhibited the progression of androgen-dependent LNCaP tumors to androgen independence and the growth of androgen-independent PC-3 prostate tumors in severe combined immunodeficient (SCID) mice more effectively than either agent alone. 22,23) Clinically, however, cardiac toxicity is a concern for celecoxib with long-term use increasing the risk of cardiovascular events limiting the development of the combination of atorvastatin and celecoxib in prostate cancer. …”

“…This combination inhibited the progression of androgen-dependent LNCaP tumors to androgen independence and the growth of androgen-independent PC-3 prostate tumors in severe combined immunodeficient (SCID) mice more effectively than either agent alone. 22,23) Clinically, however, cardiac toxicity is a concern for celecoxib with long-term use increasing the risk of cardiovascular events limiting the development of the combination of atorvastatin and celecoxib in prostate cancer. 24) Based on epidemiologic evidence and the preclinical data for metformin and atorvastatin individually in prostate cancer, we assessed the effects of metformin and atorvastatin alone or in combination on cultured prostate cancer cells and in xenograft prostate tumors in SCID mice.…”