4). == Amount 2. which the known degrees of IL-6 and survivin expression were increased when LNCaP tumors became androgen-independent. Treatment of the mice with atorvastatin or celecoxib by itself caused reduction in the degrees of IL-6 and survivin as LNCaP tumors became androgen-independent, Cspg2 but treatment of the mice with a combined BMS-962212 mix of celecoxib and atorvastatin led to a stronger inhibition in the upsurge in IL-6 and survivin expression. Our results indicate that decreases in IL-6 and survivin levels by atorvastatin and celecoxib administration are associated with increased apoptosis in LNCaP cells treated with this drug combination. Ourin vivostudies indicate that this inhibitory effect of a combination of atorvastatin and celecoxib around the progression of androgen-dependent LNCaP xenograft tumors to androgen independence is associated with inhibition of the increase in IL-6 and survivin that occurs when androgen-dependent LNCaP prostate tumors become androgen-independent. Keywords:prostate cancer, IL-6, atorvastatin, celecoxib, xenograft tumor == Introduction == Advanced prostate cancer requires androgen for growth and usually responds to androgen deprivation therapy (14). The disease progresses, however, due to the development of mechanisms of resistance to an androgen-independent state (also referred to as castration-resistant or hormone-refractory) (5,6). Additional therapies such as chemotherapy and newer antiandrogens are only temporarily effective (7,8). Therefore, novel and less toxic approaches for delaying the progression of prostate cancer to androgen independence or delaying the need to start such additional therapies would change the treatment paradigm for managing prostate cancer and be of great benefit for patients. Atorvastatin is usually a widely used statin drug for lowering cholesterol (9,10). Celecoxib is usually a selective cyclooxygenase-2 (COX-2) inhibitor. Previous studies investigating either statin drugs (including atorvastatin) or celecoxib have found that they have anti-prostate cancer activity (1116). However, the effects of these two drugs in combination on prostate cancer progression to androgen independence have not yet been studied. Our previous study found that administration of a combination of atorvastatin and celecoxib was more effective than either agent alone for inhibiting azoxymethane-induced colon carcinogenesis in rats (17). More recently we found that atorvastatin and celecoxib in combination synergistically inhibited the growth and induced apoptosis in cultured prostate cancer cells. This combination inhibited the progression of androgen-dependent LNCaP tumors to androgen independence BMS-962212 and the growth of androgen-independent PC-3 prostate tumors in SCID mice more effectively than either agent alone (18,19). Based on our preclinical studies, we have a phase II clinical trial underway to determine whether a combination of atorvastatin and celecoxib can stabilize or decrease a previously rising PSA in prostate cancer patients who developed biochemical relapse after surgery or radiation therapy. Due to the beneficial effects, the study has now been expanded into a national trial involving multiple cancer centers (NCT01220973). Although BMS-962212 our previousin vitrocell culture andin vivoanimal experiments showed that atorvastatin in combination with celecoxib inhibited androgen-independent growth of prostate cancer cells, the mechanisms for the effect are not clear. Since increased interleukin (IL)-6 has been associated with progression of androgen-dependent prostate cancer to androgen independence (2026), we hypothesized that atorvastatin and BMS-962212 celecoxib in combination would strongly inhibit the increased formation of IL-6 that occurs during the formation of androgen-independent LNCaP prostate tumors and that this inhibition would lead to the suppression of prostate cancer growth. In the present study, we decided the effect of atorvastatin and celecoxib administration alone or in combination on IL-6 levels in androgen-dependent prostate cancer LNCaP cells grown in androgen-deficient medium. We found that culturing LNCaP cells in androgen-depleted (AD) medium increased the levels of IL-6 and survivin, and treatment of these cells with atorvastatin in combination with celecoxib inhibited the increase in IL-6 and survivin. In animal experiments, we found that IL-6 expression was increased in androgen-independent LNCaP tumors. Treatment of the mice with atorvastatin or celecoxib alone inhibited the increase in IL-6 and survivin as LNCaP tumors became androgen-independent, and treatment of the mice with a combination of.