Inhibition of IL-6 expression in LNCaP prostate cancer cells by a combination of atorvastatin and celecoxib.

Abstract

In the present study, we investigated the effect of a combination of atorvastatin and celecoxib on the formation of interleukin (IL)-6, a cytokine that is increased during the progression of LNCaP tumors from androgen dependence to androgen independence. Culturing LNCaP cells in androgen‑depleted (AD) medium increased the levels of IL-6 and survivin, and treatment of the cells in AD medium with a combination of atorvastatin and celecoxib strongly inhibited the increase in IL-6 and survivin which is one of the downstream targets of the IL-6 signaling pathway. Addition of recombinant IL-6 partially abrogated the combined effect of atorvastatin and celecoxib on apoptosis in LNCaP cells cultured in AD medium. In SCID mice, we found that the levels of IL-6 and survivin expression were increased when LNCaP tumors became androgen-independent. Treatment of the mice with atorvastatin or celecoxib alone caused decrease in the levels of IL-6 and survivin as LNCaP tumors became androgen-independent, but treatment of the mice with a combination of celecoxib and atorvastatin resulted in a much stronger inhibition in the increase 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. Our in vivo studies indicate that the inhibitory effect of a combination of atorvastatin and celecoxib on 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.

• Authors: Huaqian Wang, Xiao-Xing Cui, Susan Goodin, Ning Ding, Jeremiah Van Doren, Zhiyun Du, Mou-Tuan Huang, Yue Liu, Xiaodong Cheng, Robert S Dipaola, Allan H Conney, Xi Zheng
• Journal: Oncology reports (Oncol Rep) Vol. 31 Issue 2 Pg. 835-41 (Feb 2014) ISSN: 1791-2431 [Electronic] Greece
• PMID: 24296978 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• Cyclooxygenase 2 Inhibitors
• Enzyme Inhibitors
• Heptanoic Acids
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• IL6 protein, human
• Inhibitor of Apoptosis Proteins
• Interleukin-6
• Pyrazoles
• Pyrroles
• Sulfonamides
• Survivin
• Atorvastatin
• Celecoxib

Topics

• Animals
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Atorvastatin
• Castration
• Celecoxib
• Cell Survival
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Disease Progression
• Enzyme Inhibitors (pharmacology)
• Heptanoic Acids (pharmacology)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Inhibitor of Apoptosis Proteins (biosynthesis)
• Interleukin-6 (biosynthesis, pharmacology)
• Male
• Mice
• Mice, SCID
• Prostatic Neoplasms (drug therapy)
• Pyrazoles (pharmacology)
• Pyrroles (pharmacology)
• Sulfonamides (pharmacology)
• Survivin
• Xenograft Model Antitumor Assays