Resistance to Finasteride Therapy in Prostate Epithelial Cells
Yinong Niu, M.D., Christian R. Diaz, MD, Wenhua Li, MD, Zongwei Wang, PhD, Aria F. Olumi, M.D..
Massachusetts General Hospital, Boston, MA, USA.
INTRODUCTION: Finasteride, an inhibitor of 5 α-reductase type 2 enzyme, is commonly used for treatment of patients suffering from bladder outlet obstruction secondary to benign prostatic hyperplasia (BPH). Annually, an estimated 3 billion tablets of Finasteride are used by 8.2 million American men for an estimated cost of $2.2 billion. Since many patients are refractory to Finasteride therapy, and some patients may paradoxically develop high grade prostate cancer while on finasteride therapy , we postulate that alternative Finasteride-related mechanisms of actions may exist which are poorly understood.
METHODS: Immunohistochemistry was performed to determine the relative expression level of 5-α reductase in human prostate tissues. RT-PCR was carried out to evaluate the 5-α reductase mRNA transcription in initiated and malignant prostate epithelial cells. BPH-1 and LNCaP cells were grown alone or in coculture transwells with fibroblasts in the presence or absence of Finasteride. Cell viability (MTS), phosphorylated Akt and phosphorylated ERK1/2 (Western blot) were evaluated.
RESULTS: In benign human prostate tissue, 5-α reductase type 2 was expressed at variable levels, and 5-α reductase 2 mRNA transcription was not detected in several initiated and malignant prostate epithelial cells. BPH-1 and LNCaP cells were resistant to Finasteride at very high doses. In addition, after Finasteride treatment, we found that phosphorylated Akt and phosphorylated ERK1/2 were upregulated, two molecules which are commonly responsible for proliferation and tumor progression in prostate cancer. However, when BPH-1 and LNCaP cells were grown in co-cocultures with fibroblasts, Finasteride’s pro-apoptotic function was restored and it induced cell death in 30% of cells (p<0.05). In contrast to mono-cultures, expression of p-Akt and p-ERK1/2 were significantly repressed in co-cultures.
CONCLUSIONS: Some prostate epithelial cells may be resistant to Finasteride due to lack of expression of 5 α reductase type 2 gene, leading to activation of molecular pathways that promote prostate epithelial proliferation. Fibroblasts restore the pro-apoptotic function of Finasteride in prostate epithelial cells, suggesting that the fibroblastic microenvironment plays an important role in the therapeutic effects of Finasteride. These studies have significant implications in the current therapeutic strategies for men with BPH and chemoprevention for prostate cancer, and can lead the way to developing novel compounds for patients who are refractory to Finasteride.