Effect of Bisphosphonates on Anticancer Activity in Prostate Cancer Cells

Bisphosphonates are widely used to treat for osteoporosis and have recently been suggested to be effective in preventing tumor metastasis to the bone. One of the mechanisms underlying metastasis inhibition by bisphosphonates has been explained on the basis of the direct effects of these drugs on cancer cells in the bone microenvironment. Here we have focused on the effect of bisphosphonates on anticancer activity in prostate cancer cells because these cancer cells frequently metastasize to the bone. We found that nitrogen-containing bisphosphonates induced apoptosis and inhibited invasion in prostate cancer PC-3 cells. Bisphosphonate pretreatment was found to enhance cell death induced by anticancer drugs. The expression of the apoptosis- or invasion- related factors, bcl-2, protein kinase C (PKC), aminopeptidase-N (AP-N), and urokinase-type plasminogen activator (uPA) decreased on treatment with nitrogen-containing bisphosphonates. The molecular mechanisms underlying the decrease in bcl-2, AP-N, and uPA expression involved suppression of protein prenylation through inhibition of the mevalonate pathway. These findings have implications with respect to understanding the mechanisms underlying the suppressive effect of bisphosphonates on bone metastasis of prostate cancer.