Faculty of Pharmacy, Department of Pharmaceutics, University of Kuopio, Finland.
Bone. 2009 Dec;45(6):1153-60. doi: 10.1016/j.bone.2009.08.010. Epub 2009 Aug 21.
Bisphosphonates are potent inhibitors of osteoclast function widely used to treat excessive bone resorption associated, e.g., with bone metastases. They have also antitumor activity. However, it is unclear whether this reflects an indirect effect via inhibition of bone resorption or a direct antitumor effect. Nitrogen-containing bisphosphonates (N-BPs), including zoledronic acid (ZOL), act by inhibiting farnesyl pyrophosphate synthase (FPPS). The mevalonate pathway is blocked and the accumulation of isopentenyl pyrophosphate (IPP) consequently occurs. IPP is conjugated to AMP to form a novel ATP analog (ApppI). The present study was undertaken to clarify whether IPP and/or ApppI has a direct involvement in apoptosis caused by ZOL in different cancer cell lines. There are marked differences in ZOL-induced ApppI formation between different cancer cell lines. On this basis, we selected three cancer cell lines that differ significantly from each other in their ZOL-induced IPP and ApppI accumulation: human estrogen-dependent (MCF7) and estrogen-independent (MDA-MB 436) breast cancer cell lines and a human myeloma cell line (RPMI 8226). The amount of IPP/ApppI correlated with the capacity of cells to undergo apoptosis. Geranylgeraniol (GGOH), an intermediate of mevalonate metabolism, blocks both IPP and ApppI formation and to some degree ZOL-induced apoptosis in a cell line-dependent manner. In addition, lovastatin (LOV), an inhibitor of the enzyme HMGCoA reductase, completely blocks IPP/ApppI formation as determined by mass spectrometry analysis, but enhances apoptosis. In conclusion, the current data suggest that ZOL-induced IPP/ApppI formation can contribute to ZOL-induced apoptosis. This mechanism and the inhibition of protein prenylation, both outcomes of FPPS inhibition in mevalonate pathway, seem to act in concert in ZOL-induced apoptosis in cancer cells.
双膦酸盐是一种强效的破骨细胞功能抑制剂，广泛用于治疗与骨转移等相关的过度骨质吸收。它们还具有抗肿瘤活性。然而，目前尚不清楚这是否反映了通过抑制骨质吸收的间接作用，还是直接的抗肿瘤作用。含氮双膦酸盐（N-BP），包括唑来膦酸（ZOL），通过抑制法呢基焦磷酸合酶（FPPS）起作用。甲羟戊酸途径被阻断，异戊烯焦磷酸（IPP）因此积累。本研究旨在阐明 IPP 和/或 ApppI 是否直接参与不同癌细胞系中 ZOL 诱导的细胞凋亡。不同癌细胞系中 ZOL 诱导的 ApppI 形成存在明显差异。在此基础上，我们选择了三种在 ZOL 诱导的 IPP 和 ApppI 积累方面差异显著的癌细胞系：人雌激素依赖性（MCF7）和雌激素非依赖性（MDA-MB 436）乳腺癌细胞系和人骨髓瘤细胞系（RPMI 8226）。IPP/ApppI 的量与细胞发生凋亡的能力相关。法尼醇（GGOH），甲羟戊酸代谢的中间产物，以细胞系依赖的方式阻断 IPP 和 ApppI 的形成，并在一定程度上阻断 ZOL 诱导的细胞凋亡。此外，洛伐他汀（LOV），HMGCoA 还原酶的抑制剂，通过质谱分析完全阻断 IPP/ApppI 的形成，但增强了凋亡。总之，目前的数据表明，ZOL 诱导的 IPP/ApppI 形成可能有助于 ZOL 诱导的细胞凋亡。这种机制和蛋白质异戊烯化的抑制，都是甲羟戊酸途径中 FPPS 抑制的结果，似乎在 ZOL 诱导的癌细胞凋亡中协同作用。
