Microtubule Control of Metabolism in Prostate Cancer

摘要

The current standard chemotherapy treatment for metastatic castrate- resistant prostate cancer is the microtubule-stabilizing drug, docetaxel, but the median increase in survival is limited to several months. One avenue for improved treatment outcome is to find agents that increase cell death when combined with docetaxel. Here we tested whether two metabolic inhibitors, metformin or 2- deoxy-glucose, function synergistically with docetaxel to block prostate cancer cell proliferation. LNCaP and PC-3 prostate cancer cell lines were incubated in drugs targeting the microtubule cytoskeleton (docetaxel, paclitaxel, or nocodazole) singly, or in combination with metabolic inhibitors (metformin or 2-deoxy-glucose). Microtubule-targeted drugs, which either stabilize or destabilize microtubules, acted synergistically with either metformin or 2-deoxy-glucose to block cell proliferation and cause cell death in both prostate cancer cell lines tested. Synergy was consistently calculated at the ED50 for each drug, but for many drug combinations, the combination index shifted toward antagonism at higher drug doses. Microtubule stabilizers (docetaxel, paclitaxel) showed greater synergy than did a microtubule destabilizer (nocodazole) when combined with either of the metabolic inhibitor tested. The more-than-additive cell killing measured in two commonly used prostate cancer lines treated with a mixture of microtubule-targeted drugs and metabolic inhibitors indicates that these drug combinations could provide more effective tumor cell killing than either drug alone.