Posts
Docetaxel (Doc) is the gold standard chemotherapy drug used clinically against androgen-independent prostate cancer (AI-PC) and when combined with prednisone results in a small but significant increase in survival. It is likely other drugs combined with Doc will further increase survival, which is the ultimate goal for treating patients with AI-PC. We chose to study the combination of 2-methoxyestradiol (2ME2) with Doc using preclinical models of human prostate cancer cell lines and the FG/Tag transgenic mouse model of AI-PC. Doc and 2ME2 target microtubules, block mitosis, and eventually increase apoptotic cell death. Although the combination of Doc + 2ME2 at first appears counterintuitive, i.e., they both have similar mechanisms targeting microtubules, our results provide interesting insights in preclinical models.
An attractive feature of 2ME2 is its non-toxic effect on normal cells and tissues. Since Doc has been shown to have neuropathy side effects in patients, our interest was to determine if lower, less toxic doses of Doc can be used in combination with 2ME2. Our results in prostate cancer cell lines and in the FG/Tag mice showed that lower doses of Doc combined with 2ME2 blocked mitosis and increased cell death via apoptosis or non-apoptotic mechanisms. Unfortunately, combining higher doses of Doc and 2ME2 provided no additional benefits compared to the single high doses. Clinically, perhaps it will be better to use the low dose combination for less toxicity to normal cells and tissues but still obtain a strong anti-prostate cancer effect.
In our study, the most important prognostic marker for measuring drug response or prostate cancer cell death is the ability of Doc, 2ME2, or their combinations to block mitosis. In FG/Tag mice, the Doc + 2ME2 combination blocked mitosis after one day of treatment. Only the doses of Doc and 2ME2 that resulted in mitotic block had an increase in apoptosis and reduced the weights of the primary prostate tumors. Strikingly, all or most treatments reduced angiogenesis and proliferation but only the doses of 2ME2 and Doc that blocked mitosis increased cell death and reduced tumor weights. Clinically, perhaps a measure of biological response to antimitotic drugs could be measuring cell cycle from biopsies after treatment for a short time.
An aspect of our study that surprised us was that the 2ME2 + Doc combination did not increase apoptosis in PC-3 AI-PC cells, yet there was an effect as measured by the clonogenic assay, which can measure all forms of cell death. We term this death by a non-apoptotic mechanism. It may be that prostate cancer cells like PC-3, which are defective in apoptosis (mutant p53), can still be killed by drugs using a mechanism termed necroptosis or necrosis. Investigating the mechanisms of how antimitotic drugs can increase non-apoptotic cell death in prostate cancer cells like PC-3 is a current interest in the Perez-Stable laboratory. Whereas we were previously frustrated that many drugs had little effect on increasing apoptosis in cells like PC-3, we are now encouraged that they can be killed by non-apoptotic mechanisms that are still intact in the most aggressive advanced prostate cancer cells. Our hope is that a better understanding of these non-apoptotic cell death mechanisms will lead to chemotherapy combinations that will increase survival to a greater extent than the Doc + prednisone combination.
Custom Search
Registration of your site
