Targeting mitosis by
taxanes is one of the most common chemotherapeutic approaches in various malignant solid
tumors, but
cancer cells may survive
antimitotic treatment with attainable in vivo concentrations due to mitotic slippage with a residual activity of the
ubiquitin ligase anaphase-promoting complex (APC/C) and a continuous slow
ubiquitin-
proteasome-dependent
cyclin B-degradation leading to mitotic exit. Therefore, blocking
cyclin B-proteolysis via additional
proteasome (PI) or APC/C-inhibition may have the potential to enhance
tumor cell eradication by inducing a more robust mitotic block and mitotic cell death. Here, we analyzed this approach in different cell lines and more physiological patient-derived xenografts (PDX) from lung and
breast cancer. The sequential combination of
paclitaxel with the PI
bortezomib enhanced cell death, but in contrast to the hypothesis during interphase and not in mitosis in both lung and
breast cancer. APC/C-inhibition alone or in sequential combination with
paclitaxel led to strong mitotic cell death in
lung cancer. But in
breast cancer, with high expression of the anti-apoptotic regulator Mcl-1, cell death in interphase was induced. Here, combined APC/C- and Mcl-1-inhibition with or without
paclitaxel was highly lethal but still resulted in interphase cell death. Taken together, the combination of
antimitotic agents with a clinically approved PI or inhibitors of the APC/C and Mcl-1 is a promising approach to improve treatment response in different solid
tumors, even though they act entity-dependent at different cell cycle phases.