Abstract
Interfering with mitosis for cancer treatment is an old concept that has proven highly successful in the clinics. Microtubule poisons are used to treat patients with different types of blood or solid cancer since more than 20 years, but how these drugs achieve clinical response is still unclear. Arresting cells in mitosis can promote their demise, at least in a petri dish. Yet, at the molecular level, this type of cell death is poorly defined and cancer cells often find ways to escape. The signaling pathways activated can lead to mitotic slippage, cell death, or senescence. Therefore, any attempt to unravel the mechanistic action of microtubule poisons will have to investigate aspects of cell cycle control, cell death initiation in mitosis and after slippage, at single‐cell resolution. Here, we discuss possible mechanisms and signaling pathways controlling cell death in mitosis or after escape from mitotic arrest, as well as secondary consequences of mitotic errors, particularly sterile inflammation, and finally address the question how clinical efficacy of anti‐mitotic drugs may come about and could be improved.
Highlights
Anti-mitotic drugs, including vinca alkaloids or taxanes and derivatives that target microtubules, are used successfully in the clinics to treat multiple types of cancer but negative side effects, such as neurotoxicity and frequent drug resistance, limit their therapeutic use [1]. This has led to the development of second-generation compounds, often referred to as “mitotic blockers”, that aim to interfere with proper spindle formation, chromosome segregation, and/or mitotic exit, for example, by targeting microtubule motor proteins, including kinesins KIF11 or CENP-E, polo-like kinase (PLK)1, or Aurora A kinase, as well as the anaphase-promoting complex or cyclosome (APC/C) E3-ligase complex, respectively
The feature of promoting chromosomal instability (CIN) and aneuploidy upon drug treatment appears as a double-edged sword: On the one hand, aneuploidy itself will have a negative impact on the cellular fitness, but on the other hand, it harbors the inherent problem that therapy exploiting these features will be selecting for complex karyotypes that promote cell survival and aneuploidy tolerance
The death of mitotically arrested cells is controlled predominantly by the B-cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL2) family that comprises a set of anti-apoptotic molecules, including BCL2, BCLXL, MCL1, BCLW, and BFL1, their antagonists of the “BH3-only” subgroup, such as BIM, BID, PUMA, NOXA, BAD, and BMF, as well as the central regulators of mitochondrial outer membrane permeabilization (MOMP), BAX, and BAK1
Summary
Anti-mitotic drugs, including vinca alkaloids or taxanes and derivatives that target microtubules, are used successfully in the clinics to treat multiple types of cancer but negative side effects, such as neurotoxicity and frequent drug resistance, limit their therapeutic use [1] This has led to the development of second-generation compounds, often referred to as “mitotic blockers”, that aim to interfere with proper spindle formation, chromosome segregation, and/or mitotic exit, for example, by targeting microtubule motor proteins, including kinesins KIF11 or CENP-E, polo-like kinase (PLK), or Aurora A kinase, as well as the APC/C E3-ligase complex, respectively. In support of the competing network model, overexpression of anti-apoptotic proteins, such as B-cell CLL/lymphoma 2 (BCL2), can prevent death of mitotically arrested cells long enough for cyclin B levels to drop below a threshold for slippage. In the absence of p53, or a forced reduction in arrest proficiency by INK4a or p21 RNAi, the outcome becomes less clear and cells can continue to cycle and
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