Abstract
The quest to develop novel antimitotic chemotherapy agents has led to the generation of several small molecule inhibitors targeting Plk1, a protein kinase required for multiple aspects of cell division. Previous studies have shown that upon exposure to Plk1 inhibitors, cells enter mitosis, delay briefly in prophase and then arrest in mitosis due to an inability to undergo centrosome separation. Here, we show that four different classes of Plk1 inhibitor block mitotic entry in several cancer cell lines and non-transformed RPE-1 cells. The proportion of cells that arrest in G2 is cell line and concentration dependent, and is subject to non-genetic heterogeneity. Following inhibitor washout, the G2 block is alleviated and cells enter mitosis but then fail to complete cell division indicating that most Plk1 inhibitors are not fully reversible. An exception is CYC140844; in contrast to five other inhibitors examined here, this novel Plk1 inhibitor is fully reversible. We discuss the implications for developing Plk1 inhibitors as chemotherapy agents and research tools.
Highlights
Antimitotic agents, including the taxanes, are used extensively to treat breast and ovarian cancer as well as various leukemias [1]
When asynchronous populations of various cell lines are exposed to Plk1 inhibitors, cells undergo mitotic arrest exhibiting the prototypical “polo” phenotype that arises when centrosomes fail to separate [27,28,29,30]
We show here a paradoxical relationship between Plk1 inhibitor concentration and the induction of cell death, whereby lower concentrations are more effective at inducing apoptosis
Summary
Antimitotic agents, including the taxanes, are used extensively to treat breast and ovarian cancer as well as various leukemias [1]. All clinically relevant antimitotic agents inhibit microtubule dynamics, and while this has potential to impact multiple aspects of tumor biology, microtubule function is important during cell division when the mitotic spindle apparatus is assembled [2, 3]. Patient responses to antimitotic agents are unpredictable, resistance is common, and toxicity in the form of neuropathies can be problematic [6,7,8]. To address these limitations, a plethora of second generation antimitotic agents have been developed, including excellent drugs targeting mitotic kinesins, such as Eg5/KSP and Cenp-E, and mitotic kinases, such as Plk, Aurora A and Aurora B [9,10,11]. We set out to examine cell fate in response to Plk inhibitors using a single-cell-based time-lapse microscopy approach that previously revealed extensive intra- and interline variation when cancer cells are exposed to microtubule toxins [26]
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