Elsevier

Biochemical Pharmacology

Volume 86, Issue 6, 15 September 2013, Pages 703-710
Biochemical Pharmacology

Commentary
Antimitotic drugs in cancer chemotherapy: Promises and pitfalls

https://doi.org/10.1016/j.bcp.2013.07.010Get rights and content

Abstract

Cancer cells usually display higher proliferation rates than normal cells. Some currently used antitumor drugs, such as vinca alkaloids and taxanes, act by targeting microtubules and inhibiting mitosis. In the last years, different mitotic regulators have been proposed as drug target candidates for antitumor therapies. In particular, inhibitors of Cdks, Chks, Aurora kinase and Polo-like kinase have been synthesized and evaluated in vitro and in animal models and some of them have reached clinical trials. However, to date, none of these inhibitors has been still approved for use in chemotherapy regimes. We will discuss here the most recent preclinical information on those new antimitotic drugs, as well as the possible molecular bases underlying their lack of clinical efficiency. Also, advances in the identification of other mitosis-related targets will be also summarized.

Section snippets

Currently used antimitotic drugs in cancer chemotherapy

Although cell behavior is quite heterogeneous among different types of tumors, and even among patients, a frequent feature of tumor cells is the increased rate of proliferation when compared to normal cells. This capacity is usually a consequence of unresponsiveness to growth inhibitory signals, self-sufficiency in growth factors or both [1]. Moreover, some of the compounds used in cancer chemotherapy that were initially identified in unbiased screening have lately been shown to act by blocking

Cdks and Chks inhibitors

Cyclin-dependent kinases and checkpoint kinases control transitions during cell cycle phases (Fig. 1). Cyclin-dependent kinase 1 (Cdk1) regulates cell entry into mitosis by phosphorylating several proteins that orchestrate different aspects of cell division, such as chromosome condensins, nuclear lamins, centrosome and microtubule-associated proteins and Golgi matrix proteins. Other Cdks are activated at different stages of cell cycle and their activity is required for G1/S or G2/M transitions.

Chk and Cdk inhibitors

First antimitotic compounds to enter clinical trials were flavopiridol and UCN-01, in the late 90s. Since then, at least 60 trials of flavopiridol and UCN-01 have been conducted (www.clinicaltrials.gov). In some cases combinations with other compounds were evaluated (Table 1). These combinations included agents that induce DNA damage (oxaliplatin, cisplatin, carboplatin, doxorubicin, irinotecan, mitoxantrone), nucleoside analogs (gemcitabine, fluorouracil, cytarabine, fludarabine),

The pitfalls: which could be the molecular basis for the failure of antimitotics?

Despite promising preclinical results, many of the selected antimitotic drugs have not shown to be very effective in clinical trials. Many can be the reasons for this limited activity. In some cases, cell resistance caused to overexpression of efflux pumps can prevent accumulation of the drug inside tumor cells. A recent work has demonstrated that the low activity of the Plk1 inhibitor BI2536 could be explained by its low accumulation inside tumors [55]. However, although some of the new

Concluding remarks

So far, novel antimitotic agents have shown limited efficacy in clinical trials and classical antimicrotubule drugs are still the best approach in targeting mitosis to fight cancer. Nevertheless, several clinical trials are still ongoing and could yield better results, especially those combining antimitotics with other antitumoral drugs. The development of bifunctional inhibitors that combine the high binding affinity of ATP inhibitors with the specificity of competitive inhibitors has been

Acknowledgements

This work was supported by grants from Ministerio de Ciencia e Innovación (SAF2010-14920) and Gobierno de Aragón/Fondo Social Europeo (B16).

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