Future prospects for mitosis-targeted antitumor therapies

Valle, Alfonso; Reina-Ortiz, Chantal; Benedi, Andrea; Anel, Alberto; Naval, Javier; Marzo, Isabel

doi:10.1016/j.bcp.2021.114655

Cited by 33 publications

(30 citation statements)

References 173 publications

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Section: Discussionmentioning

confidence: 99%

“…Some other compounds acting as Eg5 inhibitors are currently utilized as antitumor agents in phase I and II clinical trials, and their good tolerability and lack of neurotoxicity have been reported [37]. When used in monotherapy, these agents demonstrated a limited clinical response, while their effect was more significant when used in combination with other antitumor drugs, resulting in important enhancements of both drug activities [37,38]. Another interesting point is that K858 induces mitotic cell death exclusively in cancer cells and not in normal nontransformed epithelial cells [19], as our group had previously shown in HaCaT cells and immortalized human keratinocytes [21]; this is explained by the fact that the efficacy of K858 is mainly directed toward cells with a high rate of Eg5 kinesin expression.…”

Section: Discussionmentioning

confidence: 99%

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The kinesin Eg5 inhibitor K858 exerts antiproliferative and proapoptotic effects and attenuates the invasive potential of head and neck squamous carcinoma cells

et al. 2022

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Our group recently demonstrated that K858, an inhibitor of motor kinesin Eg5, has important antiproliferative and apoptotic effects on breast cancer, prostatic cancer, melanoma and glioblastoma cells. Since high levels of kinesin Eg5 expression have been correlated with a poor prognosis in laryngeal carcinoma, we decided to test the anticancer activity of K858 toward this tumor, which belongs to the group of head and neck squamous cell carcinomas (HNSCCs). These cancers are characterized by low responsiveness to therapy. The effects of K858 on the proliferation and assembly of mitotic spindles of three human HNSCC cell lines were studied using cytotoxicity assays and immunofluorescence for tubulin. The effect of K858 on the cell cycle was analyzed by FACS. The expression levels of cyclin B1 and several markers of apoptosis and invasion were studied by Western blot. Finally, the negative regulation of the malignant phenotype by K858 was evaluated by an invasion assay. K858 inhibited cell replication by rendering cells incapable of developing normal bipolar mitotic spindles. At the same time, K858 blocked the cell cycle in the G2 phase and induced the accumulation of cytoplasmic cyclin B and, eventually, apoptosis. Additionally, K858 inhibited cell migration and attenuated the malignant phenotype. The data described confirm that kinesin Eg5 is an interesting target for new anticancer strategies and suggest that this compound may be a powerful tool for an alternative therapeutic approach to HNSCCs.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

The kinesin Eg5 inhibitor K858 exerts antiproliferative and proapoptotic effects and attenuates the invasive potential of head and neck squamous carcinoma cells

et al. 2022

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“…Discodermolide, isolated from sponges ( Discodermia dissolute ), is the most promising natural product discovered to date. Discodermolide has been shown to be more effective than taxol and is being tested for the treatment of solid tumors ( 107 , 108 ).…”

Section: Research Progress On Marine Bioactive Compounds In Oral Healthmentioning

confidence: 99%

Marine Bioactive Compounds as Nutraceutical and Functional Food Ingredients for Potential Oral Health

et al. 2021

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Oral diseases have received considerable attention worldwide as one of the major global public health problems. The development of oral diseases is influenced by socioeconomic, physiological, traumatic, biological, dietary and hygienic practices factors. Currently, the main prevention strategy for oral diseases is to inhibit the growth of biofilm-producing plaque bacteria. Tooth brushing is the most common method of cleaning plaque, aided by mouthwash and sugar-free chewing gum in the daily routine. As the global nutraceutical market grows, marine bioactive compounds are becoming increasingly popular among consumers for their antibacterial, anti-inflammatory and antitumor properties. However, to date, few systematic summaries and studies on the application of marine bioactive compounds in oral health exist. This review provides a comprehensive overview of different marine-sourced bioactive compounds and their health benefits in dental caries, gingivitis, periodontitis, halitosis, oral cancer, and their potential use as functional food ingredients for oral health. In addition, limitations and challenges of the application of these active ingredients are discussed and some observations on current work and future trends are presented in the conclusion section.

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“…A number of elements both within and outside the cell precisely regulate the intricate and delicate process of mitosis. , Mitosis disorder is related to the occurrence and development of many diseases, especially tumors . Some mitosis-associated protein kinases, including cyclin-dependent kinases (CDKs), aurora kinases (AURKs), NIMA-related kinases (NEKs), and polo-like kinases (PLKs), have been proved to have distinctive and crucial functions in cell division, and some of these are the subject of chemotherapeutic drug research.…”

Section: Introductionmentioning

confidence: 99%

“…Some mitosis-associated protein kinases, including cyclin-dependent kinases (CDKs), aurora kinases (AURKs), NIMA-related kinases (NEKs), and polo-like kinases (PLKs), have been proved to have distinctive and crucial functions in cell division, and some of these are the subject of chemotherapeutic drug research. Studies have found that one of the most effective therapeutic approaches for cancer involves blocking cell division by inhibiting mitosis. − Thus, any one of the mitosis-associated protein kinases is considered a potential target for cancer intervention and treatment.…”

Section: Introductionmentioning

confidence: 99%

Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia

et al. 2023

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Recent studies demonstrate that PLK4 has emerged as a therapeutic target for the treatment of multiple cancers owing to its indispensable role in cell division. Herein, starting from previously identified effective compound CZS-034, based on rational drug design strategies, tyrosine kinase receptor A (TRKA) selectivity- and metabolic stability-guided structure–activity relationship (SAR) exploration were carried out to discover a highly potent (IC50 = 2.6 nM) and selective (SF = 1054.4 over TRKA) PLK4 inhibitor B43 (CZS-241) with acceptable human liver microsome stability (t 1/2 = 31.5 min). Moreover, compound B43 effectively inhibited leukemia cells in 29 tested cell lines, especially chronic myeloid leukemia (CML) cell lines K562 and KU-812. Pharmacokinetic characteristics revealed that compound B43 possessed over 4 h of half-life and 70.8% bioavailability in mice. In the K562 cells xenograft mouse model, a 20 mg/kg/day dosage treatment obviously suppressed tumor progression. As a potential and novel PLK4-targeted candidate drug for CML, compound B43 is undergoing extensive preclinical safety evaluation.

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Future prospects for mitosis-targeted antitumor therapies

Cited by 33 publications

References 173 publications

The kinesin Eg5 inhibitor K858 exerts antiproliferative and proapoptotic effects and attenuates the invasive potential of head and neck squamous carcinoma cells

The kinesin Eg5 inhibitor K858 exerts antiproliferative and proapoptotic effects and attenuates the invasive potential of head and neck squamous carcinoma cells

Marine Bioactive Compounds as Nutraceutical and Functional Food Ingredients for Potential Oral Health

Discovery of CZS-241: A Potent, Selective, and Orally Available Polo-Like Kinase 4 Inhibitor for the Treatment of Chronic Myeloid Leukemia

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