Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Gutteridge, Rosie Elizabeth Ann; Ndiaye, Mary A.; Liu, Xiaoqi; Ahmad, Nihal

doi:10.1158/1535-7163.mct-15-0897

Cited by 328 publications

(301 citation statements)

References 92 publications

(117 reference statements)

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“…However, so far, the small molecule inhibitors of PLK1 including BI2536 have not achieved a satisfactory therapeutic effect in clinical trials [138]. One main reason is the dose-limiting toxicities of PLK1 inhibitors [10].…”

Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

348

269

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Polo-like kinase 1 (PLK1) plays an important role in the initiation, maintenance, and completion of mitosis. Dysfunction of PLK1 may promote cancerous transformation and drive its progression. PLK1 overexpression has been found in a variety of human cancers and was associated with poor prognoses in cancers. Many studies have showed that inhibition of PLK1 could lead to death of cancer cells by interfering with multiple stages of mitosis. Thus, PLK1 is expected to be a potential target for cancer therapy. In this article, we examined PLK1’s structural characteristics, its regulatory roles in cell mitosis, PLK1 expression, and its association with survival prognoses of cancer patients in a wide variety of cancer types, PLK1 interaction networks, and PLK1 inhibitors under investigation. Finally, we discussed the key issues in the development of PLK1-targeted cancer therapy.

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Section: Plk1 and Human Cancermentioning

confidence: 99%

PLK1, A Potential Target for Cancer Therapy

Liu

Sun

Wang

2017

Translational Oncology

348

269

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“…As shown for energy depletion, volasertib did not significantly interfere with the increase of cytosolic Ca 2+ activity and did not modify ceramide formation. In theory, eryptosis could involve Pololike kinase 1 (Plk1), wich is specifically inhibited by volasertib [1][2][3][4][5][6][7][8][9][10]. However, the effects of volasertib are not restricted to the polo-like kinase 1 (Plk1) isoform but the substance inhibits, albeit to a lesser extent, the isoforms Plk2 and Plk3 [8].…”

Section: Discussionmentioning

confidence: 99%

“…The Polo-like kinase 1 (Plk1) inhibitor volasertib (BI6727) [1][2][3][4][5][6][7][8][9][10] has been successfully used in preclinical and clinical studies for the treatment of several malignancies [1,2,[7][8][9][10][11][12][13][14] including acute myeloid leukaemia (AML) [2-9, 11, 15-20]. Volasertib is in part effective by triggering suicidal death or apoptosis of tumor cells [1,7].…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Suicidal Erythrocyte Death by Volasertib

Bhuyan

Haque

Sahu

et al. 2017

Cell Physiol Biochem

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Background/Aims: The Polo-like kinase 1 (Plk1) inhibitor volasertib is used in the treatment of malignancy. Volasertib is partially effective by triggering suicidal death or apoptosis of tumor cells. Similar to apoptosis of nucleated cells, erythrocytes may enter suicidal cell death or eryptosis, which is characterized by cell membrane scrambling with phosphatidylserine translocation to the cell surface and by cell shrinkage. Stimulators of eryptosis include energy depletion, hyperosmotic shock, oxidative stress and excessive increase of cytosolic Ca 2+ activity ([Ca 2+ ] i ). The present study explored, whether volasertib impacts on eryptosis. Methods: Human erythrocytes have been exposed to energy depletion (glucose withdrawal for 48 hours), hyperosmotic shock (addition of 550 mM sucrose for 6 hours), oxidative stress (addition of 0.3 mM tert-butylhydroperoxide [tBOOH] for 50 min) or Ca 2+ ionophore ionomycin (1 µM for 60 min) in absence and presence of volasertib (0.5-1.5 µg/ml) and flow cytometry was employed to quantify phosphatidylserine exposure at the cell surface from annexin-Vbinding, cell volume from forward scatter, [Ca 2+ ] i from Fluo3 fluorescence, reactive oxygen species from 2',7'-dichlorodihydrofluorescein diacetate (DCFDA) fluorescence and ceramide abundance utilizing antibodies. For comparison, annexin-V-binding and forward scatter were determined following a 48 hours exposure of human leukemic K562 cells in RPMI-1640 medium to volasertib. Results: Treatment with volasertib alone did not significantly modify annexin-V-binding or forward scatter in mature erythrocytes. Energy depletion, hyperosmotic shock, oxidative stress and ionomycin, all markedly and significantly increased the percentage of annexin-V-binding erythrocytes, and decreased the forward scatter. Volasertib significantly blunted the effect of energy depletion and hyperosmotic shock, but not of oxidative stress and ionomycin on annexin-V-binding. Volasertib did not significantly influence the effect of any maneuver on forward scatter. In K562 cells, volasertib enhanced annexin-V-binding and

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“…The PLK1 inhibitor volasertib has shown considerable promise in clinical studies of AML, having reached phase III trials (21,22). Other PLK1 inhibitors, including GSK461364A, TKM-080301, GW843682, purpurogallin and poloxin are in early clinical development (23). …”

Section: Introductionmentioning

confidence: 99%

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

Tao

et al. 2017

Oncology Reports

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Decreased autophagy is accompanied by the development of a myeloproliferative state or acute myeloid leukemia (AML). AML cells are often sensitive to autophagy-inducing stimuli, prompting the idea that targeting autophagy can be useful in AML cytotoxic therapy. AML NB4 cells overexpressing microtubule-associated protein 1 light chain 3-green fluorescent protein were screened with 69 inhibitors to analyze autophagy activity. AML cells were treated with the polo-like kinase 1 (PLK1) inhibitors RO3280 and BI2536 before autophagy analysis. Cleaved LC3 (LC3-II) and the phosphorylation of mammalian target of rapamycin (mTOR), adenosine monophosphate-activated protein kinase, and Unc-51-like kinase 1 during autophagy was detected with western blotting. Autophagosomes were detected using transmission electron microscopy. Several inhibitors had promising autophagy inducer effects: BI2536, MLN0905, SK1-I, SBE13 HCL and RO3280. Moreover, these inhibitors all targeted PLK1. Autophagy activity was increased in the NB4 cells treated with RO3280 and BI2536. Inhibition of PLK1 expression in NB4, K562 and HL-60 leukemia cells with RNA interference increased LC3-II and autophagy activity. The phosphorylation of mTOR was reduced significantly in NB4 cells treated with RO3280 and BI2536, and was also reduced significantly when PLK1 expression was downregulated in the NB4, K562 and HL-60 cells. We demonstrate that PLK1 inhibition induces AML cell autophagy and that it results in mTOR dephosphorylation. These results may provide new insights into the molecular mechanism of PLK1 in regulating autophagy.

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Plk1 Inhibitors in Cancer Therapy: From Laboratory to Clinics

Cited by 328 publications

References 92 publications

PLK1, A Potential Target for Cancer Therapy

PLK1, A Potential Target for Cancer Therapy

Inhibition of Suicidal Erythrocyte Death by Volasertib

Inhibiting PLK1 induces autophagy of acute myeloid leukemia cells via mammalian target of rapamycin pathway dephosphorylation

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