Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics

Chopra, Puneet; Sethi, Gautam; Dastidar, Sunanda G.; Ray, Abhijit

doi:10.1517/13543780903483191

Cited by 102 publications

(89 citation statements)

References 94 publications

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“…PLK1 is known to play a pivotal role in the regulation of mitotic entry, chromosome segregation, and cytokinesis (Lowery et al 2005). Owing to the strong association of this kinase with cell proliferation and elevated expression in a variety of tumors, including colon tumors, inhibition of PLK1 function has been suggested as a potential alternative for cancer therapy (Chopra et al 2010). Moreover, depletion of PLK1 is associated with the decrease in cell viability and induction of apoptosis in various cancerous cells (Liu and Erikson 2003).…”

Section: Discussionmentioning

confidence: 99%

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

et al. 2012

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In this work, the effect of rosemary extracts rich on polyphenols obtained using pressurized fluids was investigated on the gene expression of human SW480 and HT29 colon cancer cells. The application of transcriptomic profiling and functional enrichment analysis was done via two computational approaches, Ingenuity Pathway Analysis and Gene Set Enrichment Analysis. These two approaches were used for functional enrichment analysis as a previous step for a reliable interpretation of the data obtained from microarray analysis. Reverse transcription quantitative-PCR was used to confirm relative changes in mRNA levels of selected genes from microarrays. The selection of genes was based on their expression change, adjusted p value, and known biological function. According to genome-wide transcriptomics analysis, rosemary polyphenols altered the expression of *4 % of the genes covered by the Affymetrix Human Gene 1.0ST chip in both colon cancer cells. However, only *18 % of the differentially expressed genes were common to both cell lines, indicating markedly different expression profiles in response to the treatment. Differences in induction of G2/ M arrest observed by rosemary polyphenols in the two colon adenocarcinoma cell lines suggest that the extract may be differentially effective against tumors with specific mutational pattern. From our results, it is also concluded that rosemary polyphenols induced a low degree of apoptosis indicating that other multiple signaling pathways may contribute to colon cancer cell death.

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Section: Discussionmentioning

confidence: 99%

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

et al. 2012

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“…Indeed, ENMD-2076 is currently undergoing phase I trial [18]. Whether Plk1 inhibitors or aurora kinase inhibitors will ultimately prove most useful in the treatment of MM will depend on the efficacy with which they kill tumor cells and the levels of patient tolerance to the drug [32].…”

Section: Discussionmentioning

confidence: 99%

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Stewart

Kishikova

Powell

et al. 2011

Experimental Hematology

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Objective. Polo-like kinase 1 (Plk1) is a regulator of the cell cycle that has been implicated in the pathology of many cancers. We have investigated whether this kinase plays a role in multiple myeloma (MM) using the Plk1 inhibitor BI 2536. Materials and Methods. We have used six MM cell lines and six patient-derived samples to determine the effects of the Plk1 inhibitor, BI 2536, on cell viability, apoptosis, and cytokinesis. We have also examined the effect of the microenvironment on these parameters and the effects of BI 2536 in combination with other antimyeloma agents. Results. We show that MM cell lines and patient samples express PLK1 and that cell death by apoptosis occurs when Plk1 is inhibited. Cells treated with BI 2536 accumulate in the G 2 /M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells. Conclusions. Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Our data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma. Ó

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“…7 The inhibition of this kinase by different methods has been shown to cause cell cycle arrest and to increase apoptosis in several models. 8 Moreover, depletion by siRNA has recently been reported to radiosensitize rectal and head-and-neck squamous carcinoma cells. 9,10 Recently, BI 2536, an ATP-competitor dihydropteridinone, has been shown to efficiently inhibit the activity of PLK1.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

Pezuk

Brassesco

Morales

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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Despite efforts to improve surgical, radiologic, and chemotherapeutic strategies, the outcome of patients with glioblastoma (GBM) is still poor. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays key roles in cell cycle control and has been associated with tumor growth and prognosis. Here, we aimed at testing the radiosensitizing effects of the PLK1 inhibitor BI 2536 on eight GBM cell lines. For cell cycle analysis, T98G, U251, U343 MG-a, LN319, SF188, U138 MG, and U87 MG cell lines were treated with 10, 50, or 100 nM of BI 2536 for 24 hours. In addition, cell cultures exposed to BI 2536 50 nM for 24 hours were irradiated with c-rays from 60 Cobalt source at final doses of 2, 4, and 6 Gy. Combinatorial effects were evaluated through proliferation and clonogenic capacity assays. Treatment with BI 2536 caused mitotic arrest after 24 hours, and increased apoptosis in GBM cells. Moreover, our results demonstrate that pretreatment with this drug sensitized six out of seven GBM cell lines to different doses of c-irradiation as shown by decreased growth and abrogation of colony-formation capacity. Our data suggest that PLK1 blockage has a radiosensitizing effect on GBM, which could improve treatment strategies for this devastating tumor.

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Polo-like kinase inhibitors: an emerging opportunity for cancer therapeutics

Abstract: The current literature about Plk1 inhibitors and knockout studies favor Plk1 inhibition as a potential antitumor therapy.

Cited by 102 publications

References 94 publications

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

Effect of rosemary polyphenols on human colon cancer cells: transcriptomic profiling and functional enrichment analysis

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Inhibition of Polo-Like Kinase 1 Induces Cell Cycle Arrest and Sensitizes Glioblastoma Cells to Ionizing Radiation

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