Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK)

Uckun, Fatih M.; Dıbırdık, İlker; Qazi, Sanjive; Vassilev, Alexei; Ma, Hong; Chen, Mao; Benyumov, Alexey O.; Emami, Katayoon H.

doi:10.1016/j.bmc.2006.10.050

Cited by 54 publications

(64 citation statements)

References 37 publications

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“…Moreover, PLK1 expression levels have been observed to correlate with the metastatic potential of tumors (29) and with the prognosis of cancer patients (28,(30)(31)(32). Depletion or specific inhibition of PLK1 results in reduced survival of various types of cancer cells in vitro and inhibition of tumor growth in vivo in xenograft models (15,33,34). PLK1 inhibition specifically induces spindle assembly checkpoint-induced prometaphase arrest (13), which may avoid some of the severe side effects commonly observed with other antimitotic agents such as taxanes and Vinca alkaloid derivatives that affect many critical cellular processes (e.g., axonal transport) unrelated to mitosis (14,35).…”

Section: Discussionmentioning

confidence: 99%

Polo-Like Kinase 1 is a Therapeutic Target in High-Risk Neuroblastoma

Ackermann

Goeser

Schulte

et al. 2011

Clinical Cancer Research

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Purpose: High-risk neuroblastoma remains a therapeutic challenge for pediatric oncologists. The Pololike kinase 1 (PLK1) is highly expressed in many human cancers and is a target of the novel small-molecule inhibitor BI 2536, which has shown promising anticancer activity in adult malignancies. Here, we investigated the effect of BI 2536 on neuroblastoma cells in vitro and in vivo to explore PLK1 as a potential target in high-risk neuroblastoma therapy.Experimental Design: PLK1 transcript levels were analyzed by microarrays in 476 primary neuroblastoma specimens, and correlation with prognostic markers and patient outcome was examined. To explore the effect of PLK1 inhibition on neuroblastoma cells, 7 cell lines were treated with BI 2536 and changes in growth properties were determined. Furthermore, nude mice with IMR-32 and SK-N-AS xenografts were treated with BI 2536.Results: PLK1 is highly expressed in unfavorable neuroblastoma and in neuroblastoma cell lines. Expression of PLK1 is associated with unfavorable prognostic markers such as stage 4, age >18 months, MYCN amplification, unfavorable gene expression-based classification, and adverse patient outcome (P < 0.001 each). On treatment with nanomolar doses of BI 2536, all neuroblastoma cell lines analyzed showed significantly reduced proliferation, cell cycle arrest, and cell death. Moreover, BI 2536 abrogated growth of neuroblastoma xenografts in nude mice.Conclusions: Elevated PLK1 expression is significantly associated with high-risk neuroblastoma and unfavorable patient outcome. Inhibition of PLK1 using BI 2536 exhibits strong antitumor activity on human neuroblastoma cells in vitro and in vivo, opening encouraging new perspectives for the treatment of high-risk neuroblastoma.

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Section: Discussionmentioning

confidence: 99%

Polo-Like Kinase 1 is a Therapeutic Target in High-Risk Neuroblastoma

Ackermann

Goeser

Schulte

et al. 2011

Clinical Cancer Research

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“…Among them, PLK1 has emerged as a promising candidate (15,16). PLK1 depletion/inhibition reduces survival of several cancer cells and inhibits tumor growth in vivo in xenograft models (19)(20)(21)(22)(23)(24)(25)(26)(27). It is feasible that, based on the specific role of PLK1 in mitosis, its inhibition may avoid some of the side effects associated with current antimitotic agents (such as taxanes and Vinca alkaloid derivatives) that, by targeting microtubules, affect many critical cellular processes (e.g., axonal transport) unrelated to mitosis (15,16).…”

Section: Discussionmentioning

confidence: 99%

“…Adoptive overexpression of PLK1 causes cell transformation, whereas its depletion/inactivation leads to mitotic arrest and cell death (18)(19)(20)(21). Therefore, PLK1 has been envisaged as a potential target in cancer therapy (17,(22)(23)(24)(25)(26)(27)(28).…”

Section: Introductionmentioning

confidence: 99%

Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma

et al. 2009

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Anaplastic thyroid carcinoma (ATC) is one of the most aggressive and chemoresistant cancers. The serine/threonine kinase Polo-like kinase 1 (PLK1), a key regulator of multiple steps during mitotic progression, is highly expressed in ATC. Here, we used the BI 2536 PLK1 inhibitor on ATC and nontransformed thyroid follicular cell lines. Our data show that ATC cells are addicted to high levels of PLK1 activity for proliferation, survival, anchorage-independent growth, and tumorigenicity. On treatment with nanomolar doses of BI 2536, ATC cells progressed normally through S phase but died thereafter, directly from mitotic arrest. Immunofluorescence microscopy, immunoblot, and flow cytometry analysis showed that, on PLK1 blockade, ATC cells arrested in prometaphase with a 4N DNA content. Treated ATC cells accumulated phosphohistone H3 and displayed characteristic mitotic (Polo) spindle aberrations. Nontransformed thyroid cells were 3.2-to 18.4-fold less susceptible to BI 2536-induced cell cycle effects compared with ATC cells. These findings identify PLK1 as a promising target for the molecular therapy of ATC. [Cancer Res 2009;69(5):1916-23]

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“…Studies implicating a role for Btk in the regulation of NF-B, and not p38 MAPK, activation were conducted in nonmyeloid cell lines 15 and murine models, 16,22 and conflicting findings might thus be the result of differences between species, as well as myeloid and nonmyeloid cell systems. In addition, studies conducted using high concentrations of LFM-A13 as Btk inhibitor need to be reviewed in light of recent findings that this inhibitor is not specific for Btk 33,34 and was shown to be toxic at high concentrations in our hands.…”

Section: Discussionmentioning

confidence: 99%

Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NFκB activity

Palmer

Mutch

Workman

et al. 2008

Blood

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Chronic inflammation, as seen in conditions such as rheumatoid arthritis and Crohn disease, is in part driven by discordant production of inflammatory cytokines, such as tumor necrosis factor-␣ and interleukin-6 (IL-6). Tyrosine kinase activity is essential to lipopolysaccharideinduced cytokine production in monocytes, and previous studies by us and others have implicated a role for the Tec kinase Bruton's tyrosine kinase (Btk) in inflammatory cytokine production. Here we show that knockdown of Btk using RNA interference results in decreased tumor necrosis factor-␣, but not IL-6 production. Further investigations into the signaling mechanisms regulating IL-6 production led to the discovery that the Tec kinase bone marrow tyrosine kinase gene in chromosome X (Bmx) regulates Tolllike receptor-induced IL-6 production. Our data further showed that Bmx-dependent super-induction of IL-6 does not involve nuclear factor-B activity. More detailed investigations of pathways downstream of Bmx signaling revealed that Bmx targets the IL-6 3 untranslated region to increase mRNA stabilization via a novel, thus far undefined, p38 mitogen activated protein kinase-independent pathway. These data have important implications for the design of therapeutics targeted against specific cytokines and their regulators in inflammatory disease. (Blood.

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Anti-breast cancer activity of LFM-A13, a potent inhibitor of Polo-like kinase (PLK)

Cited by 54 publications

References 37 publications

Polo-Like Kinase 1 is a Therapeutic Target in High-Risk Neuroblastoma

Polo-Like Kinase 1 is a Therapeutic Target in High-Risk Neuroblastoma

Identification of Polo-like Kinase 1 as a Potential Therapeutic Target in Anaplastic Thyroid Carcinoma

Bmx tyrosine kinase regulates TLR4-induced IL-6 production in human macrophages independently of p38 MAPK and NFκB activity

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