Molecular Targeting of the Oncoprotein PLK1 in Pediatric Acute Myeloid Leukemia: RO3280, a Novel PLK1 Inhibitor, Induces Apoptosis in Leukemia Cells

Polo-like kinase 1 (Plk1) plays key roles in regulating mitotic processes that are critical for cellular proliferation. Overexpression of Plk1 is tightly associated with the development of certain cancers in humans, and a large body of evidence suggests that Plk1 is an attractive target for anticancer therapeutic development. Drugs targeting Plk1 can potentially be directed at two distinct sites: the N-terminal catalytic domain, which phosphorylates substrates, and the C-terminal polo-box domain, which is essential for protein–protein interactions. In this review, we will summarize recent advances and new challenges in the development of Plk1 inhibitors targeting these two domains. We will also discuss novel strategies for designing and developing next-generation inhibitors to effectively treat Plk1-associated human disorders.

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“…Although RO3280 is still at the preclinical stage of development, it appears to have a potential therapeutic value for AML [84, 112]. …”

Section: Targeting the Catalytic Domain Of Plk1mentioning

confidence: 99%

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Lee

Burke

Park

et al. 2015

Trends in Pharmacological Sciences

107

134

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“…Additionally, RO3280 exhibited robust antitumor activity at a dose 40 mg/kg/week and reduced 72% of tumor growth, whereas at higher dose of RO3280 reduced tumor growth completely in vivo [ 49 ]. RO3280-treated leukemic cells exhibited apoptosis induction and cell cycle disorder caused by the inhibition of Bcl-2, BTK, and CASP1 [ 50 ].…”

Section: Targeting Against the Plk-1 Kinase Domainmentioning

confidence: 99%

PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis

Kumar

Kim

2015

BioMed Research International

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Mitotic kinases are the key components of the cell cycle machinery and play vital roles in cell cycle progression. PLK-1 (Polo-like kinase-1) is a crucial mitotic protein kinase that plays an essential role in both the onset of G2/M transition and cytokinesis. The overexpression of PLK-1 is strongly correlated with a wide spectrum of human cancers and poor prognosis. The (si)RNA-mediated depletion of PLK-1 arrests tumor growth and triggers apoptosis in cancer cells without affecting normal cells. Therefore, PLK-1 has been selected as an attractive anticancer therapeutic drug target. Some small molecules have been discovered to target the catalytic and noncatalytic domains of PLK-1. These domains regulate the catalytic activation and subcellular localization of PLK-1. However, while PLK-1 inhibitors block tumor growth, they have been shown to cause severe adverse complications, such as toxicity, neutropenia, and bone marrow suppression during clinical trials, due to a lack of selectivity and specificity within the human kinome. To minimize these toxicities, inhibitors should be tested against all protein kinases in vivo and in vitro to enhance selectivity and specificity against targets. Here, we discuss the potency and selectivity of PLK-1-targeted inhibitors and their molecular interactions with PLK-1 domains.

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“…Four hundred microliters of 1X binding buffer was added to each tube. Cells were analyzed by flow cytometry within 1 h (26). …”

Section: Methodsmentioning

confidence: 99%

“…For western blotting, protocol was introduced as described (26). Cellular proteins were blocked and then probed with antibodies against PARP (cat.…”

Section: Methodsmentioning

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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Molecular Targeting of the Oncoprotein PLK1 in Pediatric Acute Myeloid Leukemia: RO3280, a Novel PLK1 Inhibitor, Induces Apoptosis in Leukemia Cells

Cited by 23 publications

References 54 publications

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

Recent Advances and New Strategies in Targeting Plk1 for Anticancer Therapy

PLK-1 Targeted Inhibitors and Their Potential against Tumorigenesis

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

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