Casein kinase II (CK2) as a therapeutic target for hematological malignancies

Gowda, Chandrika; Sachdev, Mansi; Muthusami, Sunil; Kapadia, Malika; Petrovic-Dovat, Lidija; Hartman, Melanie; Ding, Yali; Song, Chunhua; Payne, Joseph Frank; Tan, Bi Hua; Dovat, Sinisa

doi:10.2174/1381612822666161006154311

Cited by 36 publications

(43 citation statements)

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“…CK2 is a target of increasing interest in pharmaceutical research. It has a vast array of physiological targets and participates in a complex series of cellular functions, including the maintenance of cell viability, the development of different malignancies (Gowda et al 2017;Litchfield 2003), cell survival and DNA damage response (Rabalski et al 2016). CK2 inhibitors mostly work by competing with ATP at the respective binding pocket (Gowda et al 2017).…”

Section: Discussionmentioning

confidence: 99%

“…It has a vast array of physiological targets and participates in a complex series of cellular functions, including the maintenance of cell viability, the development of different malignancies (Gowda et al 2017;Litchfield 2003), cell survival and DNA damage response (Rabalski et al 2016). CK2 inhibitors mostly work by competing with ATP at the respective binding pocket (Gowda et al 2017). Thus, based on the present study, alternariol might provide a promising scaffold for the development of novel CK2 inhibitors, but the result collected also raise the question on the relevance of CK2 for the toxicological mode of action of AOH.…”

Section: Discussionmentioning

confidence: 99%

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Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

et al. 2020

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Emerging mycotoxins produced by Alternaria spp. were previously reported to exert cytotoxic, genotoxic, but also estrogenic effects in human cells. The involved mechanisms are very complex and not fully elucidated yet. Thus, we followed an in silico target fishing approach to extend knowledge on the possible biological targets underlying the activity of alternariol, taken as the signature compound of Alternaria toxins. Combining ligand-based screening and structure-based modeling, the ubiquitous casein kinase 2 (CK2) was identified as a potential target for the compound. This result was validated in a cellfree in vitro CK2 activity assay, where alternariol inhibited CK2 with an IC 50 of 707 nM. As CK2 was recently discussed to influence estrogen receptor (ER) transcription and DNA-binding affinity, we assessed a potential impact on the mRNA levels of ERα or ERβ by qRT-PCR and on nuclear localization of the receptors by confocal microscopy, using estrogen-sensitive Ishikawa cells as a model. While AOH did not affect the transcription of ERα or ERβ, an increase in nuclear localization of ERα after incubation with 10 µM AOH was observed. However, this effect might be due to ER binding affinity and therefore estrogenicity of AOH. Furthermore, in silico docking simulation revealed not only AOH, but also a number of other Alternaria toxins as potential inhibitors of CK2, including alternariol monomethyl ether and the perylene quinone derivative altertoxin II (ATX-II). These findings were representatively confirmed in vitro for the perylene quinone derivative altertoxin II, which was found to inhibit the kinase with an IC 50 of 5.1 µM. Taken together, we propose CK2 inhibition as an additional mechanism to consider in future studies for alternariol and several other Alternaria toxins.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

et al. 2020

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“…In B-ALL cells, CX-4945 mediated inhibition of CK2 increased apoptosis in B-ALL cell lines and primary B-ALL cells but did not affect apoptosis in normal primary myeloid cells (Gomes et al, 2014). CX-4945 inhibited CK2-induced cell proliferation (Gowda et al, 2017). There are two possible mechanisms by which CX-4945 inhibits B-ALL: lowering levels of both total PTEN and phosphorylated PTEN (Gomes et al, 2014), and decreasing the phosphorylation of Ikaros, a tumor suppressor, thus restore the anti-leukemic function of Ikaros (Gowda et al, 2017).…”

Section: Leukemiamentioning

confidence: 94%

“…CX-4945 inhibited CK2-induced cell proliferation (Gowda et al, 2017). There are two possible mechanisms by which CX-4945 inhibits B-ALL: lowering levels of both total PTEN and phosphorylated PTEN (Gomes et al, 2014), and decreasing the phosphorylation of Ikaros, a tumor suppressor, thus restore the anti-leukemic function of Ikaros (Gowda et al, 2017). It is noteworthy that in both xenograft models of B-ALL cells and cell lines, CX-4945 inhibited leukemic cell growth and increased mouse survival (Gowda et al, 2017).…”

Section: Leukemiamentioning

confidence: 99%

Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management

Lian

Shu

Zhu

et al. 2019

Asian Pac J Cancer Prev

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The Protein kinase CK2 (formerly known as casein kinase 2) is a highly conserved serine/ threonine kinase overexpressed in various human carcinomas and its high expression often correlates with poor prognosis. CK2 protein is localized in the nucleus of many tumor cells and correlates with clinical features in many cases. Increased expression of CK2 in mice results in the development of various types of carcinomas (both solids and blood related tumors, such as (breast carcinoma, lymphoma, etc), which reveals its carcinogenic properties. CK2 plays essential roles in many key biological processes related to carcinoma, including cell apoptosis, DNA damage responses and cell cycle regulation. CK2 has become a potential anti-carcinoma target. Various CK2 inhibitors have been developed with anti-neoplastic properties against a variety of carcinomas. Some CK2 inhibitors have showed good results in in vitro and pre-clinical models, and have even entered in clinical trials. This article will review effects of CK2 and its inhibitors on common carcinomas in in vitro and pre-clinical studies.

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“…It has been proposed that it is kept inactive by an unusual self‐inhibitory assembly into high order oligomeric states and its activity restored upon necessity . Although not being an oncogene, its activity has been found elevated in various cancers, especially haematological malignancies . Its antiapoptotic role has been associated with its involvement in sustaining cancer growth and in protecting cancerous cells.…”

Section: Introductionmentioning

confidence: 99%

Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin

et al. 2019

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Protein kinase CK2 is an antiapoptotic cancer-sustaining protein. Curcumin, reported previously as a CK2 inhibitor, is too bulky to be accommodated in the CK2 active site and rapidly degrades in solution generating various ATP-mimetic inhibitors; with a detailed comparative analysis, by means of both protein crystallography and enzymatic inhibition, ferulic acid was identified as the principal curcumin degradation product responsible for CK2 inhibition. The other curcumin derivatives vanillin, feruloylmethane and coniferyl aldehyde are weaker CK2 inhibitors. The high instability of curcumin in standard buffered solutions flags this compound, which is included in many commercial libraries, as a possible source of misleading interpretations, as was the case for CK2. Ferulic acid does not show any cytotoxicity and any inhibition of cellular CK2, due to its poor cellular permeability. However, curcumin acts as a prodrug in the cellular context, by generating its degradation products inside the treated cells, thus rescuing CK2 inhibition and consequently inducing cell death. Through the intracellular release of its degradation products, curcumin is expected to affect various target families; here, we identify the first bromodomain of BRD4 as a new target for those compounds. DatabaseStructural data are available in the PDB database under the accession numbers 6HOP (CK2a/ curcumin), 6HOQ (CK2a/ferulic acid), 6HOR (CK2a/feruloylmethane), 6HOT (CK2a/ferulic aldehyde), 6HOU (CK2a/vanillin) and 6HOV (BRD4/ferulic acid). AbbreviationsBET, bromodomain and extra-terminal motif; CK2, casein kinase 2; FGF, fibroblast growth factor; FGFR, fibroblast growth factor receptor; HA, heavy atom, nonhydrogen atom; Kac, acetylated-lysine; LE, ligand efficiency; MTT, 3-(4,5-dimethylthiazol-2-yl)-3,5-diphenyltriazolium bromide; TBCA, tetrabromocinnamic acid.

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Casein kinase II (CK2) as a therapeutic target for hematological malignancies

Abstract: CK2 is an attractive target in treatment of various cancers. Currently only a few specific CK2 inhibitors are available. Preclinical studies using CK2 inhibitor, CX4945 in high risk pediatric leukemias have shown promising results and warrants further testing in other types of leukemia.

Cited by 36 publications

References 0 publications

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

Alternaria toxins as casein kinase 2 inhibitors and possible consequences for estrogenicity: a hybrid in silico/in vitro study

Protein Kinase CK2, a Potential Therapeutic Target in Carcinoma Management

Biochemical and cellular mechanism of protein kinase CK2 inhibition by deceptive curcumin

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