Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth

Chilamakuri, Rameswari; Rouse, Danielle C.; Agarwal, Saurabh

doi:10.3390/ph15050523

Cited by 3 publications

(4 citation statements)

References 41 publications

(56 reference statements)

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“…Some of these drugs, henceforth referred to as “geroprotective drugs”, including Carnosol [37], Curcumin [38], Cucurbitacin B [39], Isonicotinamide [40], Meclofenoxate [41], Scriptaid [42], and Withaferin A [43] have already been shown to have potential geroprotective effects in various animal models, including humans. Among these 150 geroprotective drug candidates, we found several FDA-approved anti-cancer drugs, including Trametinib, Doxorubicin, Alisertib, Actinomycin-d, Toremifene, and Plumbagin, as well as several investigational drugs with potential anti-tumor effects including Avrainvillamide analogs [44], aurora kinase inhibitors (MK-5108, AT-9283) [45], Avicins [46], HMN-214 [47], Chaetocin [48], ron kinase inhibitors [49], and Linifanib [50], among others.…”

Section: Resultsmentioning

confidence: 99%

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma

Saha,

Ben Guebila,

Fanfani

et al. 2024

Preprint

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Aging is the primary risk factor for many individual cancer types, including lung adenocarcinoma (LUAD). To understand how aging-related alterations in the regulation of key cellular processes might affect LUAD risk and survival outcomes, we built individual (person)-specific gene regulatory networks integrating gene expression, transcription factor protein-protein interaction, and sequence motif data, using PANDA/LIONESS algorithms, for both non-cancerous lung tissue samples from the Genotype Tissue Expression (GTEx) project and LUAD samples from The Cancer Genome Atlas (TCGA). In GTEx, we found that pathways involved in cell proliferation and immune response are increasingly targeted by regulatory transcription factors with age; these aging-associated alterations are accelerated by tobacco smoking and resemble oncogenic shifts in the regulatory landscape observed in LUAD and suggests that dysregulation of aging pathways might be associated with an increased risk of LUAD. Comparing normal adjacent samples from individuals with LUAD with healthy lung tissue samples from those without LUAD, we found that aging-associated genes show greater aging-biased targeting patterns in younger individuals with LUAD compared to their healthy counterparts of similar age, a pattern suggestive of age acceleration. This implies that an accelerated aging process may be responsible for tumor incidence in younger individuals. Using drug repurposing tool CLUEreg, we found small molecule drugs with potential geroprotective effects that may alter the accelerating aging profiles we found. We also observed that, in contrast to chronological age, a network-informed aging signature was associated with survival and response to chemotherapy in LUAD.

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Section: Resultsmentioning

confidence: 99%

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma

Saha,

Ben Guebila,

Fanfani

et al. 2024

Preprint

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“…We further evaluated the genes with a strong association with favorable (β < 0) or poor (β > 0) survival during the murine sympathoadrenal development ( Figure 7 a,b and Figure S11 ). The expression of many 1:1 orthologues between human and mouse that are associated with a poor survival probability (β > 0) have been described to be important in NB outcome, including DKC1 , PLK1 , FBXO8, ODC1 , and CDK4 [ 43 , 75 , 77 , 78 , 79 , 80 ]. PLK1 is a serine/threonine kinase that plays a crucial role in cell division and cell cycle progression [ 81 ].…”

Section: Resultsmentioning

confidence: 99%

“…DKC1 and PLK1 stabilize MYC proteins, particularly MYCN, which in turn promotes their expression in a positive feedback loop. Furthermore, DKC1 and PLK1 upregulation is linked to unfavorable outcomes in NB [ 77 , 79 ]. Similarly, Ornithine decarboxylase ( ODC1 ) is involved in polyamine biosynthesis and is upregulated in tumors, especially in MYC-driven cancers [ 82 ].…”

Section: Resultsmentioning

confidence: 99%

Target Genes of c-MYC and MYCN with Prognostic Power in Neuroblastoma Exhibit Different Expressions during Sympathoadrenal Development

Yuan,

Alzrigat,

Rodriguez-Garcia

et al. 2023

Cancers

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Deregulation of the MYC family of transcription factors c-MYC (encoded by MYC), MYCN, and MYCL is prevalent in most human cancers, with an impact on tumor initiation and progression, as well as response to therapy. In neuroblastoma (NB), amplification of the MYCN oncogene and over-expression of MYC characterize approximately 40% and 10% of all high-risk NB cases, respectively. However, the mechanism and stage of neural crest development in which MYCN and c-MYC contribute to the onset and/or progression of NB are not yet fully understood. Here, we hypothesized that subtle differences in the expression of MYCN and/or c-MYC targets could more accurately stratify NB patients in different risk groups rather than using the expression of either MYC gene alone. We employed an integrative approach using the transcriptome of 498 NB patients from the SEQC cohort and previously defined c-MYC and MYCN target genes to model a multigene transcriptional risk score. Our findings demonstrate that defined sets of c-MYC and MYCN targets with significant prognostic value, effectively stratify NB patients into different groups with varying overall survival probabilities. In particular, patients exhibiting a high-risk signature score present unfavorable clinical parameters, including increased clinical risk, higher INSS stage, MYCN amplification, and disease progression. Notably, target genes with prognostic value differ between c-MYC and MYCN, exhibiting distinct expression patterns in the developing sympathoadrenal system. Genes associated with poor outcomes are mainly found in sympathoblasts rather than in chromaffin cells during the sympathoadrenal development.

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“…The gap between 2D cell cultures and animal models can be bridged by complex three-dimensional systems that closely recapitulate the course of human cancer [ 2 , 116 , 144 , 156 , 171 ]. Recent developments in three-dimensional, microfluidic, and multicellular systems used for neuroblastoma research [ 150 ] are promising, especially for testing new therapeutic approaches [ 118 , 160 , 253 , 254 ], including natural product research [ 177 ], immunotherapy [ 172 , 255 , 256 ], and new multimodal strategies for high-risk neuroblastoma [ 149 ]. A heterogenous disease such as neuroblastoma may largely benefit from comprehensive approaches involving a combination of various biological models supplemented by mathematical simulations [ 146 , 235 , 257 , 258 ].…”

Section: Discussionmentioning

confidence: 99%

Preclinical Models of Neuroblastoma—Current Status and Perspectives

Krawczyk

Kitlińska

2023

Cancers

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Preclinical in vitro and in vivo models remain indispensable tools in cancer research. These classic models, including two- and three-dimensional cell culture techniques and animal models, are crucial for basic and translational studies. However, each model has its own limitations and typically does not fully recapitulate the course of the human disease. Therefore, there is an urgent need for the development of novel, advanced systems that can allow for efficient evaluation of the mechanisms underlying cancer development and progression, more accurately reflect the disease pathophysiology and complexity, and effectively inform therapeutic decisions for patients. Preclinical models are especially important for rare cancers, such as neuroblastoma, where the availability of patient-derived specimens that could be used for potential therapy evaluation and screening is limited. Neuroblastoma modeling is further complicated by the disease heterogeneity. In this review, we present the current status of preclinical models for neuroblastoma research, discuss their development and characteristics emphasizing strengths and limitations, and describe the necessity of the development of novel, more advanced and clinically relevant approaches.

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Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth

Cited by 3 publications

References 41 publications

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma

Aging-associated Alterations in the Gene Regulatory Network Landscape Associate with Risk, Prognosis and Response to Therapy in Lung Adenocarcinoma

Target Genes of c-MYC and MYCN with Prognostic Power in Neuroblastoma Exhibit Different Expressions during Sympathoadrenal Development

Preclinical Models of Neuroblastoma—Current Status and Perspectives

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