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Pharmaceuticals
Special Issues
Neuroblastoma Pathogenesis and Therapy
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Neuroblastoma Pathogenesis and Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 25 July 2024 | Viewed by 9777

Special Issue Editor

Dr. Saurabh Agarwal

E-Mail Website
Guest Editor
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, New York, NY 11439, USA
Interests: pediatric cancers; neuroblastoma; cancer stem cells; metastasis; signaling pathways in cancer; immunotherapy; epigenetics; genetics; small molecule inhibitors; translational therapeutics; p53-myc interaction
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Neuroblastoma is an aggressive pediatric cancer that originates from neural crest tissues of the sympathetic nervous system. High-risk neuroblastoma accounts for almost 15% of all pediatric cancer-related deaths, with overall survival rates lower than 50%. This situation become murkier when the majority of neuroblastoma patients relapse with an aggressive, refractory, and metastatic disease, with an overall survival rate of only 10%. Therefore, understanding the causes of neuroblastoma pathogenesis, relapse, and developing novel therapeutic approaches is mandatory to effectively cure neuroblastoma.

Neuroblastoma is a highly heterogeneous tumor both from a clinical and a molecular perspective. The clinical impact and unique biology of neuroblastoma have made this aggressive solid tumor an interesting disease model for concerted translational research efforts. These efforts include novel insights into neuroblastoma tumor biology, molecular and epigenetic mechanisms, novel targeted therapeutic approaches including small molecule inhibitors, epigenetic, non-coding RNA, and cell-based immunologic therapies.

In this Special Issue, we invite authors to contribute articles focusing on different aspects of neuroblastoma tumor biology, pathogenesis, developmental therapeutics, and treatment approaches. The collected articles in this Special Issue will further enhance our knowledge and understanding of the complex neuroblastoma pathogenesis and drive the development of novel therapeutic strategies.

Dr. Saurabh Agarwal
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Neuroblastoma
  • Pediatric cancers
  • Neural crest
  • Pathogenesis
  • Metastasis
  • Epigenetics
  • Therapeutic approach
  • Tumorigenesis
  • Signaling mechanisms
  • Epithelial-to-mesenchymal transition

Published Papers (3 papers)

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Research

12 pages, 7074 KiB  
Article
Inhibition of Polo-like Kinase 1 by HMN-214 Blocks Cell Cycle Progression and Inhibits Neuroblastoma Growth
by Rameswari Chilamakuri, Danielle Crystal Rouse and Saurabh Agarwal
Pharmaceuticals 2022, 15(5), 523; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15050523 - 24 Apr 2022
Cited by 2 | Viewed by 2704
Abstract
Polo-like kinase 1 (PLK1) is an essential cell cycle mitotic kinase component that plays an important role in cell cycle progression and has been reported to be involved in various cancers, including neuroblastoma (NB). PLK1 also regulates G2/M transition, chromosomal segregation, spindle assembly [...] Read more.
Polo-like kinase 1 (PLK1) is an essential cell cycle mitotic kinase component that plays an important role in cell cycle progression and has been reported to be involved in various cancers, including neuroblastoma (NB). PLK1 also regulates G2/M transition, chromosomal segregation, spindle assembly maturation, and mitotic exit. NB is an early embryonic-stage heterogeneous solid tumor and accounts for 15% of all pediatric cancer-related deaths. Therefore, we aimed to develop a targeting strategy for PLK1 by repurposing HMN-214 in NB. HMN-214 is a prodrug of HMN-176 and is known to selectively interfere with PLK1 function. In the present study, we performed the transcriptomic analysis of a large cohort of primary NB patient samples and revealed that PLK1 expression is inversely correlated with the overall survival of NB patients. Additionally, we found that PLK1 strongly correlates with NB disease and stage progression. HMN-214 significantly inhibited NB proliferation and colony formation in both MYCN-amplified and -nonamplified cell lines in a dose-dependent manner. Furthermore, HMN-214 induces apoptosis and significantly obstructs the cell cycle at the G2/M phase in NB cells by inhibiting multiple cell-cycle-related genes, such as PLK1, WEE1, CDK1, CDK2, Cyclin B1, CHK1, and CHK2. HMN-214 significantly inhibits cell cycle regulator CDK1 and the phosphorylation and activation of PLK1 in NB. In the NB 3D spheroid tumor model, HMN-214 significantly and in a dose-dependent manner inhibits spheroid tumor mass and growth. Overall, our study highlights that targeting PLK1 using HMN-214 is a novel therapeutic approach for NB. Full article
(This article belongs to the Special Issue Neuroblastoma Pathogenesis and Therapy)
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16 pages, 4063 KiB  
Article
BI-2536 Promotes Neuroblastoma Cell Death via Minichromosome Maintenance Complex Components 2 and 10
by Chiao-Hui Hsieh, Hsiang-Ning Yeh, Chen-Tsung Huang, Wei-Hsuan Wang, Wen-Ming Hsu, Hsuan-Cheng Huang and Hsueh-Fen Juan
Pharmaceuticals 2022, 15(1), 37; https://0-doi-org.brum.beds.ac.uk/10.3390/ph15010037 - 28 Dec 2021
Cited by 7 | Viewed by 3285
Abstract
DNA replication is initiated with the recognition of the starting point of multiple replication forks by the origin recognition complex and activation of the minichromosome maintenance complex 10 (MCM10). Subsequently, DNA helicase, consisting of the MCM protein subunits MCM2-7, unwinds double-stranded DNA and [...] Read more.
DNA replication is initiated with the recognition of the starting point of multiple replication forks by the origin recognition complex and activation of the minichromosome maintenance complex 10 (MCM10). Subsequently, DNA helicase, consisting of the MCM protein subunits MCM2-7, unwinds double-stranded DNA and DNA synthesis begins. In previous studies, replication factors have been used as clinical targets in cancer therapy. The results showed that MCM2 could be a proliferation marker for numerous types of malignant cancer. We analyzed samples obtained from patients with neuroblastoma, revealing that higher levels of MCM2 and MCM10 mRNA were associated with poor survival rate. Furthermore, we combined the results of the perturbation-induced reversal effects on the expression levels of MCM2 and MCM10 and the sensitivity correlation between perturbations and MCM2 and MCM10 from the Cancer Therapeutics Response Portal database. Small molecule BI-2536, a polo-like kinase 1 (PLK-1) inhibitor, is a candidate for the inhibition of MCM2 and MCM10 expression. To test this hypothesis, we treated neuroblastoma cells with BI-2536. The results showed that the drug decreased cell viability and reduced the expression levels of MCM2 and MCM10. Functional analysis further revealed enrichments of gene sets involved in mitochondria, cell cycle, and DNA replication for BI-2536-perturbed transcriptome. We used cellular assays to demonstrate that BI-2536 promoted mitochondria fusion, G2/M arrest, and apoptosis. In summary, our findings provide a new strategy for neuroblastoma therapy with BI-2536. Full article
(This article belongs to the Special Issue Neuroblastoma Pathogenesis and Therapy)
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30 pages, 3986 KiB  
Article
In Vitro Assessment of the Role of p53 on Chemotherapy Treatments in Neuroblastoma Cell Lines
by Idoia Blanco-Luquin, Paula Lázcoz, Jon Celay, Javier S. Castresana and Ignacio J. Encío
Pharmaceuticals 2021, 14(11), 1184; https://0-doi-org.brum.beds.ac.uk/10.3390/ph14111184 - 19 Nov 2021
Cited by 3 | Viewed by 2591
Abstract
Neuroblastoma is the most frequent malignant extracranial solid tumor of infancy. The overall objective of this work consists of determining the presence of alterations in the p53/MDM2/p14ARF signaling pathway in neuroblastoma cell lines and deciphering their possible relationship with resistance to known antineoplastic [...] Read more.
Neuroblastoma is the most frequent malignant extracranial solid tumor of infancy. The overall objective of this work consists of determining the presence of alterations in the p53/MDM2/p14ARF signaling pathway in neuroblastoma cell lines and deciphering their possible relationship with resistance to known antineoplastic drugs and to differentiation agents. Firstly, we characterized 10 neuroblastoma cell lines for alterations at the p53/MDM2/p14ARF signaling pathway by analysis of TP53 point mutations, MYCN and MDM2 amplification, and p14ARF methylation, homozygous deletions, and expression. Secondly, we chose SK-N-FI (mutated at TP53) and SK-N-Be(2) (wild-type TP53) cell lines, treated them with chemotherapeutic agents (doxorubicin, etoposide, cisplatin, and melphalan) and with two isomers of retinoic acid (RA): (9-cis and all-trans). Finally, we analyzed the distribution of the cell cycle, the induction of apoptosis, and the expression levels of p53, p21, and Bcl-2 in those two cell lines. P14ARF did not present promoter methylation, homozygous deletions, and protein expression in any of the 10 neuroblastoma cell lines. One TP53 point mutation was detected in the SK-N-FI cell line. MYCN amplification was frequent, while most cell lines did not present MDM2 amplification. Treatment of SK-N-FI and SK-N-Be(2) cells with doxorubicin, etoposide, cisplatin, and melphalan increased apoptosis and blocked the cycle in G2/M, while retinoic acid isomers induced apoptosis and decreased the percentage of cells in S phase in TP53 mutated SK-N-FI cells, but not in TP53 wild-type SK-N-Be(2) cells. Treatment with cisplatin, melphalan, or 9-cis RA decreased p53 expression levels in SK-N-FI cells but not in SK-N-Be (2). The expression of p21 was not modified in either of the two cell lines. Bcl-2 levels were reduced only in SK-N-FI cells after treatment with cisplatin. However, treatments with doxorubicin, etoposide, or 9-cis-RA did not modify the levels of this protein in either of the two cell lines. In conclusion, TP53 mutated SK-N-FI cells respond better to the retinoic isomers than TP53 wild-type SK-N-Be(2) cells. Although these are in vitro results, it seems that deciphering the molecular alterations of the p53/MDM2/p14ARF signaling pathway prior to treating patients of neuroblastoma might be useful for standardizing therapies with the aim of improving survival. Full article
(This article belongs to the Special Issue Neuroblastoma Pathogenesis and Therapy)
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