Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jul 3;41(8):194.
doi: 10.1007/s12032-024-02428-z.

Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line

Özlem Kaplan  1 , Nazan Gökşen Tosun  2
Affiliations

Molecular pathway of anticancer effect of next-generation HSP90 inhibitors XL-888 and Debio0932 in neuroblastoma cell line

Özlem Kaplan et al. Med Oncol. .

Abstract

Neuroblastoma is a common nervous system tumor in childhood, and current treatments are not adequate. HSP90 is a molecular chaperone protein that plays a critical role in the regulation of cancer-related proteins. HSP90 inhibition may exert anticancer effects by targeting cancer-related processes such as tumor growth, cell proliferation, metastasis, and apoptosis. Therefore, HSP90 inhibition is a promising strategy in the treatment of various types of cancer, and the development of next-generation inhibitors could potentially lead to more effective and safer treatments. XL-888 and Debio0932 is a next-generation HSP90 inhibitor and can inhibit the correct folding and stabilization of client proteins that cancer-associated HSP90 helps to fold correctly. In this study, we aimed to investigate the comprehensive molecular pathways of the anticancer activity of XL-888 and Debio0932 in human neuroblastoma cells SH-SY5Y. The cytotoxic effects of XL-888 and Debio0932 on the neuroblastoma cell line SH-SY5Y cells were evaluated by MTT assay. Then, the effect of these HSP90 inhibitors on the expression of important genes in cancer was revealed by Quantitative Real Time Polymerase Chain Reaction (qRT-PCR) method. The qRT-PCR data were evaluated using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) biological process tools. Finally, the effect of HSP90 inhibitors on HSP27, HSP70 and HSP90 protein expression was investigated by Western blotting analysis. The results revealed that XL-888 and Debio0932 had a role in regulating many cancer-related pathways such as migration, invasion, metastasis, angiogenesis, and apoptosis in SH-SY5Y cells. In conclusion, it shows that HSP90 inhibitors can be considered as a promising candidate in the treatment of neuroblastoma and resistance to chemotherapy.

Keywords: Cancer; Debio0932; HSP90 inhibition; Neuroblastoma; XL-888.

PubMed Disclaimer

Conflict of interest statement

The authors confirm that this article content has no conflicts of interest.

Figures

Fig. 1
Fig. 1
Debio0932 (A) and XL-888 (B) cytotoxicity and IC50 values in SH-SY5Y cells after 24 h and 48 h
Fig. 2
Fig. 2
Heatmap of gene expression profiles of SH-SY5Y cells treated with XL-888 and Debio0932
Fig. 3
Fig. 3
A network represented by pathway from the KEGG database consisting of significantly enriched terms in SH-SY5Y cells treated with XL-888 (A) and Debio0932 (B)
Fig. 4
Fig. 4
GO Biological Process enrichment analysis A. Top ten GO terms for XL-888 (A) and Debio0932 (B)
Fig. 5
Fig. 5
Changes in the expression of heat shock proteins (Hsp27, HSP70, HSP90) in SH-SY-5Y cells after a 48 h treatment with XL-888 and Debio0932. The protein expression (A) changes in HSPs (HSP27, HSP70, HSP90) and the abundance HSPs in SH-SY5Y (B). (*p < 0.05, **p < 0.01, ***p < 0.001, and ****p < 0.0001, ns not significant)
See this image and copyright information in PMC

Similar articles

See all similar articles

References

    1. Qiao J, Lee S, Paul P, Qiao L, Taylor CJ, Schlegel C, et al. Akt2 regulates metastatic potential in neuroblastoma. PLoS ONE. 2013;8:e56382. 10.1371/journal.pone.0056382 - DOI - PMC - PubMed
    1. Gerges A, Canning U. Neuroblastoma and its target therapies: a medicinal chemistry review. ChemMedChem. 2023. 10.1002/cmdc.202300535.10.1002/cmdc.202300535 - DOI - PubMed
    1. Qiu B, Matthay KK. Advancing therapy for neuroblastoma. Nat Rev Clin Oncol. 2022;19:515–33. 10.1038/s41571-022-00643-z - DOI - PubMed
    1. Magwenyane AM, Ugbaja SC, Amoako DG, Somboro AM, Khan RB, Kumalo HM. Heat shock protein 90 (HSP90) inhibitors as anticancer medicines: a review on the computer-aided drug discovery approaches over the past 5 years. Comput Math Methods Med. 2022;2022:2147763. 10.1155/2022/2147763. 10.1155/2022/2147763 - DOI - PMC - PubMed
    1. Kaplan Ö. Synergistic induction of apoptosis in liver cancer cells: exploring the combined potential of doxorubicin and XL-888. Med Oncol. 2023;40:318. 10.1007/s12032-023-02181-9. 10.1007/s12032-023-02181-9 - DOI - PubMed

MeSH terms

Substances