Glucosylceramide synthase silencing combined with the receptor tyrosine kinase inhibitor axitinib as a new multimodal strategy for glioblastoma

• Type: Article in International Scientific Journal
• Date: 2019

Authors

Morais, CM (Author) Other; Cunha, PP (Author) Other; Melo, T (Author) Other; Cardoso, AM (Author) Other; Domingues, P (Author) Other; Domingues, MR (Author) Other; de Lima, MCP (Author) Other; Jurado, AS (Author) Other

Journal

Title: Human Molecular Genetics

Vol. 28

Pages: 3664-3679

ISSN: 0964-6906

Publisher: Oxford University Press

Indexing

ISI Web of Knowledge - 0 Citations

Scopus - 2 Citations

Other information

Authenticus ID: P-00R-J4F

DOI: 10.1093/hmg/ddz152

Abstract (EN): A great deal of evidence revealing that lipid metabolism is drastically altered during tumorigenesis has been accumulated. In this work, glucosylceramide synthase (GCS) was targeted, using RNA interference technology (siRNAs), in U87 and DBTRG human glioblastoma (GBM) cells, as in both cell types GCS showed to be overexpressed with respect to normal human astrocytes. The efficacy of a combined therapy to tackle GBM, allying GCS silencing to the new generation chemotherapeutics sunitinib and axitinib, or to the alkylating drugs etoposide and temozolomide, is evaluated here for the first time. With this purpose, studies addressing GBM cell viability and proliferation, cell cycle and apoptosis were performed, which revealed that combination of GCS silencing with axitinib treatment represents a promising therapeutic approach. The reduction of cell viability induced by this combined therapy is proposed to be mediated by excessive production of reactive oxygen species. This work, identifying GCS as a key molecular target to increase GBM susceptibility to a new generation chemotherapeutic, opens windows to the development of innovative strategies to halt GBM recurrence after surgical resection.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 16