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Stroma-Mediated Resistance to S63845 and Venetoclax through MCL-1 and BCL-2 Expression Changes Induced by miR-193b-3p and miR-21-5p Dysregulation in Multiple Myeloma

Abstract: BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pro-apoptotic BIM protein in MM cells. In this study, we assess the efficacy of S63845 and venetoclax in MM cells in direct co-culture with MSCs derived from MM patients (pMSCs) to identify additional mechanisms involved in the stroma-induced resistance to these agents. MicroRNAs miR-193b-3p and miR-21-5p emerged among the top deregulated miRNAs in myeloma cells when directly co-cultured with pMSCs, and we show their contribution to changes in MCL-1 and BCL-2 protein expression and in the activity of S63845 and venetoclax. Additionally, direct contact with pMSCs under S63845 and/or venetoclax treatment modifies myeloma cell dependence on different BCL-2 family anti-apoptotic proteins in relation to BIM, making myeloma cells more dependent on the non-targeted anti-apoptotic protein or BCL-XL. Finally, we show a potent effect of the combination of S63845 and venetoclax even in the presence of pMSCs, which supports this combinatorial approach for the treatment of MM.

 Fuente: Cells . 2021 Mar 4;10(3):559

Editorial: MDPI

 Año de publicación: 2021

Nº de páginas: 16

Tipo de publicación: Artículo de Revista

 DOI: 10.3390/cells10030559

ISSN: 2073-4409

Url de la publicación: https://doi.org/ 10.3390/cells10030559

Autores/as

ALGARÍN, ESPERANZA M.

QUWAIDER, DALIA

CAMPOS-LABORIE, FRANCISCO J.

DÍAZ-TEJEDOR, ANDREA

MOGOLLÓN, PEDRO

VUELTA, ELENA

MARTÍN-SÁNCHEZ, MONTSERRAT

SAN-SEGUNDO, LAURA

GONZÁLEZ-MÉNDEZ, LORENA

GUTIÉRREZ, NORMA C.

GARCÍA-SANZ, RAMÓN

PAÍNO, TERESA

RIVAS, JAVIER DE LAS

GARAYOA, MERCEDES