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Tytuł pozycji:

DLBCL Cells with Acquired Resistance to Venetoclax Are Not Sensitized to BIRD-2 But Can Be Resensitized to Venetoclax through Bcl-XL Inhibition

Tytuł:
DLBCL Cells with Acquired Resistance to Venetoclax Are Not Sensitized to BIRD-2 But Can Be Resensitized to Venetoclax through Bcl-XL Inhibition
Autorzy:
Martijn Kerkhofs
Tamara Vervloessem
Kinga B. Stopa
Victoria M. Smith
Meike Vogler
Geert Bultynck
Temat:
Ca2+ signaling
ABT-199
BH3 mimetics
Bcl-2
Bcl-XL
IP3 receptors
Microbiology
QR1-502
Źródło:
Biomolecules, Vol 10, Iss 7, p 1081 (2020)
Wydawca:
MDPI AG, 2020.
Rok publikacji:
2020
Kolekcja:
LCC:Microbiology
Typ dokumentu:
article
Opis pliku:
electronic resource
Język:
English
ISSN:
2218-273X
Relacje:
https://www.mdpi.com/2218-273X/10/7/1081; https://doaj.org/toc/2218-273X
DOI:
10.3390/biom10071081
Dostęp URL:
https://doaj.org/article/5dc737e9b1024e6ea4c0b0e4142b228f  Link otwiera się w nowym oknie
Numer akcesji:
edsdoj.5dc737e9b1024e6ea4c0b0e4142b228f
Czasopismo naukowe
Anti-apoptotic Bcl-2-family members are frequently dysregulated in both blood and solid cancers, contributing to their survival despite ongoing oncogenic stress. Yet, such cancer cells often are highly dependent on Bcl-2 for their survival, a feature that is exploited by so-called BH3-mimetic drugs. Venetoclax (ABT-199) is a selective BH3-mimetic Bcl-2 antagonist that is currently used in the clinic for treatment of chronic lymphocytic leukemia patients. Unfortunately, venetoclax resistance has already emerged in patients, limiting the therapeutic success. Here, we examined strategies to overcome venetoclax resistance. Therefore, we used two diffuse large B-cell lymphoma (DLBCL) cell lines, Riva WT and venetoclax-resistant Riva (VR). The latter was obtained by prolonged culturing in the presence of venetoclax. We report that Riva VR cells did not become more sensitive to BIRD-2, a peptide targeting the Bcl-2 BH4 domain, and established cross-resistance towards BDA-366, a putative BH4-domain antagonist of Bcl-2. However, we found that Bcl-XL, another Bcl-2-family protein, is upregulated in Riva VR, while Mcl-1 expression levels are not different in comparison with Riva WT, hinting towards an increased dependence of Riva VR cells to Bcl-XL. Indeed, Riva VR cells could be resensitized to venetoclax by A-1155463, a selective BH3 mimetic Bcl-XL inhibitor. This is underpinned by siRNA experiments, demonstrating that lowering Bcl-XL-expression levels also augmented the sensitivity of Riva VR cells to venetoclax. Overall, this work demonstrates that Bcl-XL upregulation contributes to acquired resistance of DLBCL cancer cells towards venetoclax and that antagonizing Bcl-XL can resensitize such cells towards venetoclax.
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