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Conformational Switching in Bcl-xL: Enabling Non-Canonic Inhibition of Apoptosis Involves Multiple Intermediates and Lipid Interactions
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Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies

1
Clinical Hematology, Nantes University Hospital, 1 place A. Ricordeau, 44000 Nantes, France
2
CRCINA, INSERM, CNRS, Angers University, Nantes University, 8 quai Moncousu, 44000 Nantes, France
3
Integrated Cancer Research Center (SIRIC), ILIAD, 5 Allée de l’Ile Gloriette, 44093 Nantes, France
*
Author to whom correspondence should be addressed.
Cells 2020, 9(3), 717; https://doi.org/10.3390/cells9030717
Received: 4 February 2020 / Revised: 8 March 2020 / Accepted: 12 March 2020 / Published: 14 March 2020
(This article belongs to the Special Issue Regulation of Apoptosis by the Bcl-2 Family of Proteins)
Apoptosis is a highly conserved mechanism enabling the removal of unwanted cells. Mitochondrial apoptosis is governed by the B-cell lymphoma (BCL-2) family, including anti-apoptotic and pro-apoptotic proteins. Apoptosis evasion by dysregulation of anti-apoptotic BCL-2 members (BCL-2, MCL-1, BCL-XL) is a common hallmark in cancers. To divert this dysregulation into vulnerability, researchers have developed BH3 mimetics, which are small molecules that restore effective apoptosis in neoplastic cells by interfering with anti-apoptotic proteins. Among them, venetoclax is a potent and selective BCL-2 inhibitor, which has demonstrated the strongest clinical activity in mature B-cell malignancies, including chronic lymphoid leukemia, mantle-cell lymphoma, and multiple myeloma. Nevertheless, mechanisms of primary and acquired resistance have been recently described and several features such as cytogenetic abnormalities, BCL-2 family expression, and ex vivo drug testing have to be considered for predicting sensitivity to BH3 mimetics and helping in the identification of patients able to respond. The medical need to overcome resistance to BH3 mimetics supports the evaluation of innovative combination strategies. Novel agents including MCL-1 targeting BH3 mimetics are currently evaluated and may represent new therapeutic options in the field. The present review summarizes the current knowledge regarding venetoclax and other BH3 mimetics for the treatment of mature B-cell malignancies. View Full-Text
Keywords: venetoclax; BH3 mimetics; BCL-2; MCL-1; apoptosis; myeloma; lymphoma; leukemia venetoclax; BH3 mimetics; BCL-2; MCL-1; apoptosis; myeloma; lymphoma; leukemia
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Jullien, M.; Gomez-Bougie, P.; Chiron, D.; Touzeau, C. Restoring Apoptosis with BH3 Mimetics in Mature B-Cell Malignancies. Cells 2020, 9, 717.

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