Navitoclax Most Promising BH3 Mimetic for Combination Therapy in Hodgkin Lymphoma

Myra Langendonk, Nienke A.M. Smit, Wouter Plattel, Arjan Diepstra, Tom van Meerten, Lydia Visser*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
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Abstract

The treatment of young patients with Hodgkin lymphoma (HL) is often successful but a significant proportion of patients suffers from late toxicity. In the current era there are new opportunities for less toxic and more targeted treatment options. In this respect, the anti-apoptotic pathway is an attractive target since Hodgkin tumor cells abundantly express components of this pathway. We measured the effect of BH3 mimetics that interfere with anti-apoptotic proteins in cell lines, also in combination with the standard of care chemotherapeutic doxorubicin and the recently discovered preclinically active tamoxifen. Several anti-apoptotic BCL-2 family proteins were expressed in each case (n = 84) and in HL cell lines (n = 5). Cell lines were checked for sensitivity to BH3 mimetics by BH3 profiling and metabolic assays and monotherapy was only partially successful. Doxorubicin was synergistic with a BCL-XL inhibitor and BCL2/XL/W inhibitor navitoclax. Tamoxifen that targets the estrogen receptor β present in the mitochondria of the cell lines, could induce cell death, and was synergistic with several BH3 mimetics including/as well as navitoclax. In conclusion, targeting the anti-apoptotic pathway by the triple inhibitor navitoclax in combination with doxorubicin or tamoxifen is a promising treatment strategy in HL.

Original languageEnglish
Article number13751
Number of pages12
JournalInternational Journal of Molecular Sciences
Volume23
Issue number22
DOIs
Publication statusPublished - Nov-2022

Keywords

  • anti-apoptotic proteins
  • BH3 profiling
  • Hodgkin lymphoma
  • therapy

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