The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response
Introduction: Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impress...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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SAGE Publishing
2023-10-01
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| Series: | Technology in Cancer Research & Treatment |
| Online Access: | https://doi.org/10.1177/15330338231208608 |
| _version_ | 1797648804622630912 |
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| author | Sheng Yuan MS Wei Zuo MS Tingting Liu MS Huan Fu MS |
| author_facet | Sheng Yuan MS Wei Zuo MS Tingting Liu MS Huan Fu MS |
| author_sort | Sheng Yuan MS |
| collection | DOAJ |
| description | Introduction: Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impressive clinical responses and improve prognoses, MCL remains an incurable disease with frequent relapses. Additional therapeutic interventions are therefore unmet medical needs for the management of patients with MCL. Methods: Cell viability and apoptosis assays were employed to analyze the therapeutic interaction of venetoclax combined with selinexor in MCL cells. Western blot was used to investigate the potential mechanism of action for the synergy of venetoclax in combination with selinexor in MCL cells. Results: In this study, we revealed that both blastoid and classical MCL cells were vulnerable to the cytotoxic effects of selinexor, a well-established XPO1 inhibitor, manifested by loss of cell viability and induction of cell apoptosis. Moreover, our data indicated that the addition of venetoclax to selinexor showed synergistically decreased cell viabilities and increased cell deaths in blastoid and classical MCL cells compared to each single drug treatment. Either selinexor or venetoclax treatment alone decreased MCL1 expressions and increased BAX levels in MCL cells, and these effects were further enhanced by their combined regimen. Mechanistically, our findings demonstrated that induction of DNA damage and inactivation of DNA damage response were involved in the synergistic interaction of the drug combination regimen. Conclusion: Collectively, this study might provide a potential attractive therapy option for the treatment of MCL. However, the conclusion needs additional experimental validation in in vivo models and clinical evaluations are mandatory. |
| first_indexed | 2024-03-11T15:37:19Z |
| format | Article |
| id | doaj.art-7c192874c00f491c89c76d7171154403 |
| institution | Directory Open Access Journal |
| issn | 1533-0338 |
| language | English |
| last_indexed | 2024-03-11T15:37:19Z |
| publishDate | 2023-10-01 |
| publisher | SAGE Publishing |
| record_format | Article |
| series | Technology in Cancer Research & Treatment |
| spelling | doaj.art-7c192874c00f491c89c76d71711544032023-10-26T14:35:36ZengSAGE PublishingTechnology in Cancer Research & Treatment1533-03382023-10-012210.1177/15330338231208608The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage ResponseSheng Yuan MS0Wei Zuo MS1Tingting Liu MS2Huan Fu MS3 Department of Pathology, , The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China Department of Hematology, , The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China Department of Hematology, , The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, China Department of Hematology, , The First Affiliated Hospital of Nanchang Medical College, Nanchang, Jiangxi, ChinaIntroduction: Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impressive clinical responses and improve prognoses, MCL remains an incurable disease with frequent relapses. Additional therapeutic interventions are therefore unmet medical needs for the management of patients with MCL. Methods: Cell viability and apoptosis assays were employed to analyze the therapeutic interaction of venetoclax combined with selinexor in MCL cells. Western blot was used to investigate the potential mechanism of action for the synergy of venetoclax in combination with selinexor in MCL cells. Results: In this study, we revealed that both blastoid and classical MCL cells were vulnerable to the cytotoxic effects of selinexor, a well-established XPO1 inhibitor, manifested by loss of cell viability and induction of cell apoptosis. Moreover, our data indicated that the addition of venetoclax to selinexor showed synergistically decreased cell viabilities and increased cell deaths in blastoid and classical MCL cells compared to each single drug treatment. Either selinexor or venetoclax treatment alone decreased MCL1 expressions and increased BAX levels in MCL cells, and these effects were further enhanced by their combined regimen. Mechanistically, our findings demonstrated that induction of DNA damage and inactivation of DNA damage response were involved in the synergistic interaction of the drug combination regimen. Conclusion: Collectively, this study might provide a potential attractive therapy option for the treatment of MCL. However, the conclusion needs additional experimental validation in in vivo models and clinical evaluations are mandatory.https://doi.org/10.1177/15330338231208608 |
| spellingShingle | Sheng Yuan MS Wei Zuo MS Tingting Liu MS Huan Fu MS The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response Technology in Cancer Research & Treatment |
| title | The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response |
| title_full | The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response |
| title_fullStr | The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response |
| title_full_unstemmed | The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response |
| title_short | The Therapeutic Synergy of Selinexor and Venetoclax in Mantle Cell Lymphoma Through Induction of DNA Damage and Perturbation of the DNA Damage Response |
| title_sort | therapeutic synergy of selinexor and venetoclax in mantle cell lymphoma through induction of dna damage and perturbation of the dna damage response |
| url | https://doi.org/10.1177/15330338231208608 |
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