Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models
ABSTRACT Background Despite significant therapeutic progress, many lymphoma subtypes remain difficult to manage due to resistance, relapse, and dose‐limiting toxicity. Methods To elucidate the mechanism of action of the semi‐synthetic flavonoid derivative (SND) compounds, we conducted a screening of...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2025-06-01
|
| Series: | eJHaem |
| Online Access: | https://doi.org/10.1002/jha2.70081 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849685441127645184 |
|---|---|
| author | Eugenio Gaudio Paulina Biniecka Alberto J. Arribas Eleonora Cannas Guido J. R. Zaman Derya Unutmaz Francesco Bertoni Dan F. Stoicescu |
| author_facet | Eugenio Gaudio Paulina Biniecka Alberto J. Arribas Eleonora Cannas Guido J. R. Zaman Derya Unutmaz Francesco Bertoni Dan F. Stoicescu |
| author_sort | Eugenio Gaudio |
| collection | DOAJ |
| description | ABSTRACT Background Despite significant therapeutic progress, many lymphoma subtypes remain difficult to manage due to resistance, relapse, and dose‐limiting toxicity. Methods To elucidate the mechanism of action of the semi‐synthetic flavonoid derivative (SND) compounds, we conducted a screening of cancer cell lines using proliferation, cell cycle, and apoptosis assays. We then performed computational modeling of the compounds’ binding to tubulin, and finally evaluated in vivo activity using nanoNail technology alongside xenograft experiment. Results Here, we describe a series of SNDs that exhibit low‐nanomolar to picomolar cytotoxicity across multiple lymphoma models, including those resistant to BTK and PI3K inhibitors. Mechanistic studies show that these compounds trigger robust apoptosis via cytoskeletal disruption and mitochondrial dysfunction. Notably, SND207 also potently inhibits Protein Kinase N1, suggesting a synergistic link between kinase blockade and cytoskeletal interference. High‐throughput profiling places them near classical microtubule agents, although tubulin assays indicate more nuanced mechanisms than straightforward stabilization or depolymerization. In murine xenografts, SND207 significantly reduced tumor burden, and its combination with a BTK inhibitor demonstrates potential synergy. Furthermore, localized NanoNail delivery achieves high intratumoral drug concentrations at low doses, underscoring a favorable therapeutic index. Conclusions Overall, these findings highlight the translational promise of the SND series for future studies in the lymphoma field. Clinical Trial Registration The authors have confirmed clinical trial registration is not needed for this submission. |
| format | Article |
| id | doaj-art-eab87606e64740ce8fd6a9ec76714629 |
| institution | DOAJ |
| issn | 2688-6146 |
| language | English |
| publishDate | 2025-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | eJHaem |
| spelling | doaj-art-eab87606e64740ce8fd6a9ec767146292025-08-20T03:23:08ZengWileyeJHaem2688-61462025-06-0163n/an/a10.1002/jha2.70081Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma ModelsEugenio Gaudio0Paulina Biniecka1Alberto J. Arribas2Eleonora Cannas3Guido J. R. Zaman4Derya Unutmaz5Francesco Bertoni6Dan F. Stoicescu7Floratek Pharma SA Aubonne SwitzerlandFloratek Pharma SA Aubonne SwitzerlandInstitute of Oncology Research Faculty of Biomedical Sciences USI Bellinzona SwitzerlandInstitute of Oncology Research Faculty of Biomedical Sciences USI Bellinzona SwitzerlandOncolines BV OSS the NetherlandsThe Jackson Laboratory Farmington Connecticut USAInstitute of Oncology Research Faculty of Biomedical Sciences USI Bellinzona SwitzerlandFloratek Pharma SA Aubonne SwitzerlandABSTRACT Background Despite significant therapeutic progress, many lymphoma subtypes remain difficult to manage due to resistance, relapse, and dose‐limiting toxicity. Methods To elucidate the mechanism of action of the semi‐synthetic flavonoid derivative (SND) compounds, we conducted a screening of cancer cell lines using proliferation, cell cycle, and apoptosis assays. We then performed computational modeling of the compounds’ binding to tubulin, and finally evaluated in vivo activity using nanoNail technology alongside xenograft experiment. Results Here, we describe a series of SNDs that exhibit low‐nanomolar to picomolar cytotoxicity across multiple lymphoma models, including those resistant to BTK and PI3K inhibitors. Mechanistic studies show that these compounds trigger robust apoptosis via cytoskeletal disruption and mitochondrial dysfunction. Notably, SND207 also potently inhibits Protein Kinase N1, suggesting a synergistic link between kinase blockade and cytoskeletal interference. High‐throughput profiling places them near classical microtubule agents, although tubulin assays indicate more nuanced mechanisms than straightforward stabilization or depolymerization. In murine xenografts, SND207 significantly reduced tumor burden, and its combination with a BTK inhibitor demonstrates potential synergy. Furthermore, localized NanoNail delivery achieves high intratumoral drug concentrations at low doses, underscoring a favorable therapeutic index. Conclusions Overall, these findings highlight the translational promise of the SND series for future studies in the lymphoma field. Clinical Trial Registration The authors have confirmed clinical trial registration is not needed for this submission.https://doi.org/10.1002/jha2.70081 |
| spellingShingle | Eugenio Gaudio Paulina Biniecka Alberto J. Arribas Eleonora Cannas Guido J. R. Zaman Derya Unutmaz Francesco Bertoni Dan F. Stoicescu Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models eJHaem |
| title | Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models |
| title_full | Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models |
| title_fullStr | Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models |
| title_full_unstemmed | Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models |
| title_short | Novel Flavonoid Derivatives Show Potent Efficacy in Human Lymphoma Models |
| title_sort | novel flavonoid derivatives show potent efficacy in human lymphoma models |
| url | https://doi.org/10.1002/jha2.70081 |
| work_keys_str_mv | AT eugeniogaudio novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT paulinabiniecka novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT albertojarribas novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT eleonoracannas novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT guidojrzaman novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT deryaunutmaz novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT francescobertoni novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels AT danfstoicescu novelflavonoidderivativesshowpotentefficacyinhumanlymphomamodels |