Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors
Background: Arsenic trioxide (ATO) is an anticancer agent for treating acute promyelocytic leukemia (APL). However, 5–10% of patients fail to respond, developing relapsed/refractory disease. The aim of this study was to identify potential new therapeutic approaches for ATO-unresponsive APL by target...
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MDPI AG
2024-11-01
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| author | Manuela Giansanti Tiziana Ottone Serena Travaglini Maria Teresa Voso Grazia Graziani Isabella Faraoni |
| author_facet | Manuela Giansanti Tiziana Ottone Serena Travaglini Maria Teresa Voso Grazia Graziani Isabella Faraoni |
| author_sort | Manuela Giansanti |
| collection | DOAJ |
| description | Background: Arsenic trioxide (ATO) is an anticancer agent for treating acute promyelocytic leukemia (APL). However, 5–10% of patients fail to respond, developing relapsed/refractory disease. The aim of this study was to identify potential new therapeutic approaches for ATO-unresponsive APL by targeting the anti-apoptotic genes that contribute to drug resistance. Methods: RNA expression of dysregulated genes involved in the apoptotic pathway was analyzed by comparing ATO-resistant APL cell clones generated in our lab with the corresponding sensitive clones, at basal levels and after 48 h of treatment with ATO. Results: ATO-resistant APL cells showed upregulation of <i>APAF1</i>, <i>BCL2</i>, <i>BIRC3</i>, and <i>NOL3</i> genes, while <i>CD70</i> and <i>IL10</i> genes were downregulated, compared to ATO-sensitive cells. Treatment with ATO strongly increased the expression of the anti-apoptotic genes <i>BIRC3</i>, <i>NOL3</i>, and <i>BCL2A1</i> and significantly downregulated <i>BCL2</i> in ATO-sensitive clones. Although all these genes can be relevant to ATO-resistance, we selected BCL2 and BIRC3 as druggable targets. A direct correlation between <i>BCL2</i> expression and the sensitivity to the BCL2 inhibitor venetoclax was observed, indicating <i>BCL2</i> as predictive biomarker of the response. Moreover, the combination of venetoclax with ATO exerted synergistic cytotoxic effects, thus reverting the resistance to ATO. APL treatment with SMAC mimetics such as LCL161 and xevinapant (inhibitors of BIRC3) was not as effective as the BCL2 inhibitor as a monotherapy but exerted synergistic effects in combination with ATO in cells with low <i>BIRC</i> expression. Conclusions: This study demonstrates the therapeutic potential of venetoclax in combination with ATO in vitro and strongly encourages further investigation of relapsed/refractory APL with high <i>BCL2</i> expression. |
| format | Article |
| id | doaj-art-2644cd1886e3415fb05146a7b5b15068 |
| institution | Kabale University |
| issn | 1424-8247 |
| language | English |
| publishDate | 2024-11-01 |
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| spelling | doaj-art-2644cd1886e3415fb05146a7b5b150682024-11-26T18:17:30ZengMDPI AGPharmaceuticals1424-82472024-11-011711152910.3390/ph17111529Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene InhibitorsManuela Giansanti0Tiziana Ottone1Serena Travaglini2Maria Teresa Voso3Grazia Graziani4Isabella Faraoni5Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Biomedicine and Prevention, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, ItalyDepartment of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, ItalyBackground: Arsenic trioxide (ATO) is an anticancer agent for treating acute promyelocytic leukemia (APL). However, 5–10% of patients fail to respond, developing relapsed/refractory disease. The aim of this study was to identify potential new therapeutic approaches for ATO-unresponsive APL by targeting the anti-apoptotic genes that contribute to drug resistance. Methods: RNA expression of dysregulated genes involved in the apoptotic pathway was analyzed by comparing ATO-resistant APL cell clones generated in our lab with the corresponding sensitive clones, at basal levels and after 48 h of treatment with ATO. Results: ATO-resistant APL cells showed upregulation of <i>APAF1</i>, <i>BCL2</i>, <i>BIRC3</i>, and <i>NOL3</i> genes, while <i>CD70</i> and <i>IL10</i> genes were downregulated, compared to ATO-sensitive cells. Treatment with ATO strongly increased the expression of the anti-apoptotic genes <i>BIRC3</i>, <i>NOL3</i>, and <i>BCL2A1</i> and significantly downregulated <i>BCL2</i> in ATO-sensitive clones. Although all these genes can be relevant to ATO-resistance, we selected BCL2 and BIRC3 as druggable targets. A direct correlation between <i>BCL2</i> expression and the sensitivity to the BCL2 inhibitor venetoclax was observed, indicating <i>BCL2</i> as predictive biomarker of the response. Moreover, the combination of venetoclax with ATO exerted synergistic cytotoxic effects, thus reverting the resistance to ATO. APL treatment with SMAC mimetics such as LCL161 and xevinapant (inhibitors of BIRC3) was not as effective as the BCL2 inhibitor as a monotherapy but exerted synergistic effects in combination with ATO in cells with low <i>BIRC</i> expression. Conclusions: This study demonstrates the therapeutic potential of venetoclax in combination with ATO in vitro and strongly encourages further investigation of relapsed/refractory APL with high <i>BCL2</i> expression.https://www.mdpi.com/1424-8247/17/11/1529APLarsenic resistanceapoptosisBCL2venetoclaxBIRC3 |
| spellingShingle | Manuela Giansanti Tiziana Ottone Serena Travaglini Maria Teresa Voso Grazia Graziani Isabella Faraoni Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors Pharmaceuticals APL arsenic resistance apoptosis BCL2 venetoclax BIRC3 |
| title | Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors |
| title_full | Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors |
| title_fullStr | Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors |
| title_full_unstemmed | Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors |
| title_short | Combination Treatment of Resistant Acute Promyelocytic Leukemia Cells with Arsenic Trioxide and Anti-Apoptotic Gene Inhibitors |
| title_sort | combination treatment of resistant acute promyelocytic leukemia cells with arsenic trioxide and anti apoptotic gene inhibitors |
| topic | APL arsenic resistance apoptosis BCL2 venetoclax BIRC3 |
| url | https://www.mdpi.com/1424-8247/17/11/1529 |
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