Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism
It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to int...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/6/1446 |
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| author | Dinh Hoa Hoang Corey Morales Ivan Rodriguez Rodriguez Melissa Valerio Jiamin Guo Min-Hsuan Chen Xiwei Wu David Horne Varsha Gandhi Lisa S. Chen Bin Zhang Vinod Pullarkat Steven T. Rosen Guido Marcucci Ralf Buettner Le Xuan Truong Nguyen |
| author_facet | Dinh Hoa Hoang Corey Morales Ivan Rodriguez Rodriguez Melissa Valerio Jiamin Guo Min-Hsuan Chen Xiwei Wu David Horne Varsha Gandhi Lisa S. Chen Bin Zhang Vinod Pullarkat Steven T. Rosen Guido Marcucci Ralf Buettner Le Xuan Truong Nguyen |
| author_sort | Dinh Hoa Hoang |
| collection | DOAJ |
| description | It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML. |
| first_indexed | 2024-03-09T13:48:05Z |
| format | Article |
| id | doaj.art-5828136d7d964d3f83462b45fe69048c |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T13:48:05Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-5828136d7d964d3f83462b45fe69048c2023-11-30T20:55:38ZengMDPI AGCancers2072-66942022-03-01146144610.3390/cancers14061446Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid MetabolismDinh Hoa Hoang0Corey Morales1Ivan Rodriguez Rodriguez2Melissa Valerio3Jiamin Guo4Min-Hsuan Chen5Xiwei Wu6David Horne7Varsha Gandhi8Lisa S. Chen9Bin Zhang10Vinod Pullarkat11Steven T. Rosen12Guido Marcucci13Ralf Buettner14Le Xuan Truong Nguyen15Gehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USACity of Hope National Medical Center, Integrative Genomics Core, Beckman Research Institute, Duarte, CA 91010, USACity of Hope National Medical Center, Integrative Genomics Core, Beckman Research Institute, Duarte, CA 91010, USADepartment of Molecular Medicine, City of Hope National Medical Center, Duarte, CA 91010, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USADepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAGehr Family Center for Leukemia Research, City of Hope National Medical Center, Hematology Malignancies and Stem Cell Transplantation Institute, Duarte, CA 91010, USAIt is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML.https://www.mdpi.com/2072-6694/14/6/1446acute myeloid leukemiavenetoclax8-chloro-adenosinerRNA synthesismetabolism |
| spellingShingle | Dinh Hoa Hoang Corey Morales Ivan Rodriguez Rodriguez Melissa Valerio Jiamin Guo Min-Hsuan Chen Xiwei Wu David Horne Varsha Gandhi Lisa S. Chen Bin Zhang Vinod Pullarkat Steven T. Rosen Guido Marcucci Ralf Buettner Le Xuan Truong Nguyen Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism Cancers acute myeloid leukemia venetoclax 8-chloro-adenosine rRNA synthesis metabolism |
| title | Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism |
| title_full | Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism |
| title_fullStr | Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism |
| title_full_unstemmed | Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism |
| title_short | Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism |
| title_sort | synergy of venetoclax and 8 chloro adenosine in aml the interplay of rrna inhibition and fatty acid metabolism |
| topic | acute myeloid leukemia venetoclax 8-chloro-adenosine rRNA synthesis metabolism |
| url | https://www.mdpi.com/2072-6694/14/6/1446 |
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