(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation
Abstract Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently...
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Nature Portfolio
2025-05-01
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| Online Access: | https://doi.org/10.1038/s41598-025-98534-7 |
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| author | Hiroshi Ureshino Taichi Ueshima Tomonori Yamaguchi Miyuki Takashima Yusuke Sanuki Tatsuo Ichinohe |
| author_facet | Hiroshi Ureshino Taichi Ueshima Tomonori Yamaguchi Miyuki Takashima Yusuke Sanuki Tatsuo Ichinohe |
| author_sort | Hiroshi Ureshino |
| collection | DOAJ |
| description | Abstract Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently upregulated in VEN-resistant cells, playing a major role in VEN resistance. Previously, we demonstrated that (R)-WAC-224 is effective against AML with minimal cardiac toxicity. (R)-WAC-224 combined with VEN demonstrated strong antileukemia effects on VEN-resistant AML cells overexpressing MCL-1 in vitro. Gene expression profiles revealed that (R)-WAC-224 with VEN induced DNA damage pathways leading to cell apoptosis. (R)-WAC-224 elicited caspase 3 activation, which cleaved MCL-1; this effect was reversed by a caspase inhibitor, thus overcoming VEN resistance. A combination of azacitidine (AZA), a hypomethylating agent, VEN, and (R)-WAC-224 was highly effective against VEN-resistant AML in vivo without increasing toxicity. (R)-WAC-224 exhibited antileukemia effects on VEN-resistant AML via MCL-1 downregulation in vitro and in vivo. The combination of AZA, VEN, and (R)-WAC-224 may be a promising treatment strategy for patients with AML. |
| format | Article |
| id | doaj-art-f91f56efecb0419a86c1850bf125e0e7 |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Portfolio |
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| spelling | doaj-art-f91f56efecb0419a86c1850bf125e0e72025-08-20T01:49:47ZengNature PortfolioScientific Reports2045-23222025-05-011511910.1038/s41598-025-98534-7(R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulationHiroshi Ureshino0Taichi Ueshima1Tomonori Yamaguchi2Miyuki Takashima3Yusuke Sanuki4Tatsuo Ichinohe5Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima UniversityDrug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.Drug Discovery Laboratory, Wakunaga Pharmaceutical Co., Ltd.Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima UniversityAbstract Hypomethylating agents combined with venetoclax (VEN), a BCL-2 inhibitor, represent a standard treatment strategy for patients with acute myeloid leukemia (AML). Although this combination is highly effective, acquired resistance commonly occurs. MCL-1, a BCL-2 family molecule, is frequently upregulated in VEN-resistant cells, playing a major role in VEN resistance. Previously, we demonstrated that (R)-WAC-224 is effective against AML with minimal cardiac toxicity. (R)-WAC-224 combined with VEN demonstrated strong antileukemia effects on VEN-resistant AML cells overexpressing MCL-1 in vitro. Gene expression profiles revealed that (R)-WAC-224 with VEN induced DNA damage pathways leading to cell apoptosis. (R)-WAC-224 elicited caspase 3 activation, which cleaved MCL-1; this effect was reversed by a caspase inhibitor, thus overcoming VEN resistance. A combination of azacitidine (AZA), a hypomethylating agent, VEN, and (R)-WAC-224 was highly effective against VEN-resistant AML in vivo without increasing toxicity. (R)-WAC-224 exhibited antileukemia effects on VEN-resistant AML via MCL-1 downregulation in vitro and in vivo. The combination of AZA, VEN, and (R)-WAC-224 may be a promising treatment strategy for patients with AML.https://doi.org/10.1038/s41598-025-98534-7Acute myeloid leukemia(R)-WAC-224Anticancer quinoloneVenetoclaxMCL-1 |
| spellingShingle | Hiroshi Ureshino Taichi Ueshima Tomonori Yamaguchi Miyuki Takashima Yusuke Sanuki Tatsuo Ichinohe (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation Scientific Reports Acute myeloid leukemia (R)-WAC-224 Anticancer quinolone Venetoclax MCL-1 |
| title | (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation |
| title_full | (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation |
| title_fullStr | (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation |
| title_full_unstemmed | (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation |
| title_short | (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation |
| title_sort | r wac 224 a new anticancer quinolone combined with venetoclax and azacitidine overcomes venetoclax resistant aml through mcl 1 downregulation |
| topic | Acute myeloid leukemia (R)-WAC-224 Anticancer quinolone Venetoclax MCL-1 |
| url | https://doi.org/10.1038/s41598-025-98534-7 |
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