Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation
Abstract KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme...
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| Format: | Article |
| Language: | English |
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BMC
2021-06-01
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| Series: | Journal of Hematology & Oncology |
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| Online Access: | https://doi.org/10.1186/s13045-021-01107-0 |
| _version_ | 1818907573914435584 |
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| author | Shaneice Mitchell Pu Zhang Matthew Cannon Larry Beaver Amy Lehman Bonnie Harrington Deepa Sampath John C. Byrd Rosa Lapalombella |
| author_facet | Shaneice Mitchell Pu Zhang Matthew Cannon Larry Beaver Amy Lehman Bonnie Harrington Deepa Sampath John C. Byrd Rosa Lapalombella |
| author_sort | Shaneice Mitchell |
| collection | DOAJ |
| description | Abstract KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor. |
| first_indexed | 2024-12-19T21:57:17Z |
| format | Article |
| id | doaj.art-fe02419664a049739c44ce0e6885ce29 |
| institution | Directory Open Access Journal |
| issn | 1756-8722 |
| language | English |
| last_indexed | 2024-12-19T21:57:17Z |
| publishDate | 2021-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Hematology & Oncology |
| spelling | doaj.art-fe02419664a049739c44ce0e6885ce292022-12-21T20:04:15ZengBMCJournal of Hematology & Oncology1756-87222021-06-011411510.1186/s13045-021-01107-0Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylationShaneice Mitchell0Pu Zhang1Matthew Cannon2Larry Beaver3Amy Lehman4Bonnie Harrington5Deepa Sampath6John C. Byrd7Rosa Lapalombella8Division of Hematology, The Ohio State UniversityDivision of Hematology, The Ohio State UniversityDivision of Hematology, The Ohio State UniversityDivision of Hematology, The Ohio State UniversityCenter for Biostatistics, Department of Bioinformatics, The Ohio State UniversityCollege of Veterinary Medicine, Michigan State UniversityDivision of Hematology, The Ohio State UniversityDivision of Hematology, The Ohio State UniversityDivision of Hematology, The Ohio State UniversityAbstract KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD+ production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD+ generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.https://doi.org/10.1186/s13045-021-01107-0NAMPTLeukemiaErythropoietinNiacinSOD |
| spellingShingle | Shaneice Mitchell Pu Zhang Matthew Cannon Larry Beaver Amy Lehman Bonnie Harrington Deepa Sampath John C. Byrd Rosa Lapalombella Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation Journal of Hematology & Oncology NAMPT Leukemia Erythropoietin Niacin SOD |
| title | Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation |
| title_full | Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation |
| title_fullStr | Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation |
| title_full_unstemmed | Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation |
| title_short | Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation |
| title_sort | anti tumor nampt inhibitor kpt 9274 mediates gender dependent murine anemia and nephrotoxicity by regulating sirt3 mediated sod deacetylation |
| topic | NAMPT Leukemia Erythropoietin Niacin SOD |
| url | https://doi.org/10.1186/s13045-021-01107-0 |
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