Full metadata record
DC Field | Value | Language |
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dc.contributor.author | 차선신 | * |
dc.date.accessioned | 2024-02-15T16:30:09Z | - |
dc.date.available | 2024-02-15T16:30:09Z | - |
dc.date.issued | 2023 | * |
dc.identifier.issn | 1838-7640 | * |
dc.identifier.other | OAK-34305 | * |
dc.identifier.uri | https://dspace.ewha.ac.kr/handle/2015.oak/267939 | - |
dc.description.abstract | Background: Exploiting synthetic lethality (SL) relationships between protein pairs has emerged as an important avenue for the development of anti-cancer drugs. Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme of the NAD+ salvage pathway, having an SL relationship with nicotinic acid phosphoribosyltransferase (NAPRT), the key enzyme in the NAD+ Preiss-Handler pathway. NAMPT inhibitor holds clinical potential not only as a promising cancer treatment but also as a means of protection against chemotherapy-induced-peripheral-neuropathy (CIPN). However, as NAD+ is essential for normal cells, the clinical use of NAMPT inhibitors is challenging. This study aimed to identify a novel NAMPT inhibitor with enhanced selective cytotoxicity against NAPRT-deficient cancer cells as well as prominent efficacy in alleviating CIPN.Methods: We began by conducting drug derivatives screening in a panel of lung cancer cell lines to select an agent with the broadest therapeutic window between the NAPRT-negative and-positive cancer cell lines. Both in vitro and In vivo comparative analyses were conducted between A4276 and other NAMPT inhibitors to evaluate the NAPRT-negative cancer cell selectivity and the underlying distinct NAMPT inhibition mechanism of A4276. Patient-derived tumor transcriptomic data and protein levels in various cancer cell lines were analyzed to confirm the correlation between NAPRT depletion and epithelial-to-mesenchymal transition (EMT)-like features in various cancer types. Finally, the efficacy of A4276 for axonal protection and CIPN remedy was examined in vitro and in vivo.Results: The biomarker-driven phenotypic screening led to a discovery of A4276 with prominent selectivity against NAPRT-negative cancer cells compared with NAPRT-positive cancer cells and normal cells. The cytotoxic effect of A4276 on NAPRT-negative cells is achieved through its direct binding to NAMPT, inhibiting its enzymatic function at an optimal and balanced level allowing NAPRT-positive cells to survive through NAPRT-dependent NAD+ synthesis. NAPRT deficiency serves as a biomarker for the response to A4276 as well as an indicator of EMT-subtype cancer in various tumor types. Notably, A4276 protects axons from Wallerian degeneration more effectively than other NAMPT inhibitors by decreasing NMN-to-NAD+ ratio.Conclusion: This study demonstrates that A4276 selectively targets NAPRT-deficient EMT-subtype cancer cells and prevents chemotherapy-induced peripheral neuropathy, highlighting its potential as a promising anti-cancer agent for use in cancer monotherapy or combination therapy with conventional chemotherapeutics. | * |
dc.language | English | * |
dc.publisher | IVYSPRING INT PUBL | * |
dc.subject | Synthetic lethality | * |
dc.subject | NAMPT inhibitor | * |
dc.subject | Epithelial-to-mesenchymal transition (EMT) | * |
dc.subject | Wallerian degeneration | * |
dc.subject | Chemotherapy-induced peripheral neuropathy (CIPN) | * |
dc.title | Discovery of a novel NAMPT inhibitor that selectively targets NAPRT-deficient EMT-subtype cancer cells and alleviates chemotherapy-induced peripheral neuropathy | * |
dc.type | Article | * |
dc.relation.issue | 14 | * |
dc.relation.volume | 13 | * |
dc.relation.index | SCIE | * |
dc.relation.index | SCOPUS | * |
dc.relation.startpage | 5075 | * |
dc.relation.lastpage | 5098 | * |
dc.relation.journaltitle | THERANOSTICS | * |
dc.identifier.doi | 10.7150/thno.85356 | * |
dc.identifier.wosid | WOS:001085028000020 | * |
dc.author.google | Kim, Minjee | * |
dc.author.google | Kim, Hyeyoung | * |
dc.author.google | Kang, Bu-Gyeong | * |
dc.author.google | Lee, Jooyoung | * |
dc.author.google | Kim, Taegun | * |
dc.author.google | Lee, Hwanho | * |
dc.author.google | Jung, Jane | * |
dc.author.google | Oh, Myung Joon | * |
dc.author.google | Seo, Seungyoon | * |
dc.author.google | Ryu, Myung-Jeom | * |
dc.author.google | Sung, Yeojin | * |
dc.author.google | Lee, Yunji | * |
dc.author.google | Yeom, Jeonghun | * |
dc.author.google | Han, Gyoonhee | * |
dc.author.google | Cha, Sun-Shin | * |
dc.author.google | Jung, Hosung | * |
dc.author.google | Kim, Hyun Seok | * |
dc.contributor.scopusid | 차선신(7201864593) | * |
dc.date.modifydate | 20240429134916 | * |