Jason Sallbach, Melanie Woods, Birgit Rasenberger, Markus Christmann , Maja T. Tomicic
{"title":"细胞周期抑制剂 p21CIP1 对伊立替康诱导的衰老至关重要,并在耐替莫唑胺的胶质母细胞瘤细胞对伊立替康的再敏感化过程中起着决定性作用。","authors":"Jason Sallbach, Melanie Woods, Birgit Rasenberger, Markus Christmann , Maja T. Tomicic","doi":"10.1016/j.biopha.2024.117634","DOIUrl":null,"url":null,"abstract":"<div><h3>Background and purpose</h3><div>Standard of care for glioblastomas includes radio-chemotherapy with the monoalkylating compound temozolomide. Temozolomide induces primarily senescence, inefficiently killing glioblastoma cells. Recurrences are inevitable. Although recurrences presumably arise from cells evading/escaping TMZ-induced senescence, becoming resistant, they are often again treated with TMZ. As an alternative treatment, irinotecan could be used. Our aim was to examine to what extent and conditions the topoisomerase I inhibitor irinotecan induces senescence and to analyze the underlying mechanism.</div></div><div><h3>Results</h3><div>Multiple glioblastoma lines with different genetic signatures for p53, p21<sup>CIP1</sup>, p16<sup>INK4A</sup>, p14<sup>ARF</sup>, and PTEN were used. By means of LN229 glioblastoma clones which escaped from temozolomide-induced senescence, thus, being potentially recurrence-forming, we show that this escape is accompanied by increased p21<sup>CIP1</sup> protein levels in temozolomide-unexposed senescence-evading clones and inability of temozolomide to induce p21<sup>CIP1</sup>. In contrast, irinotecan was still able to induce p21<sup>CIP1</sup> and could elevate senescence and cell death. In combination with the senolytic drug BV6, irinotecan-induced senescence was significantly reduced. Differential response clusters were also observed in paired samples of newly diagnosed and recurrent patients’ tumors. This can partially explain a significantly prolonged progression-free time until surgery for recurrence in patients additionally treated with irinotecan after temozolomide consolidation and upon the first onset of recurrence.</div></div><div><h3>Conclusions</h3><div>p21<sup>CIP1</sup> is essentially involved in induction and maintenance of irinotecan-induced senescence. Neither p16<sup>INK4A</sup>, p14<sup>ARF</sup>, nor PTEN contribute to senescence, if p21<sup>CIP1</sup> cannot be induced. Based on the positive results of the irinotecan/BV6 treatment, combatting recurrent glioblastomas by targeting senescence cell antiapoptotic pathways (SCAPs) should be considered.</div></div>","PeriodicalId":8966,"journal":{"name":"Biomedicine & Pharmacotherapy","volume":"181 ","pages":"Article 117634"},"PeriodicalIF":6.9000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The cell cycle inhibitor p21CIP1 is essential for irinotecan-induced senescence and plays a decisive role in re-sensitization of temozolomide-resistant glioblastoma cells to irinotecan\",\"authors\":\"Jason Sallbach, Melanie Woods, Birgit Rasenberger, Markus Christmann , Maja T. Tomicic\",\"doi\":\"10.1016/j.biopha.2024.117634\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background and purpose</h3><div>Standard of care for glioblastomas includes radio-chemotherapy with the monoalkylating compound temozolomide. Temozolomide induces primarily senescence, inefficiently killing glioblastoma cells. Recurrences are inevitable. Although recurrences presumably arise from cells evading/escaping TMZ-induced senescence, becoming resistant, they are often again treated with TMZ. As an alternative treatment, irinotecan could be used. Our aim was to examine to what extent and conditions the topoisomerase I inhibitor irinotecan induces senescence and to analyze the underlying mechanism.</div></div><div><h3>Results</h3><div>Multiple glioblastoma lines with different genetic signatures for p53, p21<sup>CIP1</sup>, p16<sup>INK4A</sup>, p14<sup>ARF</sup>, and PTEN were used. By means of LN229 glioblastoma clones which escaped from temozolomide-induced senescence, thus, being potentially recurrence-forming, we show that this escape is accompanied by increased p21<sup>CIP1</sup> protein levels in temozolomide-unexposed senescence-evading clones and inability of temozolomide to induce p21<sup>CIP1</sup>. In contrast, irinotecan was still able to induce p21<sup>CIP1</sup> and could elevate senescence and cell death. In combination with the senolytic drug BV6, irinotecan-induced senescence was significantly reduced. Differential response clusters were also observed in paired samples of newly diagnosed and recurrent patients’ tumors. This can partially explain a significantly prolonged progression-free time until surgery for recurrence in patients additionally treated with irinotecan after temozolomide consolidation and upon the first onset of recurrence.</div></div><div><h3>Conclusions</h3><div>p21<sup>CIP1</sup> is essentially involved in induction and maintenance of irinotecan-induced senescence. Neither p16<sup>INK4A</sup>, p14<sup>ARF</sup>, nor PTEN contribute to senescence, if p21<sup>CIP1</sup> cannot be induced. Based on the positive results of the irinotecan/BV6 treatment, combatting recurrent glioblastomas by targeting senescence cell antiapoptotic pathways (SCAPs) should be considered.</div></div>\",\"PeriodicalId\":8966,\"journal\":{\"name\":\"Biomedicine & Pharmacotherapy\",\"volume\":\"181 \",\"pages\":\"Article 117634\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2024-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomedicine & Pharmacotherapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0753332224015208\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomedicine & Pharmacotherapy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0753332224015208","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
The cell cycle inhibitor p21CIP1 is essential for irinotecan-induced senescence and plays a decisive role in re-sensitization of temozolomide-resistant glioblastoma cells to irinotecan
Background and purpose
Standard of care for glioblastomas includes radio-chemotherapy with the monoalkylating compound temozolomide. Temozolomide induces primarily senescence, inefficiently killing glioblastoma cells. Recurrences are inevitable. Although recurrences presumably arise from cells evading/escaping TMZ-induced senescence, becoming resistant, they are often again treated with TMZ. As an alternative treatment, irinotecan could be used. Our aim was to examine to what extent and conditions the topoisomerase I inhibitor irinotecan induces senescence and to analyze the underlying mechanism.
Results
Multiple glioblastoma lines with different genetic signatures for p53, p21CIP1, p16INK4A, p14ARF, and PTEN were used. By means of LN229 glioblastoma clones which escaped from temozolomide-induced senescence, thus, being potentially recurrence-forming, we show that this escape is accompanied by increased p21CIP1 protein levels in temozolomide-unexposed senescence-evading clones and inability of temozolomide to induce p21CIP1. In contrast, irinotecan was still able to induce p21CIP1 and could elevate senescence and cell death. In combination with the senolytic drug BV6, irinotecan-induced senescence was significantly reduced. Differential response clusters were also observed in paired samples of newly diagnosed and recurrent patients’ tumors. This can partially explain a significantly prolonged progression-free time until surgery for recurrence in patients additionally treated with irinotecan after temozolomide consolidation and upon the first onset of recurrence.
Conclusions
p21CIP1 is essentially involved in induction and maintenance of irinotecan-induced senescence. Neither p16INK4A, p14ARF, nor PTEN contribute to senescence, if p21CIP1 cannot be induced. Based on the positive results of the irinotecan/BV6 treatment, combatting recurrent glioblastomas by targeting senescence cell antiapoptotic pathways (SCAPs) should be considered.
期刊介绍:
Biomedicine & Pharmacotherapy stands as a multidisciplinary journal, presenting a spectrum of original research reports, reviews, and communications in the realms of clinical and basic medicine, as well as pharmacology. The journal spans various fields, including Cancer, Nutriceutics, Neurodegenerative, Cardiac, and Infectious Diseases.