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

Jason Sallbach; Melanie Woods; Birgit Rasenberger; Markus Christmann; Maja T Tomicic

doi:10.1016/j.biopha.2024.117634

The cell cycle inhibitor p21^CIP1 is essential for irinotecan-induced senescence and plays a decisive role in re-sensitization of temozolomide-resistant glioblastoma cells to irinotecan

Biomed Pharmacother. 2024 Nov 2:181:117634. doi: 10.1016/j.biopha.2024.117634. Online ahead of print.

Authors

Jason Sallbach¹, Melanie Woods², Birgit Rasenberger³, Markus Christmann⁴, Maja T Tomicic⁵

Affiliations

¹ Department of Toxicology, University Medical Center of the Johannes Gutenberg University, Obere Zahlbacher Str. 67, Mainz D-55131, Germany. Electronic address: sallbacj@uni-mainz.de.
² Department of Toxicology, University Medical Center of the Johannes Gutenberg University, Obere Zahlbacher Str. 67, Mainz D-55131, Germany. Electronic address: medzulko@uni-mainz.de.
³ Department of Toxicology, University Medical Center of the Johannes Gutenberg University, Obere Zahlbacher Str. 67, Mainz D-55131, Germany. Electronic address: rasebi00@uni-mainz.de.
⁴ Department of Toxicology, University Medical Center of the Johannes Gutenberg University, Obere Zahlbacher Str. 67, Mainz D-55131, Germany. Electronic address: mchristm@uni-mainz.de.
⁵ Department of Toxicology, University Medical Center of the Johannes Gutenberg University, Obere Zahlbacher Str. 67, Mainz D-55131, Germany. Electronic address: tomicic@uni-mainz.de.

PMID: 39489121
DOI: 10.1016/j.biopha.2024.117634

Abstract

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, p21^CIP1, p16^INK4A, p14^ARF, 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^CIP1 protein levels in temozolomide-unexposed senescence-evading clones and inability of temozolomide to induce p21^CIP1. In contrast, irinotecan was still able to induce p21^CIP1 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: p21^CIP1 is essentially involved in induction and maintenance of irinotecan-induced senescence. Neither p16^INK4A, p14^ARF, nor PTEN contribute to senescence, if p21^CIP1 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.

Keywords: Glioblastoma; Irinotecan; P21(CIP1); PTEN; Senescence; TOP1 inhibitor.