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@ARTICLE{Switzeny:302291,
      author       = {O. Switzeny and S. Pusch$^*$ and M. Christmann and B.
                      Kaina},
      title        = {{IDH}1 {M}utation {I}mpacts {DNA} {R}epair {T}hrough
                      {ALKBH}2 {R}endering {G}lioblastoma {C}ells {S}ensitive to
                      {A}rtesunate.},
      journal      = {Biomedicines},
      volume       = {13},
      number       = {6},
      issn         = {2227-9059},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2025-01310},
      pages        = {1479},
      year         = {2025},
      abstract     = {Background: Isocitrate dehydrogenase 1 and 2 (IDH1 and
                      IDH2) are enzymes that catalyze the oxidative
                      decarboxylation of isocitrate to alpha-ketoglutarate
                      (α-KG), which is essential for many metabolic processes,
                      including some steps in DNA repair. In tumors, notably in
                      gliomas, IDH1 and IDH2 are frequently mutated. The mutation
                      found in different cancers is functionally active, causing,
                      instead of α-KG, the formation of 2-hydroxyglutarate
                      (2-HG), which inhibits α-KG-dependent enzymes. Gliomas
                      harboring mutated IDH1/2 show a better prognosis than IDH1
                      wild-type (wt) tumors of the same grade, which might result
                      from the inhibition of DNA repair functions. A DNA repair
                      enzyme dependent on α-KG is alkB homolog 2 (ALKBH2), which
                      removes several lesions from DNA. These findings prompted us
                      to investigate the response of glioma cells to artesunate
                      (ART), a plant ingredient with genotoxic and anticancer
                      activity currently used in several trials. Materials and
                      Methods: We used isogenic glioblastoma cell lines that
                      express IDH1 wild-type or, based on a TET-inducible system,
                      the IDH1 mutant (mt) protein, and treated them with
                      increasing doses of artesunate. We also treated glioblastoma
                      cells with 2-HG, generated ALKBH2 knockout cells, and
                      checked their sensitivity to the cytotoxic effects of
                      artesunate. Results: We show that the cell-killing effect of
                      ART is enhanced if the IDH1 mutant (R132H) is expressed in
                      glioblastoma cells. Further, we show that 2-HG imitates the
                      effect of IDH1mt as 2-HG ameliorates the cytotoxicity of
                      ART. Finally, we demonstrate that the knockout of ALKBH2
                      causes the sensitization of glioblastoma cells to ART.
                      Conclusions: The data indicate that ALKBH2 protects against
                      the anticancer effect of ART, and the mutation of IDH1/2
                      commonly occurring in low-grade gliomas sensitizes to ART
                      via an ALKBH2-dependent mechanism. The data support the use
                      of ART in the therapy of IDH1/2-mutated cancers both in
                      combination with chemotherapy and adjuvant treatment.},
      keywords     = {ALKBH2 (Other) / DNA repair (Other) / IDH1 (Other) /
                      artesunate (Other) / glioblastoma (Other) / temozolomide
                      (Other)},
      cin          = {B300 / HD01},
      ddc          = {570},
      cid          = {I:(DE-He78)B300-20160331 / I:(DE-He78)HD01-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40564198},
      doi          = {10.3390/biomedicines13061479},
      url          = {https://inrepo02.dkfz.de/record/302291},
}