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@ARTICLE{Elbadawi:275652,
      author       = {M. Elbadawi and J. C. Boulos and M. Dawood and M. Zhou and
                      W. Gul and M. A. ElSohly and S. Klauck$^*$ and T. Efferth},
      title        = {{T}he {N}ovel {A}rtemisinin {D}imer {I}soniazide
                      {ELI}-{XXIII}-98-2 {I}nduces c-{MYC} {I}nhibition, {DNA}
                      {D}amage, and {A}utophagy in {L}eukemia {C}ells.},
      journal      = {Pharmaceutics},
      volume       = {15},
      number       = {4},
      issn         = {1999-4923},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2023-00840},
      pages        = {1107},
      year         = {2023},
      abstract     = {The proto-oncogenic transcription factor c-MYC plays a
                      pivotal role in the development of tumorigenesis, cellular
                      proliferation, and the control of cell death. Its expression
                      is frequently altered in many cancer types, including
                      hematological malignancies such as leukemia. The dimer
                      isoniazide ELI-XXIII-98-2 is a derivative of the natural
                      product artemisinin, with two artemisinin molecules and an
                      isoniazide moiety as a linker in between them. In this
                      study, we aimed to study the anticancer activity and the
                      molecular mechanisms of this dimer molecule in
                      drug-sensitive CCRF-CEM leukemia cells and their
                      corresponding multidrug-resistant CEM/ADR5000 sub-line. The
                      growth inhibitory activity was studied using the resazurin
                      assay. To reveal the molecular mechanisms underlying the
                      growth inhibitory activity, we performed in silico molecular
                      docking, followed by several in vitro approaches such as the
                      MYC reporter assay, microscale thermophoresis, microarray
                      analyses, immunoblotting, qPCR, and comet assay. The
                      artemisinin dimer isoniazide showed a potent growth
                      inhibitory activity in CCRF-CEM but a 12-fold
                      cross-resistance in multidrug-resistant CEM/ADR5000 cells.
                      The molecular docking of artemisinin dimer isoniazide with
                      c-MYC revealed a good binding (lowest binding energy of
                      -9.84 ± 0.3 kcal/mol) and a predicted inhibition constant
                      (pKi) of 66.46 ± 29.5 nM, which was confirmed by microscale
                      thermophoresis and MYC reporter cell assays. Furthermore,
                      c-MYC expression was downregulated by this compound in
                      microarray hybridization and Western blotting analyses.
                      Finally, the artemisinin dimer isoniazide modulated the
                      expression of autophagy markers (LC3B and p62) and the DNA
                      damage marker pH2AX, indicating the stimulation of both
                      autophagy and DNA damage, respectively. Additionally, DNA
                      double-strand breaks were observed in the alkaline comet
                      assay. DNA damage, apoptosis, and autophagy induction could
                      be attributed to the inhibition of c-MYC by ELI-XXIII-98-2.},
      keywords     = {artemisinin (Other) / cell death (Other) / chemotherapy
                      (Other) / leukemia (Other) / oncogenes (Other) /
                      sesquiterpenoids (Other)},
      cin          = {B063 / HD01},
      ddc          = {610},
      cid          = {I:(DE-He78)B063-20160331 / 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:37111592},
      doi          = {10.3390/pharmaceutics15041107},
      url          = {https://inrepo02.dkfz.de/record/275652},
}