@article{BoulosSaeedChatterjeeetal.2021,
  author    = {Boulos, Joelle C. and Saeed, Mohamed E. M. and Chatterjee, Manik and B{\"u}lb{\"u}l, Yagmur and Crudo, Francesco and Marko, Doris and Munder, Markus and Klauck, Sabine M. and Efferth, Thomas},
  title     = {Repurposing of the ALK inhibitor crizotinib for acute leukemia and multiple myeloma cells},
  series = {Pharmaceuticals},
  volume    = {14},
  journal   = {Pharmaceuticals},
  number    = {11},
  issn      = {1424-8247},
  doi       = {10.3390/ph14111126},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-250258},
  year      = {2021},
  abstract  = {Crizotinib was a first generation of ALK tyrosine kinase inhibitor approved for the treatment of ALK-positive non-small-cell lung carcinoma (NSCLC) patients. COMPARE and cluster analyses of transcriptomic data of the NCI cell line panel indicated that genes with different cellular functions regulated the sensitivity or resistance of cancer cells to crizotinib. Transcription factor binding motif analyses in gene promoters divulged two transcription factors possibly regulating the expression of these genes, i.e., RXRA and GATA1, which are important for leukemia and erythroid development, respectively. COMPARE analyses also implied that cell lines of various cancer types displayed varying degrees of sensitivity to crizotinib. Unexpectedly, leukemia but not lung cancer cells were the most sensitive cells among the different types of NCI cancer cell lines. Re-examining this result in another panel of cell lines indeed revealed that crizotinib exhibited potent cytotoxicity towards acute myeloid leukemia and multiple myeloma cells. P-glycoprotein-overexpressing CEM/ADR5000 leukemia cells were cross-resistant to crizotinib. NCI-H929 multiple myeloma cells were the most sensitive cells. Hence, we evaluated the mode of action of crizotinib on these cells. Although crizotinib is a TKI, it showed highest correlation rates with DNA topoisomerase II inhibitors and tubulin inhibitors. The altered gene expression profiles after crizotinib treatment predicted several networks, where TOP2A and genes related to cell cycle were downregulated. Cell cycle analyses showed that cells incubated with crizotinib for 24 h accumulated in the G\(_2\)M phase. Crizotinib also increased the number of p-H3(Ser10)-positive NCI-H929 cells illustrating crizotinib's ability to prevent mitotic exit. However, cells accumulated in the sub-G\(_0\)G\(_1\) fraction with longer incubation periods, indicating apoptosis induction. Additionally, crizotinib disassembled the tubulin network of U2OS cells expressing an α-tubulin-GFP fusion protein, preventing migration of cancer cells. This result was verified by in vitro tubulin polymerization assays. In silico molecular docking also revealed a strong binding affinity of crizotinib to the colchicine and Vinca alkaloid binding sites. Taken together, these results demonstrate that crizotinib destabilized microtubules. Additionally, the decatenation assay showed that crizotinib partwise inhibited the catalytic activity of DNA topoisomerase II. In conclusion, crizotinib exerted kinase-independent cytotoxic effects through the dual inhibition of tubulin polymerization and topoisomerase II and might be used to treat not only NSCLC but also multiple myeloma.},
  language  = {en}
}
@article{ZioutiRummlerSteynetal.2021,
  author    = {Ziouti, Fani and Rummler, Maximilian and Steyn, Beatrice and Thiele, Tobias and Seliger, Anne and Duda, Georg N. and Bogen, Bjarne and Willie, Bettina M. and Jundt, Franziska},
  title     = {Prevention of bone destruction by mechanical loading is not enhanced by the Bruton's tyrosine kinase inhibitor CC-292 in myeloma bone disease},
  series = {International Journal of Molecular Sciences},
  volume    = {22},
  journal   = {International Journal of Molecular Sciences},
  number    = {8},
  issn      = {1422-0067},
  doi       = {10.3390/ijms22083840},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284943},
  year      = {2021},
  abstract  = {Limiting bone resorption and regenerating bone tissue are treatment goals in myeloma bone disease (MMBD). Physical stimuli such as mechanical loading prevent bone destruction and enhance bone mass in the MOPC315.BM.Luc model of MMBD. It is unknown whether treatment with the Bruton's tyrosine kinase inhibitor CC-292 (spebrutinib), which regulates osteoclast differentiation and function, augments the anabolic effect of mechanical loading. CC-292 was administered alone and in combination with axial compressive tibial loading in the MOPC315.BM.Luc model for three weeks. However, neither CC-292 alone nor its use in combination with mechanical loading was more effective in reducing osteolytic bone disease or rescuing bone mass than mechanical stimuli alone, as evidenced by microcomputed tomography (microCT) and histomorphometric analysis. Further studies are needed to investigate novel anti-myeloma and anti-resorptive strategies in combination with physical stimuli to improve treatment of MMBD.},
  language  = {en}
}
@article{SolimandoKrebsBittrichetal.2022,
  author    = {Solimando, Antonio Giovanni and Krebs, Markus and Bittrich, Max and Einsele, Hermann},
  title     = {The urgent need for precision medicine in cancer and its microenvironment: the paradigmatic case of multiple myeloma},
  series = {Journal of Clinical Medicine},
  volume    = {11},
  journal   = {Journal of Clinical Medicine},
  number    = {18},
  issn      = {2077-0383},
  doi       = {10.3390/jcm11185461},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288164},
  year      = {2022},
  abstract  = {No abstract available},
  language  = {en}
}
@article{BruennertSeupelGoyaletal.2023,
  author    = {Br{\"u}nnert, Daniela and Seupel, Raina and Goyal, Pankaj and Bach, Matthias and Schraud, Heike and Kirner, Stefanie and K{\"o}ster, Eva and Feineis, Doris and Bargou, Ralf C. and Schlosser, Andreas and Bringmann, Gerhard and Chatterjee, Manik},
  title     = {Ancistrocladinium A induces apoptosis in proteasome inhibitor-resistant multiple myeloma cells: a promising therapeutic agent candidate},
  series = {Pharmaceuticals},
  volume    = {16},
  journal   = {Pharmaceuticals},
  number    = {8},
  issn      = {1424-8247},
  doi       = {10.3390/ph16081181},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-362887},
  year      = {2023},
  abstract  = {The N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A belongs to a novel class of natural products with potent antiprotozoal activity. Its effects on tumor cells, however, have not yet been explored. We demonstrate the antitumor activity of ancistrocladinium A in multiple myeloma (MM), a yet incurable blood cancer that represents a model disease for adaptation to proteotoxic stress. Viability assays showed a potent apoptosis-inducing effect of ancistrocladinium A in MM cell lines, including those with proteasome inhibitor (PI) resistance, and in primary MM cells, but not in non-malignant blood cells. Concomitant treatment with the PI carfilzomib or the histone deacetylase inhibitor panobinostat strongly enhanced the ancistrocladinium A-induced apoptosis. Mass spectrometry with biotinylated ancistrocladinium A revealed significant enrichment of RNA-splicing-associated proteins. Affected RNA-splicing-associated pathways included genes involved in proteotoxic stress response, such as PSMB5-associated genes and the heat shock proteins HSP90 and HSP70. Furthermore, we found strong induction of ATF4 and the ATM/H2AX pathway, both of which are critically involved in the integrated cellular response following proteotoxic and oxidative stress. Taken together, our data indicate that ancistrocladinium A targets cellular stress regulation in MM and improves the therapeutic response to PIs or overcomes PI resistance, and thus may represent a promising potential therapeutic agent.},
  language  = {en}
}