{
  "abstract": "Advanced systemic mastocytosis (advSM), including aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN) and mast cell leukemia (MCL), are rare, mostly KIT D816V-driven malignancies with a poor prognosis. KIT D816V-targeting drugs, such as midostaurin or avapritinib, can induce hematologic responses in most patients with advSM. However, relapses may occur. Therefore, current research focuses on novel drugs and drug combinations to improve outcomes in advSM. We here describe that the synthetic triterpenoids bardoxolone methyl and omaveloxolone suppress proliferation in various human MCL-like cell lines expressing or lacking KIT D816V, with IC50 values of 0.2–0.4 µM. Growth-inhibitory effects were accompanied by induction of apoptosis, decreased surface expression of CD44, CD71 and KIT, and downregulation of cytoplasmic AKT. Antiproliferative effects of bardoxolone methyl and omaveloxolone were also observed in primary neoplastic cells obtained from patients with advSM. Moreover, both synthetic triterpenoids were found to cooperate with midostaurin and avapritinib in suppressing the proliferation of HMC-1 and MCPV-1 cells. However, bardoxolone methyl and omaveloxolone also augmented expression of heme oxygenase-1 (HO-1), a mediator of cell survival and drug resistance in these cells. The HO-1 inhibitor SMA-ZnPP was subsequently applied and found to sensitize neoplastic mast cells against synthetic triterpenoids and KIT D816V-targeting drugs. Together, application of bardoxolone methyl and omaveloxolone, as single agents or in drug combinations involving HO-1 blockers and/or KIT D816V-targeting drugs, may be a suitable strategy to improve therapy and to overcome resistance in advSM. The clinical value of this combination approach remains to be assessed in clinical trials.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria",
    "Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria",
    "Department of Medicine III, Division of Hepatology and Gastroenterology, Medical University of Vienna, 1090 Vienna, Austria",
    "Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan",
    "Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA",
    "Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, 68167 Mannheim, Germany",
    "Departments of Oncology and Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA",
    "Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA",
    "MLL Munich Leukemia Laboratory, 81377 Munich, Germany",
    "French Reference Network for Mastocytosis (CEREMAST) and Department of Hematological Biology, Pitié-Salpêtrière Hospital, AP-HP, Paris Sorbonne University, 75013 Paris, France",
    "Research Institute of Molecular Pathology (IMP), Vienna BioCenter (VBC), 1030 Vienna, Austria",
    "Medical University of Vienna, Vienna BioCenter (VBC), 1030 Vienna, Austria",
    "Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria"
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 21,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Max Vincent John"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Yüksel Filik Schüppler"
    },
    {
      "affs": [
        0
      ],
      "name": "Nadine Witzeneder"
    },
    {
      "affs": [
        1,
        2
      ],
      "name": "Mathias Schneeweiss-Gleixner",
      "orcid": "0009-0001-5296-1212"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Barbara Peter"
    },
    {
      "affs": [
        0
      ],
      "name": "Daniela Berger"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Gabriele Stefanzl"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Isma Ishaq-Parveen"
    },
    {
      "affs": [
        3
      ],
      "name": "Jun Fang"
    },
    {
      "affs": [
        4
      ],
      "name": "Waliul Islam",
      "orcid": "0000-0001-5609-7540"
    },
    {
      "affs": [
        5
      ],
      "name": "Juliana Schwaab"
    },
    {
      "affs": [
        5
      ],
      "name": "Andreas Reiter"
    },
    {
      "affs": [
        6
      ],
      "name": "Marina Konopleva",
      "orcid": "0000-0002-9347-2212"
    },
    {
      "affs": [
        7
      ],
      "name": "Michael Andreeff",
      "orcid": "0000-0002-1144-1958"
    },
    {
      "affs": [
        1,
        8
      ],
      "name": "Gregor Hoermann",
      "orcid": "0000-0002-7374-4380"
    },
    {
      "affs": [
        9
      ],
      "name": "Michel Arock",
      "orcid": "0000-0002-3990-4408"
    },
    {
      "affs": [
        10,
        11
      ],
      "name": "Johannes Zuber"
    },
    {
      "affs": [
        12
      ],
      "name": "Klaus Schmetterer",
      "orcid": "0000-0001-9328-4871"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Wolfgang R. Sperr"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Peter Valent",
      "orcid": "0000-0003-0456-5095"
    },
    {
      "affs": [
        0,
        1
      ],
      "name": "Karoline V. Gleixner"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/67ky220qj1kpp.bib",
  "cited_by": 0,
  "doi": "10.3390/cells15201898",
  "fulltext_url": "https://europepmc.org/articles/PMC13703063",
  "id": "67ky220qj1kpp",
  "issns": [
    "2073-4409"
  ],
  "landing_url": "https://www.mdpi.com/2073-4409/15/20/1898",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "2403|Mast cells and histamine"
    ]
  ],
  "openalex": "W7222982198",
  "pdf_url": "https://europepmc.org/articles/PMC13703063?pdf=render",
  "pmcid": "PMC13703063",
  "pmid": "42929870",
  "published": "2026-10-19",
  "publisher": "MDPI AG",
  "ris": "https://research.draconitic.com/paper/67ky220qj1kpp.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:02Z",
      "native_id": "10.3390/cells15201898",
      "source": "crossref",
      "url": "https://www.mdpi.com/2073-4409/15/20/1898"
    },
    {
      "first_seen": "2026-10-30T12:22:01Z",
      "native_id": "MED:42929870",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42929870"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "openalex:2403|Mast cells and histamine",
      "subfield": "immunology"
    }
  ],
  "title": "Triterpenoid Exposure and HO-1 Blockade Sensitize Neoplastic Mast Cells Against Midostaurin and Avapritinib",
  "title_text": "Triterpenoid Exposure and HO-1 Blockade Sensitize Neoplastic Mast Cells Against Midostaurin and Avapritinib",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:22:01Z",
  "url": "https://research.draconitic.com/paper/67ky220qj1kpp",
  "venue": "Cells",
  "versions": []
}