Pixantrone demonstrates significant in vitro activity against multiple myeloma and plasma cell leukemia

Ann Hematol. 2019 Nov;98(11):2569-2578. doi: 10.1007/s00277-019-03797-6. Epub 2019 Oct 18.

Abstract

Treatment results for multiple myeloma and plasma cell leukemia have considerably improved, but cure remains elusive and establishing new therapeutic approaches constitutes a major unmet clinical need. We analyzed the anti-myeloma properties of the aza-anthracenedione pixantrone which has been successfully used in a phase III study for the treatment of patients with aggressive non-Hodgkin's lymphoma as monotherapy as well as in combination regimes in vitro and in an adapted in vivo model (ex ovo chicken chorioallantoic membrane (CAM) assay). Pixantrone significantly inhibited proliferation and metabolic activity of all investigated myeloma cell lines. Importantly, anti-myeloma effects were more pronounced in tumor cell lines than in stromal cells, mesenchymal stem cells, and peripheral blood mononuclear cells of healthy controls. Apoptosis of myeloma cell lines was observed only after a 7-day incubation period, indicating a fast cytostatic and a slower cytotoxic effect of this drug. Pixantrone reduced the viability of primary plasma cells of patients and induced downregulation of myeloma-cell growth in the CAM assay. Additionally, we demonstrate in vitro synergism between pixantrone and the histone deacetylase inhibitor panobinostat with respect to its anti-proliferative features. From these data, we conclude that systematic investigations of the clinical usefulness of pixantrone in the framework of controlled clinical trials are clearly indicated (e.g., in penta-refractory patients).

Keywords: Anti-myeloma activity; Drug screening; Multiple myeloma; Pixantrone; Plasma cell leukemia.

Publication types

  • Review

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Apoptosis / drug effects
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Chick Embryo
  • Chorioallantoic Membrane / drug effects
  • Clinical Trials as Topic
  • Drug Screening Assays, Antitumor
  • Drug Synergism
  • Energy Metabolism / drug effects
  • Female
  • Humans
  • Isoquinolines / administration & dosage
  • Isoquinolines / pharmacology
  • Isoquinolines / therapeutic use*
  • Leukemia, Plasma Cell / drug therapy*
  • Leukocytes, Mononuclear / drug effects
  • Male
  • Middle Aged
  • Mitochondria / drug effects
  • Multiple Myeloma / drug therapy*
  • Panobinostat / pharmacology
  • Retrospective Studies

Substances

  • Antineoplastic Agents
  • Isoquinolines
  • Panobinostat
  • pixantrone