β-lapachone, a novel plant product, overcomes drug resistance in human multiple myeloma cells

Deepak Gupta, Klaus Podar, Yu Tzu Tai, Boris Lin, Teru Hideshima, Masaharu Akiyama, Richard LeBlanc, Laurence Catley, Nicholas Mitsiades, Constantine Mitsiades, Dharminder Chauhan, Nikhil C Munshi, Kenneth C Anderson

Research output: Journal article (peer-reviewed)Journal article

33 Citations (Scopus)

Abstract

Objective. To evaluate the anti-tumor potential of β-lapachone in multiple myeloma (MM) cell lines (U266, RPMI8226, and MM.1S); MM cell lines resistant to dexamethasone (MM.1R), melphalan (RPMI8226/LR5), doxorubicin (RPMI8226/DOX40), and mitoxantrone (RPMI8226/ MR20); and MM cells from patients (MM1-MM4). Materials and Methods. Cytotoxicity of β-lapachone was assessed by MTT and [ 3H]-thymidine uptake assays. Apoptosis was analyzed using propidium iodide staining, DNA fragmentation, TUNEL assay, caspase-9 colorimetric assay, and immunoblotting for caspase-3, poly (ADP-ribose) polymerase (PARP), and caspase-8 cleavage products. Paracrine growth of MM cells was assessed by [ 3H]-thymidine uptake in cultures of bone marrow stromal cells (BMSCs) and MM cells. Interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF) secretion in the culture supernatants was measured by specific enzyme-linked immunosorbent assays (ELISAs). Results. β-lapachone showed significant cytotoxicity in MM cells (IC 50: 4-8 μM). In contrast, normal peripheral blood mononuclear cells (PBMCs) and BMSCs from MM patients were relatively resistant (IC 50: 8-16 μM). IL-6 did not protect against β-lapachone-induced apoptosis in MM.1S cells, and dexamethasone showed additive cytotoxicity. β-lapachone also decreased binding of MM.1S cells to BMSCs; abrogated IL-6 and VEGF secretion triggered by adhesion of BMSCs to MM.1S cells; reduced proliferation of MM.1S cells adherent to BMSCs; and decreased intracellular adhesion molecule-1 (ICAM-1) expression on MM.1S cells. Furthermore, β-lapachone induced typical PARP cleavage, increased caspase-9 proteolytic activity, and activation of caspase-3, without activation of caspase-8 in U266 cells. Conclusion. These studies provide a framework for clinical evaluation of β-lapachone to improve the outcome for patients with MM.

Original languageEnglish
Pages (from-to)711-720
Number of pages10
JournalExperimental Hematology
Volume30
Issue number7
DOIs
Publication statusPublished - Jul 2002
Externally publishedYes

Keywords

  • Antibiotics, Antineoplastic/pharmacology
  • Antineoplastic Agents, Phytogenic/pharmacology
  • Apoptosis/drug effects
  • Bone Marrow Cells/cytology
  • Caspases/metabolism
  • Cell Adhesion/drug effects
  • Cell Division/drug effects
  • Dexamethasone/pharmacology
  • Doxorubicin/pharmacology
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Enzyme Activation/drug effects
  • Enzyme Inhibitors/pharmacology
  • Enzyme Precursors/metabolism
  • Humans
  • Intercellular Adhesion Molecule-1/biosynthesis
  • Interleukin-6/pharmacology
  • Leukocytes, Mononuclear/drug effects
  • Melphalan/pharmacology
  • Mitoxantrone/pharmacology
  • Multiple Myeloma/pathology
  • Naphthoquinones/pharmacology
  • Neoplasm Proteins/antagonists & inhibitors
  • Paracrine Communication
  • Poly(ADP-ribose) Polymerases/metabolism
  • Stromal Cells/cytology
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • Tumor Cells, Cultured/drug effects

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Hematology
  • Cancer Research
  • Cell Biology

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