Honokiol overcomes conventional drug resistance in human multiple myeloma by induction of caspase-dependent and -independent apoptosis

Kenji Ishitsuka, Teru Hideshima, Makoto Hamasaki, Noopur Raje, Shaji Kumar, Hiromasa Hideshima, Norihiko Shiraishi, Hiroshi Yasui, Aldo M Roccaro, Paul Richardson, Klaus Podar, Steven Le Gouill, Dharminder Chauhan, Kazuo Tamura, Jack Arbiser, Kenneth C Anderson

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

163 Citations (Scopus)

Abstract

Honokiol (HNK) is an active component purified from magnolia, a plant used in traditional Chinese and Japanese medicine. Here we show that HNK significantly induces cytotoxicity in human multiple myeloma (MM) cell lines and tumor cells from patients with relapsed refractory MM. Neither coculture with bone marrow stromal cells nor cytokines (interleukin-6 and insulin-like growth factor-1) protect against HNK-induced cytotoxicity. Although activation of caspases 3, 7, 8, and 9 is triggered by HNK, the pan-caspase inhibitor z-VAD-fmk does not abrogate HNK-induced apoptosis. Importantly, release of an executioner of caspase-independent apoptosis, apoptosis-inducing factor (AIF), from mitochondria is induced by HNK treatment. HNK induces apoptosis in the SU-DHL4 cell line, which has low levels of caspase 3 and 8 associated with resistance to both conventional and novel drugs. These results suggest that HNK induces apoptosis via both caspase-dependent and -independent pathways. Furthermore, HNK enhances MM cell cytotoxicity and apoptosis induced by bortezomib. In addition to its direct cytotoxicity to MM cells, HNK also represses tube formation by endothelial cells, suggesting that HNK inhibits neovascurization in the bone marrow microenvironment. Taken together, our results provide the preclinical rationale for clinical protocols of HNK to improve patient outcome in MM.

Original languageEnglish
Pages (from-to)1794-1800
Number of pages7
JournalBlood
Volume106
Issue number5
DOIs
Publication statusPublished - 01 Sept 2005
Externally publishedYes

Keywords

  • Antineoplastic Agents, Phytogenic/pharmacology
  • Apoptosis/drug effects
  • Biphenyl Compounds/chemistry
  • Bone Marrow Cells/drug effects
  • Caspases/pharmacology
  • Cell Cycle/drug effects
  • Cell Line, Tumor
  • Cell Proliferation/drug effects
  • DNA/biosynthesis
  • Dose-Response Relationship, Drug
  • Drug Resistance, Multiple
  • Endothelial Cells/drug effects
  • Humans
  • Insulin-Like Growth Factor I/pharmacology
  • Interleukin-6/pharmacology
  • Lignans/chemistry
  • Multiple Myeloma/drug therapy
  • Neovascularization, Pathologic/chemically induced
  • Stromal Cells/drug effects
  • Structure-Activity Relationship

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