Melissoidesin G, a diterpenoid purified from Isodon melissoides, induces leukemic-cell apoptosis through induction of redox imbalance and exhibits synergy with other anticancer agents

Int J Cancer. 2007 Nov 1;121(9):2084-94. doi: 10.1002/ijc.22945.

Abstract

Melissoidesin G (MOG) is a new diterpenoid purified from Isodon melissoides, a plant used in Chinese traditional medicine as antitumor and anti-inflammatory agents. In our study, MOG was shown to specifically inhibit the growth of human leukemia cell lines and primary acute myeloid leukemia (AML) blasts via induction of apoptosis, with the evidence of mitochondrial DeltaPsim loss, reactive oxygen species production, caspases activation and nuclear fragmentation. Furthermore, it was shown that thiol-containing antioxidants completely blocked MOG-induced mitochondrial DeltaPsim loss and subsequent cell apoptosis, while the inhibition of apoptosis by benzyloxy-carbonyl-Val-Ala-Asp-fluoromethylketone only partially attenuated mitochondrial DeltaPsim loss, indicating that MOG-induced redox imbalance is an early event upstream to mitochondrial DeltaPsim loss and caspase-3 activation. Consistently, it was found that MOG rapidly decreased the intracellular glutathione (GSH) content in a dose-dependent manner and the significance of GSH depletion in MOG-induced apoptosis was further supported by the protective effects of tert-butylhydroquinone (tBHQ) and the facilitative effects of DL-buthionine (S,R)-sulfoximine (BSO). Furthermore, it was showed that GSH depletion induced by MOG rendered some leukemia cell lines more sensitive to arsenic trioxide (As2O3), doxorubicin or cisplatin. Additionally, the synergistic apoptotic effects of MOG with As2O3 were detected in HL-60 and primary AML cells, but not in normal cells, suggesting the selective toxicity of their combination to the malignant cells. Together, we proposed that MOG alone or administered with other anticancer agents may provide a novel therapeutic strategy for leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / isolation & purification
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Arsenic Trioxide
  • Arsenicals / pharmacology
  • Caspases / metabolism
  • Cytochromes c / metabolism
  • Diterpenes / chemistry
  • Diterpenes / isolation & purification
  • Diterpenes / pharmacology*
  • Glutathione / metabolism
  • Humans
  • Isodon / chemistry*
  • Leukemia / metabolism*
  • Leukemia / pathology*
  • Mitochondria / drug effects
  • Molecular Structure
  • Oxidation-Reduction
  • Oxides / pharmacology
  • Phytotherapy
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Arsenicals
  • Diterpenes
  • Oxides
  • melissoidesin G
  • Cytochromes c
  • Caspases
  • Glutathione
  • Arsenic Trioxide