Melissoidesin G, a diterpenoid purified from Isodon melissoides, induces leukemic-cell apoptosis through induction of redox imbalance and exhibits synergy with other anticancer agents.
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.
Yu
Zu-Yin
ZY
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Liang
Yu-Guang
YG
Department of Clinical Pharmacology, Beijing 307 Hospital, Academy of Medical Sciences, Beijing, China.
Xiao
He
H
Department of Molecular Immunology, Institute of Basic Medical Sciences, Beijing, China.
Shan
Ya-Jun
YJ
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Dong
Bo
B
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Huang
Rui
R
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Fu
Ya-Li
YL
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Zhao
Zhen-Hu
ZH
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Liu
Ze-Yuan
ZY
Department of Clinical Pharmacology, Beijing 307 Hospital, Academy of Medical Sciences, Beijing, China.
Zhao
Qin-Shi
QS
Department of Phytochemisty, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, Yunnan, China.
Wang
Sheng-Qi
SQ
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Chen
Jia-Pei
JP
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Mao
Bing-Zhi
BZ
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
Cong
Yu-Wen
YW
Department of Pathophysiology, Beijing Institute of Radiation Medicine, Beijing, China.
D000970:Antineoplastic Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D037602:Isodon / Q000737:chemistry*; D007938:Leukemia / Q000378:metabolism* / Q000473:pathology*; D008928:Mitochondria / Q000187:drug effects; D015394:Molecular Structure; D010084:Oxidation-Reduction; D010087:Oxides / Q000494:pharmacology; D008517:Phytotherapy; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001152:Arsenicals; D004224:Diterpenes; D010087:Oxides; C524357:melissoidesin G; D045304:Cytochromes c; D020169:Caspases; D005978:Glutathione; D000077237:Arsenic Trioxide