Ganoderic acid T from Ganoderma lucidum mycelia induces mitochondria mediated apoptosis in lung cancer cells.
Ganoderma lucidum is a well-known traditional Chinese medicinal herb containing many bioactive compounds. Ganoderic acid T (GA-T), which is a lanostane triterpenoid purified from methanol extract of G. lucidum mycelia, was found to exert cytotoxicity on various human carcinoma cell lines in a dose-dependent manner, while it was less toxic to normal human cell lines. Animal experiments in vivo also showed that GA-T suppressed the growth of human solid tumor in athymic mice. It markedly inhibited the proliferation of a highly metastatic lung cancer cell line (95-D) by apoptosis induction and cell cycle arrest at G(1) phase. Moreover, reduction of mitochondria membrane potential (Delta psi(m)) and release of cytochrome c were observed during the induced apoptosis. Our data further indicate that the expression of proteins p53 and Bax in 95-D cells was increased in a time-dependent manner, whereas the expression of Bcl-2 was not significantly changed; thus the ratio of Bcl-2/Bax was decreased. The results show that the apoptosis induction of GA-T was mediated by mitochondrial dysfunctions. Furthermore, stimulation of the activity of caspase-3 but not caspase-8 was observed during apoptosis. The experiments using inhibitors of caspases (Z-VAD-FMK, Z-DEVD-FMK and Z-IETD-FMK) confirmed that caspase-3 was involved in the apoptosis. All our findings demonstrate that GA-T induced apoptosis of metastatic lung tumor cells through intrinsic pathway related to mitochondrial dysfunction and p53 expression, and it may be a potentially useful chemotherapeutic agent.
Tang
Wen
W
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China.
Liu
Jian-Wen
JW
Zhao
Wei-Ming
WM
Wei
Dong-Zhi
DZ
Zhong
Jian-Jiang
JJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D061945:Caspase Inhibitors; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006538:Heptanoic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007810:Lanosterol / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D020940:Reishi / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis
D061945:Caspase Inhibitors; D006538:Heptanoic Acids; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D007810:Lanosterol; D045304:Cytochromes c; D053148:Caspase 3; D053181:Caspase 8