Induction of lung cancer cell apoptosis through a p53 pathway by [6]-shogaol and its cysteine-conjugated metabolite M2.
Dietary chemoprevention of cancer offers the possibility to suppress or inhibit cancer growth before it develops into more advanced and lethal stages. To this end, identification of novel compounds and their mechanisms of action is constantly needed. In this study, we describe that a major component of dry ginger (Zingiber officinalis), [6]-shogaol (6S), can be quickly metabolized in A549 human lung cancer cell line. One of the resulting metabolites, the cysteine-conjugated 6S (M2), exhibits toxicity to cancer cells similar to the parent compound 6S, but is relatively less toxic toward normal cells than 6S. We further demonstrate that both compounds can cause cancer cell death by activating the mitochondrial apoptotic pathway. Our results show that the cancer cell toxicity is initiated by early modulation of glutathione (GSH) intracellular content. The subsequently generated oxidative stress activates a p53 pathway that ultimately leads to the release of mitochondria-associated apoptotic molecules such as cytochrome C, and cleaved caspases 3 and 9. In a xenograft nude mouse model, a dose of 30 mg/kg of 6S or M2 was able to significantly decrease tumor burden, without any associated toxicity to the animals. This effect was correlated with an induction of apoptosis and reduction of cell proliferation in the tumor tissues. Taken together, our results show that 6S metabolism is an integral part of its anticancer activities in vitro and in vivo. This allows us to characterize M2 as a novel compound with superior in vivo chemopreventive properties that targets similar anticancer mechanisms as 6S.
Center for Excellence in Post-Harvest Technologies, North Carolina Agricultural and Technical State University , North Carolina Research Campus, 500 Laureate Way, Kannapolis, North Carolina 28081, United States.
Renaud F
RF
Warin
Huadong
H
Chen
Dominique N
DN
Soroka
Yingdong
Y
Zhu
Shengmin
S
Sang
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002396:Catechols / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D005978:Glutathione / Q000032:analysis; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008819:Mice, Nude; D018384:Oxidative Stress; D015398:Signal Transduction / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; D002396:Catechols; D016159:Tumor Suppressor Protein p53; C040115:shogaol; D005978:Glutathione; D003545:Cysteine