Induction of lung cancer cell apoptosis through a p53 pathway by [6]-shogaol and its cysteine-conjugated metabolite M2.
J Agric Food Chem
; 62(6): 1352-62, 2014 Feb 12.
Article
in En
| MEDLINE
| ID: mdl-24446736
ABSTRACT
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Catechols
/
Tumor Suppressor Protein p53
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Apoptosis
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Cysteine
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Lung Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
J Agric Food Chem
Year:
2014
Document type:
Article
Affiliation country:
United States