6-shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant Mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism.
Mahlavu cells, poorly differentiated and p53 mutants of a human hepatoma subline, are known to be highly refractory to a number of chemotherapeutic agents and radiotherapy due to their high expressions of multidrug resistance gene-1 (MDR-1) and Bcl-2 proteins. Thus, it is desirable to search for an alternative strategy for effective eradication of this type of cancer cells. We present evidence here for the first time that 6-shogaol (6-SG), an alkanone isolated from the rhizomes of ginger, can effectively induce apoptotic cell death of Mahlavu cells via an oxidative stress-mediated caspase-dependent mechanism. The cascade of events in 6-SG-induced apoptosis of these cells involved an initial overproduction of reactive oxygen species (ROS) followed by a severe depletion of intracellular glutathione (GSH) contents. Both events consequently entailed a significant drop in mitochondrial transmembrane potential (DeltaPsim), which ultimately activated the activities of caspases 3/7 resulting in the DNA fragmentation. Interestingly, we also found that N-acetylcysteine (NAC), an antioxidant and a precursor of GSH biosynthesis, could offer a near complete protection of apoptotic cell death exerted by 6-SG. Similarly, exogenously added GSH could also provide protection with an equal efficacy. However, it was paradoxical that both Boc-Asp(OMe)-fmk (a broad caspases inhibitor) and cyclosporin A (an mitochondrial permeability transition opening inhibitor) could only partially protect these cells from 6-SG-induced apoptosis. Taking these data into consideration, it is obvious that GSH depletion is the major contributing factor in arbitrating 6-SG-induced apoptosis of Mahlavu cells. In conclusion, we provide here a novel modality that can help to eradicate a p53 mutant of human hepatoma cells by using a natural consistent isolated form of ginger. These data also provide evidence to reaffirm the notion that consumption of certain foodstuffs can be beneficial to health because some of the constituents contained in them may be anticarcinogenic.
Chen
Chung-Yi
CY
Basic Medical Science Education Center and Department of Medical Technology, Fooyin University, Kaohsiung County 831, Taiwan. chench@mail.ncyu.edu.tw
Liu
Tsan-Zon
TZ
Liu
Yi-Wen
YW
Tseng
Wei-Chang
WC
Liu
Ray H
RH
Lu
Fung-Jou
FJ
Lin
Yu-Shan
YS
Kuo
Shih-Hsien
SH
Chen
Ching-Hsein
CH
D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000473:pathology*; D020169:Caspases / Q000378:metabolism*; D002396:Catechols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects; D020939:Zingiber officinale / Q000737:chemistry; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D009154:Mutation; D018384:Oxidative Stress; D010936:Plant Extracts; D018517:Plant Roots / Q000737:chemistry; D017382:Reactive Oxygen Species / Q000378:metabolism
D002396:Catechols; D010936:Plant Extracts; D017382:Reactive Oxygen Species; C040115:shogaol; D020169:Caspases