6-Shogaol (alkanone from ginger) induces apoptotic cell death of human hepatoma p53 mutant mahlavu subline via an oxidative stress-mediated caspase-dependent mechanism

被引:95
作者
Chen, Chung-Yi
Liu, Tsan-Zon
Liu, Yi-Wen
Tseng, Wei-Chang
Liu, Ray H.
Lu, Fung-Jou
Lin, Yu-Shan
Kuo, Shih-Hsien [1 ]
Chen, Ching-Hsein
机构
[1] Fooyin Univ, Basic Med Sci Educ Ctr, Kaohsiung 831, Taiwan
[2] Fooyin Univ, Dept Med Technol, Kaohsiung 831, Taiwan
[3] Chang Gung Univ, Grad Inst Med Biotechnol, Tao Yuan 333, Taiwan
[4] Natl Chiayi Univ, Grad Inst Biopharmaceut, Coll Life Sci, Chiayi 300, Taiwan
[5] Chung Shan Med Univ, Dept Appl Chem, Taichung 402, Taiwan
关键词
6-Shogaol; apoptosis; caspases; 3/7; oxidative stress; GSH depletion; Mahlavu cells;
D O I
10.1021/jf0624594
中图分类号
S [农业科学];
学科分类号
09 ;
摘要
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 (Delta Psi(m)), 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.
引用
收藏
页码:948 / 954
页数:7
相关论文
共 30 条
[1]   Mode of action of gingerols and shogaols on 5-HT3 receptors:: Binding studies, cation uptake by the receptor channel and contraction of isolated guinea-pig ileum [J].
Abdel-Aziz, H ;
Windeck, T ;
Ploch, M ;
Verspohl, EJ .
EUROPEAN JOURNAL OF PHARMACOLOGY, 2006, 530 (1-2) :136-143
[2]   Insect growth inhibition, antifeedant and antifungal activity of compounds isolated/derived from Zingiber officinale Roscoe (ginger) rhizomes [J].
Agarwal, M ;
Walia, S ;
Dhingra, S ;
Khambay, BPS .
PEST MANAGEMENT SCIENCE, 2001, 57 (03) :289-300
[3]   Extract from the leaves of Toona sinensis Roemor exerts potent antiproliferative effect on human lung cancer cells [J].
Chang, HC ;
Hung, WC ;
Huang, MS ;
Hsu, HK .
AMERICAN JOURNAL OF CHINESE MEDICINE, 2002, 30 (2-3) :307-314
[4]   Annoglabayin, a novel dimeric kaurane diterpenoid, and apoptosis in Hep G2 cells of annomontacin from the fruits of Annona glabra [J].
Chen, CH ;
Hsieh, TJ ;
Liu, TZ ;
Chern, CL ;
Hsieh, PY ;
Chen, CY .
JOURNAL OF NATURAL PRODUCTS, 2004, 67 (11) :1942-1946
[5]   Antioxidant properties of N-acetylcysteine:: their relevance in relation to chronic obstructive pulmonary disease [J].
Dekhuijzen, PNR .
EUROPEAN RESPIRATORY JOURNAL, 2004, 23 (04) :629-636
[6]   Shogaols from Zingiber officinale as promising antifouling agents [J].
Etoh, H ;
Kondoh, T ;
Noda, R ;
Singh, IP ;
Sekiwa, Y ;
Morimitsu, K ;
Kubota, K .
BIOSCIENCE BIOTECHNOLOGY AND BIOCHEMISTRY, 2002, 66 (08) :1748-1750
[7]   A critical role of glutathione in determining apoptosis sensitivity and resistance in leukemia cells [J].
Friesen, C ;
Kiess, Y ;
Debatin, KM .
CELL DEATH AND DIFFERENTIATION, 2004, 11 (Suppl 1) :S73-S85
[8]   Cardiovascular effects of ginger aqueous extract and its phenolic constituents are mediated through multiple pathways [J].
Ghayur, MN ;
Gilani, AH ;
Afridi, MB ;
Houghton, PJ .
VASCULAR PHARMACOLOGY, 2005, 43 (04) :234-241
[9]  
HALLIWELL B, 1998, FREE RADICAL BIO MED, P810
[10]   An epigrammatic (abridged) recounting of the myriad tales of astonishing deeds and dire consequences pertaining to nitric oxide and reactive oxygen species in mitochondria with an ancillary missive concerning the origins of apoptosis [J].
Heck, DE ;
Kagan, VE ;
Shvedova, AA ;
Laskin, JD .
TOXICOLOGY, 2005, 208 (02) :259-271