The Roles of 4β-Hydroxywithanolide E from Physalis peruviana on the Nrf2-Anti-Oxidant System and the Cell Cycle in Breast Cancer Cells.
4[Formula: see text]-Hydroxywithanolide E is an active component of the extract of Physalis peruviana that has been reported to exhibit antitumor effects. Although the involvement of reactive oxygen species (ROS) production and the ataxia-telangiectasia mutated protein (ATM)-dependent DNA damage signaling pathway in 4[Formula: see text]-hydroxywithanolide E-induced apoptosis of breast cancer MCF-7 cells was demonstrated in our previous study, the relationship between ROS production and the cellular defense system response in 4[Formula: see text]-hydroxywithanolide E-induced cell death requires further verification. The present study suggests that ROS play an important role in 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in which anti-oxidants, such as glutathione or N-acetylcysteine, can resist the 4[Formula: see text]-hydroxywithanolide E-induced accumulation of ROS and cell death. Furthermore, N-acetylcysteine or glutathione can reverse the 4[Formula: see text]-hydroxywithanolide E-induced changes in the cell cycle distribution and the expression of cell cycle regulators. We found that the 4[Formula: see text]-hydroxywithanolide E-induced ROS accumulation was correlated with the upregulation of Nrf2 and Nrf2-downstream genes, such as antioxidative defense enzymes. In general, the activity of Nrf2 is regulated by the Ras signalling pathway. However, we demonstrated that Nrf2 was activated during 4[Formula: see text]-hydroxywithanolide E-induced MCF-7 cell death in spite of the 4[Formula: see text]-hydroxywithanolide E-induced inhibition of the Ras/Raf/ERK pathway. The activity and protein expression of superoxide dismutase and catalase were involved in the 4[Formula: see text]-hydroxywithanolide E-induced ROS production in MCF-7 cells. Furthermore, 4[Formula: see text]-hydroxywithanolide E was demonstrated to significantly reduce the sizes of the tumor nodules in the human breast cancer MDA-MB231 xenograft tumor model.
* School of Pharmacy, China Medical University Hospital, Taichung, Taiwan.
Chieh Yu
CY
Peng
† Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, Taiwan.
Bang Jau
BJ
You
‡ Department of Cosmeceutics and Graduate Institute of Cosmeceutics, China Medical University, Taichung, Taiwan.|§ Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
Chia Lin
CL
Lee
* School of Pharmacy, China Medical University Hospital, Taichung, Taiwan.|§ Chinese Medicine Research and Development Center, China Medical University Hospital, Taichung, Taiwan.
Yang Chang
YC
Wu
* School of Pharmacy, China Medical University Hospital, Taichung, Taiwan.
Wen Hsin
WH
Lin
* School of Pharmacy, China Medical University Hospital, Taichung, Taiwan.
Te Ling
TL
Lu
¶ Pharmacy Department, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan.
Fei-Ching
FC
Chang
* School of Pharmacy, China Medical University Hospital, Taichung, Taiwan.|¶ Pharmacy Department, Tainan Municipal An-Nan Hospital-China Medical University, Tainan, Taiwan.
Hong Zin
HZ
Lee
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D005978:Glutathione; D006801:Humans; D061986:MCF-7 Cells; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D032321:Physalis / Q000737:chemistry*; D008517:Phytotherapy; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D054358:Withanolides / Q000302:isolation & purification / Q000494:pharmacology* / Q000627:therapeutic use*
D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D054358:Withanolides; D064007:Ataxia Telangiectasia Mutated Proteins; D005978:Glutathione
4-Hydroxywithanolide E; Antioxidative Defense Enzymes; Breast Cancer MCF-7 Cells; Human Breast Cancer MDA-MB231 Xenograft Tumor Model; Nrf2; Ras/Raf/ERK Pathway; Reactive Oxygen Species