Details

Autor(en) / Beteiligte

• SAHA, SHILPI
• BHATTACHARJEE, PUSHPAK
• MUKHERJEE, SHRAVANTI
• MAZUMDAR, MINAKSHI
• CHAKRABORTY, SAMIK
• KHURANA, ANIL
• NAYAK, DEBADATTA
• MANCHANDA, RAJKUMAR
• CHAKRABARTY, RATHIN
• DAS, TANYA
• SA, GAURISANKAR

Titel

Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells

Ist Teil von

• Oncology reports, 2014-04, Vol.31 (4), p.1589-1598

Ort / Verlag

Greece: D.A. Spandidos

Erscheinungsjahr

2014

Quelle

MEDLINE

Beschreibungen/Notizen

• The adverse side-effects associated with chemotherapy during cancer treatment have shifted considerable focus towards therapies that are targeted but devoid of toxic side-effects. In the present study, the antitumorigenic activity of thuja, the bioactive derivative of the medicinal plant Thuja occidentalis, was evaluated, and the molecular mechanisms underlying thuja-induced apoptosis of functional p53-expressing mammary epithelial carcinoma cells were elucidated. Our results showed that thuja successfully induced apoptosis in functional p53-expressing mammary epithelial carcinoma cells. Abrogation of intracellular reactive oxygen species (ROS), prevention of p53-activation, knockdown of p53 or inhibition of its functional activity significantly abridged ROS generation. Notably, under these conditions, thuja-induced breast cancer cell apoptosis was reduced, thereby validating the existence of an ROS-p53 feedback loop. Elucidating this feedback loop revealed bi-phasic ROS generation as a key mediator of thuja-induced apoptosis. The first phase of ROS was instrumental in ensuring activation of p53 via p38MAPK and its nuclear translocation for transactivation of Bax, which induced a second phase of mitochondrial ROS to construct the ROS-p53 feedback loop. Such molecular crosstalk induced mitochondrial changes i) to maintain and amplify the thuja signal in a positive self-regulatory feedback manner; and ii) to promote the mitochondrial death cascade through cytochrome c release and caspase-driven apoptosis. These results open the horizon for developing a targeted therapy by modulating the redox status of functional p53-expressing mammary epithelial carcinoma cells by thuja.