TY - JOUR AB - 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. AD - Division of Molecular Medicine, Bose Institute, P1/12, CIT Scheme VIIM, Kolkata 700054, India Central Council for Research in Homeopathy, 61-65 Institutional Area, Janakpuri, New Delhi 110058, India Bholanath Chakrabarty Trust, 5 Subol Koley Lane, Howrah 711101, India AU - Saha,Shilpi AU - Bhattacharjee,Pushpak AU - Mukherjee,Shravanti AU - Mazumdar,Minakshi AU - Chakraborty,Samik AU - Khurana,Anil AU - Nayak,Debadatta AU - Manchanda,Rajkumar AU - Chakrabarty,Rathin AU - Das,Tanya AU - Sa,Gaurisankar DA - 2014/04/01 DO - 10.3892/or.2014.2993 EP - 1598 IS - 4 JO - Oncol Rep KW - apoptosis Bax cancer homeopathy p38MAPK p53 ROS thuja PY - 2014 SN - 1021-335X 1791-2431 SP - 1589 ST - Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells T2 - Oncology Reports TI - Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells UR - https://doi.org/10.3892/or.2014.2993 VL - 31 ER -