Carcinogenesis Advance Access published online on May 4, 2006
Carcinogenesis, doi:10.1093/carcin/bgl051
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1 Department of Endocrinology, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Raebareli Road, Lucknow, 226 014, India
* To whom correspondence should be addressed. N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid is under clinical evaluation as a therapeutic agent in variety of cancers. Its mechanism(s) of action involves multiple overlapping pathways that still remain unclear. In glioma cells its mechanism of action is not well elucidated. Here we show that 4-HPR and not ATRA and 9-cisRA effectively induce apoptosis in glioma cell. 4-HPR-induced apoptosis is associated with hydro-peroxide production and loss of mitochondrial membrane potential (
Received February 10, 2006
Revised April 10, 2006
Accepted April 13, 2006
MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION
Mechanism of 4-HPR induced apoptosis in glioma cells: evidences suggesting role of mitochondrial-mediated pathway and endoplasmic reticulum stress
Meenakshi Tiwari 1,
Ashok Kumar 1,
Rohit Anthony Sinha 1,
Ashutosh Shrivastava 1,
Anil Kumar Balapure 2,
Ramesh Sharma 2,
Virendra Kumar Bajpai 3,
Kalyan Mitra 3,
Satish Babu 1,
and
Madan Madhav Godbole 1 *
2 Tissue Culture Laboratory, Central Drug Research Institute, Mahatma Gandhi Marg, Lucknow, 226 001 India
3 Electron Microscopy Division, Central Drug Research Institute, Mahatma Gandhi Marg, Lucknow, 226 001 India
Madan Madhav Godbole, E-mail: madangodbole{at}yahoo.co.in
Abstract 
m). Ultra structural changes further indicate 4-HPR-induced mitochondrial swelling, endoplasmic reticulum (ER) dilation as well as close proximity of mitochondria and ER. As suggested by dilated ER, 4-HPR treatment increased the free cytosolic Ca2+ as well as mitochondrial Ca2+. Chelation of extra-cellular Ca2+ by EGTA did not prevent Ca2+ elevation thus suggesting involvement of intracellular calcium stores in the release. Buffering of intracellular calcium by BAPTA-AM did not prevent 4-HPR-induced apoptosis, however blocking the release of Ca2+ from ER by heparin inhibited apoptosis, indicating the role of depletion of Ca2+ from ER stores in apoptosis. 4-HPR treatment also resulted in an increase in Bax levels along with its translocation to mitochondria that promote mitochondrial membrane permeabilization. 4-HPR-induced apoptosis was further associated with the release of cytochrome c and apoptosis inducing factor (AIF) from mitochondria to cytosol and nucleus respectively along with caspase-3 and caspase-7 activation. However, AIF nuclear translocation, peripheral chromatin condensation and apoptosis were not completely prevented by general caspase inhibitors. Thus, suggesting involvement of a caspase dependent and independent pathway in 4-HPR-induced apoptosis. Taken together, these results suggest the role of mitochondrial mediated pathway and ER stress as a key event in 4-HPR-induced apoptosis in glioma cells.
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