“…It has been suggested that nuclear retinoid receptors, ROS, ceramide, disruption of mitochondrial transmembrane potential, and some not yet identified signals could mediate 4HPR-induced apoptosis. [3][4][5][6][7][8] Recent in vitro studies with several types of cancer cell lines suggested that ROS generation that results from perturbation in the mitochondrial respiratory chain is an important early event in 4HPR-induced apoptosis, which leads to release of cytochrome c, increased caspase-3 activity, and cell death. [4][5][6][7][8][9] It is thought that the reason for the lack of effect of 4HPR in some of the clinical trials is that the levels obtained at the 200 mg/day dose were too low to induce apoptosis.…”