Evidence supporting a role for mitochondrial respiration in apoptosis induction by the synthetic retinoid CD437.

Retinoids have been shown to modulate cell proliferation, differentiation, and apoptosis. It is thought that these effects mediate the chemopreventive and therapeutic effects of retinoids. Recently, some synthetic retinoids, including 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437), have been found to induce apoptosis even in tumor cell lines that are resistant to all-trans retinoic acid. The proapoptotic activity of CD437 has been attributed to mitochondrial dysfunction via the induction of mitochondrial permeability transition (P. Marchetti et al., Cancer Res. 59: 6257-6266, 1999). The mechanistic aspects pertaining to how CD437 promotes changes in mitochondrial function are unclear. This study investigated the role of mitochondrial respiration in CD437-induced apoptosis. Human cutaneous squamous cell carcinoma COLO 16 cells were chronically exposed to ethidium bromide to inhibit mitochondrial DNA synthesis and produce respiration-deficient clones. These clones were exposed to CD437 (<or=10 microM) for 48 h and exhibited a marked resistance to mitochondrial permeability transition and apoptosis illustrating that mitochondrial respiration was required for these effects.