Apoptotic Cross-Talk between Organelles Induced by Fenretinide in Hematopoietic Malignancy.

Fenretinide (N-4-hydroxyphenyl retinamide, 4-HPR), a synthetic analogue of all trans retinoic acid (ATRA), has shown promising potentials in chemopreventive/therapeutic treatment of human malignancies due to its minimal toxicity, ability to control tumor growth in animal models, and synergism with a number of other anti-cancer agents. Clinical trials of fenretinide, as a preventive agent, have proven its efficacy in a number of tumor types including breast cancer, ovary carcinoma, prostate cancer, neuroblastoma and leukemia. In contrast to ATRA which induces cell differentiaion, fenretinide induces cell apoptosis in a variety of tumor cell lines. Although intensive studies have revealed that fenretinide may trigger apoptosis via induction of different signal molecules such as reactive oxygen species (ROS) and ceramide, mechanisms underlying fenretinide induced apoptosis are far from clear, which is largely due to the fact that a multitude of responses occur in cells upon fenretinide treatment. Accordingly, we have applied an approach integrated with cDNA microarray, advanced technology of data and literature mining, and methods of protein biochemistry to study the process of fenretinide-induced apoptosis in leukemia cell line NB4 in detail. Numerous novel features with the temporospatial relationship were revealed, indicating the coordinated regulation of molecular network from various aspects of cellular activities to program cell death. These features include changes in transcriptional regulation, translational regulation, signal transduction, metabolism and stress response. In consequence, cells treated with fenretinide appear to enter programmed cell death through complex cross-talk between organelles such as mitochondria and endoplsmic reticulum. This study may therefore have substantial impact on the development of more sophisticated protocols in leukemia and probably other malignancies as well.