Nitric Oxide and Life or Death of Human Leukemia Cells

Abstract

Nitric oxide (NO) has many actions that affect physiologic and pathologic processes. These effects are important in maintenance of appropriate smooth muscle tone, learning and memory, cell signaling, and defense from infection and neoplasia. NO is an important regulator of apoptosis and death of both normal and malignant cells, and it can serve as a mediator of inflammation, mutagenesis, and carcinogenesis. NO produced by bone marrow “stromal” cells (e.g., fibroblasts, macrophages, fat cells, and endothelial cells) can influence growth and differentiation of normal hematopoietic cells. In addition, hematopoietic cells themselves can produce NO that might influence these processes. As the importance of NO was being noted in vascular biology in the early 1980s, NO was also being recognized as the key mediator of macrophage-mediated neoplastic cell stasis and death. NO from cells or from NO pro-drugs can induce apoptosis and death of many neoplastic cells in vitro in an immunologically nonspecific manner. NO can also inhibit apoptosis and death of tumor cells by blocking activity of caspases. Malignant cells may express NO synthase (NOS), and NOS inhibitors induce apoptosis of these cells in vitro under certain conditions. High levels of NO (micromolar) cause apoptosis and death of normal bone marrow hematopoietic cells in vitro. Likewise, high levels of exogenous NO mediate cytotoxicity for acute leukemia cells and chronic lymphocytic leukemia (CLL) cells in vitro. CLL cells overexpress inducible NOS (NOS2) and neuronal NOS (NOS1), and a variety of NOS inhibitors effectively kill CLL cells in vitro. NOS1 inhibitors are the most potent at inducing cytotoxicity in CLL cells in vitro. The cytotoxicity may be caused by prevention of an NO-mediated block in caspase-mediated apoptosis of the leukemia cells. Investigators are working to move results of preclinical studies into clinical trials of NOS inhibitors or novel NO pro-drugs for treatment of human leukemias.