| Programmed cell death or apoptosis is a physiological process of cellular auto-destruction. Apoptosis plays critical roles in development, maintenance of homeostasis, and host defense in multicellular organisms. Dysfunction of this process is implicated in various diseases ranging from cancer and autoimmune disorders to neurodegenerative diseases and ischemic injuries. Effective induction of apoptosis of cancer cells is a prospective strategy for clinical cancer therapy. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), a novel member of the TNF super-family, is a promising candidate for anti-cancer therapy since it induces apoptosis preferentially in a variety of cancer cells while most normal cells remain unaffected. Since the administration of recombinant soluble TRAIL (rsTRAIL) to experimental animals decreased the carcinoma mass without systemic toxicity in vivo, it has been evaluated to determine the conditions for clinical trials. However, there are about 50% cancer cell lines resistant to TRAIL-induced cytotoxicity, especially neural system carcinoma cells. It has been reported that some chemotherapy agents were able to enhance TRAIL-induced apoptosis of these tumor cells. Therefore, the combination of the apoptosis-inducing molecule with chemotherapy agents has been proposed as a more effective strategy for cancer therapy, especially for those cells resistant to rsTRAIL. We have evaluated that rsTRAIL (95-281 a.a.), which was prepared in our lab, could induce apoptosis of various tumor cell lines. In the present study the molecular mechanisms and death signaling pathways of the hepatoma and neuroblastoma cell lines induced by rsTRAIL combined with chemotherapeutic drugs were investigated. The results are summarized as the following: Part â… : 8-chloro-adenosine sensitizes the human hepatoma cell line to TRAIL-induced apoptosis by caspase-dependent and -independent pathways...
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