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Mechanisms of 8Cl-cAMP Mediated Cytotoxicity in Multiple Myeloma
註釋8-chloro-cyclic-adenosine monophosphate (8Cl-cAMP) is an agent that has entered Phase I clinical trials against solid tumors. In this study, the ability of 8Cl-cAMP to inhibit the growth of multiple myeloma cell lines is examined. It is shown that 8C1-cAMP induces cell death through induction of apoptosis in multiple myeloma cells, and that this activity is due to the generation of an active metabolite, 8Cl-adenosine (8Cl-AD). Extracellular formation of this metabolite, through the actions of serum phosphodiesterases and 5 '-nucleotidase, is required for the cytolytic actions of 8Cl-cAMP. Also, 8Cl-AD is able to induce apoptosis at pharmacologically relevant doses in multiple myeloma cell lines that have developed resistance to glucocorticoids. In addition, it induces apoptosis in multiple myeloma cell lines that have developed the multidrug resistance phenotype through the over expression of P-glycoprotein, downregulation of topoisomerase II, and other as yet uncharacterized mechanisms of multidrug resistance. Finally, although 8Cl-AD has been reported to modulate protein kinase A (PKA) activity in other systems, 8Cl-AD does not act through PKA in multiple myeloma cells, as it is unable to stimulate the kinase activity of PKA at doses that are cytotoxic in vitro. Furthermore, while the phorbol ester PMA is shown to inhibit apoptosis induced by agents that are known to activate PKA, it is unable to inhibit the cytotoxic activity of 8Cl-AD Finally, apoptosis induced by 8Cl-AD does not involve cleavage of poly(ADP-ribose) polymerase (PARP), or protein kinase C delta (PKC-delta), two proteins known to be cleaved by caspases during most forms of apoptosis, including apoptosis induced by agents which stimulate PKA activity.