8-Cl-adenosine-induced inhibition of colorectal cancer growth in vitro andin vivo

The cAMP analogue 8-Cl-cAMP induces apoptosis and inhibits proliferation of a wide variety of malignancies in vitro and in vivo with relatively little toxicity, The antitumor effects of this compound are thought to involve it s ability to modulate type I protein kinase A (PKAI), However, a nontoxic m etabolite of 8-Cl-cAMP, 8-Cl-adenosine, with no known activity against PKAI , exerts growth inhibitory effects in breast, ovary, pancreas, and colorect al cancer cells in vitro and accumulates in xenografted tumors after 8-Cl-c AMP treatment in vivo. To characterize further the antitumor effects of 8-C l-adenosine in colorectal cancer, we examined its effects on cell growth in vitro (cell number, H-3-thymidine incorporation, and soft agar colony form ation) using the isogenically matched colorectal cancer cell lines HCT116, HCT116-E6 (p53-depleted), and 80S14 (p21(WAF1/Cip1)-null). 8-Cl- adenosine inhibited cell growth by 89%, 74%, and 79%, respectively in HCT116, HCT116- E6, and 80S14 cells after a 72-hour exposure, Growth inhibition coincided w ith DNA endoreduplication and subsequent apoptosis. Furthermore, nontoxic d oses of 8-Cl-adenosine administered i.p. twice weekly for 4 weeks to athymi c mice suppressed growth of HCT116-derived xenografts by 50%. These results show that 8-Cl-adenosine exerts antitumor activity against colorectal canc er independent of p53 and p21(WAF1/Cip1).