8-Cl-Adenosine-Induced Inhibition of Colorectal Cancer Growth In Vitro and In Vivo

• Main Authors: Chris C. Carlson, Rebecca Chinery, Laura L. Burnham, Daniel T. Dransfield
• Format: Article
• Language: English
• Published: Elsevier 2000-09-01
• Series: Neoplasia: An International Journal for Oncology Research
• Subjects: 8-Cl-adenosine; colorectal cancer; cell cycle; endoreduplication; xenograft
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558600800147
• ISSN: 1476-5586; 1522-8002

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 its ability to modulate type I protein kinase A (PKAI). However, a nontoxic metabolite of 8-Cl-cAMP, 8-Cl-adenosine, with no known activity against PKAI, exerts growth inhibitory effects in breast, ovary, pancreas, and colorectal cancer cells in vitro and accumulates in xenografted tumors after 8-Cl-cAMP treatment in vivo. To characterize further the antitumor effects of 8-Cl-adenosine in colorectal cancer, we examined its effects on cell growth in vitro (cell number, 3H-thymidine incorporation, and soft agar colony formation) using the isogenically matched colorectal cancer cell lines HCT116, HCT116-E6 (p53-depleted), and 80S14 (p21WAF1/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 with DNA endoreduplication and subsequent apoptosis. Furthermore, nontoxic doses of 8-Cl-adenosine administered i.p. twice weekly for 4 weeks to athymic mice suppressed growth of HCT116-derived xenografts by 50%. These results show that 8-Cl-adenosine exerts antitumor activity against colorectal cancer independent of p53 and p21WAF1/Cip1.