8-Cl-adenosine-induced inhibition of colorectal cancer growth in vitro and in 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 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-Cladenosine 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.
Carlson
C C
CC
Department of General Surgery, Medical College of Georgia, Augusta, USA.
Chinery
R
R
Burnham
L L
LL
Dransfield
D T
DT
D015762:2-Chloroadenosine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D020137:Base Pair Mismatch / Q000235:genetics; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects; D016158:Genes, p53; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000502:physiology; D023041:Xenograft Model Antitumor Assays
D000964:Antimetabolites, Antineoplastic; C493956:CDKN1A protein, human; C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D016159:Tumor Suppressor Protein p53; D015762:2-Chloroadenosine; D015124:8-Bromo Cyclic Adenosine Monophosphate; C044258:8-chloro-cyclic adenosine monophosphate; D017868:Cyclic AMP-Dependent Protein Kinases; C075440:8-chloroadenosine