The in vitro effects of CRE-decoy oligonucleotides in combination with conventional chemotherapy in colorectal cancer cell lines.
The cAMP response element consensus sequence directs the transcription of a wide range of genes. A 24-mer single-stranded cAMP response element decoy oligonucleotide (CDO) has been shown to compete with these sequences for binding transcription factors and therefore interferes with cAMP-induced gene transcription. We have examined the effect of this CDO alone and in combination with a range of common chemotherapeutic agents in colorectal cancer cell lines. CDO had a potent anti-proliferative effect in colorectal cell lines, yet, a similar enhancement of cell death was not observed. Simple drug-drug interaction studies showed that combining CDO with chemotherapy resulted in an enhancement of the antiproliferative effects. Furthermore, this cytostatic effect was protracted and associated with an increase in senescence-associated beta-galactosidase activity at pH 6. There is a possible role for p21(waf1) in mediating this effect, as the enhancement of cell growth inhibition was not observed in cells lacking the ability to correctly upregulate this protein. Additionally, significant decreases in cyclin-dependent kinase (CDK) 1 and CDK 4 function were seen in the responsive cells. These data provide a possible model of drug interaction in colorectal cell lines, which involves the complex interplay of the molecules regulating the cell cycle. Clinically, the cytostatic ability of CDO could improve and enhance the antiproliferative effects of conventional cytotoxic agents.
Liu
Wai M
WM
New Drug Study Group, Barry Reed Oncology Laboratory, St. Bartholomew's Hospital, London, UK. wai.liu@icr.ac.uk
Scott
Katherine A
KA
Shahin
Sipra
S
Propper
David J
DJ
D001483:Base Sequence; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000201:enzymology / Q000473:pathology*; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D005047:Etoposide / Q000494:pharmacology; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D000077146:Irinotecan; D009841:Oligonucleotides / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*
D009841:Oligonucleotides; D005047:Etoposide; D000077146:Irinotecan; D018844:Cyclin-Dependent Kinases; D005472:Fluorouracil; D002166:Camptothecin