Antisense oligodeoxynucleotide directed against c-myb has anticancer activity and potentiates the antiproliferative effect of conventional anticancer drugs acting by different mechanisms in human colorectal cancer cells.
The C-MYB proto-oncogene encodes a DNA-binding protein with transactivation properties that plays an important regulatory role in cell proliferation and differentiation. Overexpression of C-MYB in colonic tumors compared to normal mucosa suggests that c-myb may play a role in the malignant transformation of colonic mucosa and that inhibition of c-myb expression may suppress, to some extent, the proliferation of neoplastic cells. Complete suppression of tumor cell proliferation may require inhibition of multiple growth-promoting genes. Alternatively, the combination of oncogene-targeted oligodeoxynucleotides (ODNs) with standard cytotoxic agents might represent a useful therapeutic approach to improving cancer treatment. In the present study, we have investigated whether the inhibition of a growth-promoting gene, namely c-myb, affects the sensitivity of human colorectal cancer cells, in vitro, to conventional chemotherapeutic drugs: taxol, 5-fluorouracil, vinblastine and doxorubicin. We show that c-myb antisense phosphorothioate (S) ODN treatment induces growth arrest in the G(1)/G(2) phases of the cell cycle and inhibits cell proliferation in a dose- and time-dependent manner. Also, treatment with c-myb antisense (S)ODN decreases c-myb mRNA and protein expression. A greater inhibition of cell proliferation in vitro was obtained with the combination of c-myb (S)ODN and cytotoxic drugs. The combinations exerted additive and synergistic effects on human colorectal cancer cells. This study suggests that c-myb antisense (S)ODN might be useful in the therapy of colorectal cancer in combination with chemotherapeutic drugs.
Abaza
Mohamed-Salah I
MS
Division of Molecular Biology, Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait. Abaza@kuc01.kuniv.edu.kw
Al-Attiyah
Rajaa J
RJ
Al-Saffar
Amal M
AM
Al-Sawan
Shorooq M
SM
Moussa
Naguib M
NM
D000970:Antineoplastic Agents / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007700:Kinetics; D020319:Oligodeoxyribonucleotides, Antisense / Q000633:toxicity*; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb / Q000187:drug effects / Q000235:genetics*
D000970:Antineoplastic Agents; C000715470:MAS1 protein, human; D020319:Oligodeoxyribonucleotides, Antisense; D000090063:Proto-Oncogene Mas; D020598:Proto-Oncogene Proteins c-myb