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.
Division of Molecular Biology, Department of Biological Sciences, Faculty of Science, Kuwait University, Kuwait. Abaza@kuc01.kuniv.edu.kw
Mohamed-Salah I
MS
Abaza
Rajaa J
RJ
Al-Attiyah
Amal M
AM
Al-Saffar
Shorooq M
SM
Al-Sawan
Naguib M
NM
Moussa
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