c-myc antisense oligonucleotides sensitize human colorectal cancer cells to chemotherapeutic drugs.

Background/aims: Overexpression of the c-myc oncogene frequently occurs in both colon tumors and colon carcinoma cell lines. We examined the sensitization of human colorectal cancer cells to chemotherapeutic drugs using c-myc antisense (AS) phosphorothioate oligonucleotides ([S]ODNs).

Methods: Cancer cells were treated with c-myc [S]ODNs, taxol, 5-fluorouracil (5-FU), doxorubicin and vinblastine individually and in combination. The antiproliferative effects, type of interaction between c-myc [S]ODNs and cytotoxic drugs, cell cycle, apoptosis and expression of cell-cycle- and apoptosis-regulatory genes were evaluated.

Results: After treatment with c-myc AS[S]ODNs, the growth of cancer cells was markedly inhibited in a dose- and time-dependent manner and the levels of c-myc mRNA and protein were greatly decreased (p < 0.0001). The combinations of c-myc AS[S]ODNs and cytotoxic drugs produced greater growth inhibition of human colorectal cancer cells compared to single treatment with either c-myc AS[S]ODNs (p < 0.006) or cytotoxic drugs (p < 0.0001). These combinations exhibited time- and dose-dependent additive and/or synergistic antiproliferative effects. Cancer cells treated with cytotoxic drugs were growth arrested in the S phase. In contrast, cells treated with either c-myc AS[S]ODNs or by the combination of c-myc AS[S]ODNs and cytotoxic drugs were growth arrested in the G(2)/M and S phases. The combination treatments also exhibited a marked apoptotic effect compared to single treatments. c-myc AS[S]ODN treatment reduced the mRNA levels of Bcl2, BclxL, cdk2, cyclin E1, cdk1 and cyclin B1, while increasing the mRNA levels of p21, p27, bax and caspase-3.

Conclusion: This two-hit approach may be important in the quest to overcome drug resistance in cancer patients whose tumors carry an overexpressed c-myc gene.