Antisense Bcl-2 and HER-2 oligonucleotide treatment of breast cancer cells enhances their sensitivity to anticancer drugs.
Overexpression of the HER-2 correlates with drug-resistance and a poor prognosis in breast cancer, however the mechanism(s) of HER-2-mediated drug-resistance are unknown. We examined the effects of antisense Bcl-2 and HER-2 oligonucleotides (ODN) to assess the mechanism(s) through which down-regulation of Bcl-2 and HER-2 enhances drug-sensitivity. Using two human breast cancer cell lines, MDA-MB-231 and BT-474, the antitumor effects of a combination of antisense ODN and anticancer drugs, including mitomycin C (MMC), adriamycin (ADM), paclitaxel (TXL), and docetaxel (TXT) was evaluated. The expression of Bcl-2 protein was suppressed by treatment with antisense Bcl-2 ODN in a dose-dependent manner. An enhanced drug-sensitivity to MMC and TXL upon pretreatment with antisense Bcl-2 ODN was observed, with the IC50 values increasing 1.9- and 2.0-fold, respectively. Treatment of BT-474 cells with antisense HER-2 at 1.0 micro M suppressed HER-2 overexpression by 60.5%. Pretreatment with antisense HER-2 ODN increased the sensitivity of these cells to ADM and TXL 20.8- and 10.8-fold, respectively. In vivo experiments using a combination of antisense HER-2 and TXL showed the similar enhancement of antitumor effect of TXL as compared to that of antisense HER-2 or TXL alone (p=0.068). Enhancement of drug-sensitivity was associated with the induction of apoptosis. Of interest, treatment with antisense HER-2 ODN also suppressed the expression of Bcl-2 and pAkt. These results indicate that down-regulation of Bcl-2 and HER-2 increased drug-sensitivity by modulating drug-induced apoptotic pathways in breast cancer cells, and that antisense ODN therapy, targeting Bcl-2 and HER-2 may be a useful strategy to enhance drug-sensitivity.
Tanabe
Kazuaki
K
Department of Surgical Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan. ktanabe2@hiroshima-u.ac.jp
Kim
Ryungsa
R
Inoue
Hideki
H
Emi
Manabu
M
Uchida
Yoko
Y
Toge
Tetsuya
T
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D016685:Mitomycin / Q000494:pharmacology; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D011379:Prognosis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction; D043823:Taxoids / Q000494:pharmacology; D013997:Time Factors
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D000077143:Docetaxel; D004317:Doxorubicin; D016685:Mitomycin; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; D017239:Paclitaxel; D019253:Proto-Oncogene Proteins c-bcl-2; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids