Tumor inhibitory effect of gefitinib (ZD1839, Iressa) and taxane combination therapy in EGFR-overexpressing breast cancer cell lines (MCF7/ADR, MDA-MB-231).
Some kinds of breast cancer cell lines, similar to several types of solid tumors, express epidermal growth factor receptor (EGFR). However, gefitinib, an EGFR tyrosine kinase inhibitor, is not effective for all these cell lines. Similarly, taxane is effective for many of the cell lines, although some, such as the multidrug-resistant MCF7/ADR cell line, show taxane-resistance. Here, we examined the growth inhibitory effect of combination treatment with gefitinib and taxane on the breast cancer cell lines MDA-MB-231 (EGFR-positive) and MCF7/ADR (EGFR- and HER2-positive). To estimate the combined effect, a Combination Index was calculated for each cell line. The combination of gefitinib and taxane showed a strong synergistic effect on MCF7/ADR cells, but an invitro additive-antagonistic effect on MDA-MB-231 cells. Similarly, the combination treatment showed a significantly increased tumor inhibitory effect on MCF7/ADR xenografts, but not on MDA-MB-231 xenografts. Regarding the mechanism of the synergistic effect, Western blotting analysis revealed that taxane activated the EGFR-Akt pathway in MCF7/ADR cells but not in MDA-MB-231. To determine the optimal sequential administration of gefitinib and taxane for MCF7/ADR cells, we used flow cytometry to analyze the cell cycle and apoptosis; finding that taxane treatment followed by gefitinib produced a higher rate of G2 arrest and apoptosis than gefitinib treatment followed by taxane. These results suggest gefitinib overcomes the drug-resistance of these cells, thereby increasing the effects of taxane on MCF7/ADR cells. Further, activation of the EGFR-Akt pathway by taxane is related to this synergistic effect.
Takabatake
Daisuke
D
Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine and Dentistry, Shikata, Okayama, Japan. bata@ba2.so-net.ne.jp
Fujita
Takeo
T
Shien
Tadahiko
T
Kawasaki
Kensuke
K
Taira
Naruto
N
Yoshitomi
Seiji
S
Takahashi
Hirotoshi
H
Ishibe
Yoichi
Y
Ogasawara
Yutaka
Y
Doihara
Hiroyoshi
H
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D001952:Bridged-Ring Compounds / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D004317:Doxorubicin / Q000009:adverse effects; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D016195:G2 Phase / Q000187:drug effects; D000077156:Gefitinib; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
D001952:Bridged-Ring Compounds; D011799:Quinazolines; D043823:Taxoids; C080625:taxane; D004317:Doxorubicin; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib