Abstract |
Previously we showed that Akt-suppressing agents, combined with amrubicin, synergistically inhibited the growth of small cell lung cancer cells. The combined effects of chemotherapeutic agents and Akt-suppressing agents, including epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, were evaluated in A549 lung adenocarcinoma cells harboring K-ras mutation and wild-type EGFR. Only amrubicin and not other chemotherapeutics ( cisplatin, pemetrexed and paclitaxel) synergistically inhibited cell growth when combined with an Akt inhibitor, LY294002. The combination of amrubicin and LY294002 enhanced Annexin V binding to cells. A non-specific tyrosine kinase inhibitor, genistein, suppressed Akt and showed synergistic interaction in combination with amrubicin. Two EGFR tyrosine kinase inhibitors (EGFR-TKIs), gefitinib and erlotinib, suppressed Akt activity at clinically achievable concentrations and demonstrated synergism when combined with amrubicin. The suppression of K-ras expression by siRNA interfered with this synergism and inhibited both EGFR and Akt activity in A549 cells. In Ma10 cells, which harbor wild-type EGFR and K-ras, EGFR-TKIs neither suppressed Akt activity nor exhibited such synergism when combined with amrubicin. We concluded that the synergism by the combination of EGFR-TKI and amrubicin is attributable, at least partially, to K-ras mutation in A549 cells. The combination of EGFR-TKI and amrubicin may be a promising treatment for lung cancer with wild-type EGFR and K-ras mutation.
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Authors | Shizuka Ito, Tadashi Igishi, Miyako Takata, Yasuto Ueda, Shingo Matsumoto, Masahiro Kodani, Kenichi Takeda, Hiroki Izumi, Tomohiro Sakamoto, Kosuke Yamaguchi, Haruhiko Makino, Hirokazu Touge, Hiroki Chikumi, Eiji Shimizu |
Journal | International journal of oncology
(Int J Oncol)
Vol. 44
Issue 3
Pg. 685-92
(Mar 2014)
ISSN: 1791-2423 [Electronic] Greece |
PMID | 24399305
(Publication Type: Journal Article)
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Chemical References |
- Anthracyclines
- Chromones
- Morpholines
- Protein Kinase Inhibitors
- 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
- amrubicin
- ErbB Receptors
- Proto-Oncogene Proteins c-akt
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Topics |
- Adenocarcinoma
(drug therapy, genetics, pathology)
- Adenocarcinoma of Lung
- Anthracyclines
(administration & dosage)
- Carcinoma, Non-Small-Cell Lung
(drug therapy, genetics, pathology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Chromones
(administration & dosage)
- Drug Synergism
- ErbB Receptors
(antagonists & inhibitors, genetics)
- Genes, ras
(genetics)
- Humans
- Lung Neoplasms
(drug therapy, genetics, pathology)
- Morpholines
(administration & dosage)
- Mutation
- Protein Kinase Inhibitors
(administration & dosage)
- Proto-Oncogene Proteins c-akt
(antagonists & inhibitors, genetics)
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