Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells.
E7070 is a novel sulfonamide antitumor agent that exhibits potent antitumor activity in vitro and in vivo. This compound affects cell cycle progression in human tumor cells. To elucidate the mechanisms by which E7070 inhibits tumor cell growth, we established and characterized an E7070-resistant subline, A549/ER, from a human non-small cell lung cancer cell line A549. Flow cytometric analyses demonstrated an increase in G0/G1 and a decrease in S phase populations in cells treated with E7070 at 20 or 100 microg/ml for 24 h. Longer exposure to E7070, i.e. 48 and 72 h, increased the G2/M phase fraction in A549 cells. These inhibitory actions of E7070 on cell cycle progression were not observed in A549/ER cells. E7070 inhibited the phosphorylation of pRb, decreased expressions of cyclin A, B1, CDK2, and CDC2 proteins, and suppressed CDK2 catalytic activity with the induction of p53 and p21 proteins in A549 cells but not in A549/ER cells. Taken together, these results suggest that E7070 exerts its antitumor effects by disturbing the cell cycle at multiple points, including both the G1/S and the G2/M transition, in human lung cancer cells.
Fukuoka
K
K
Pharmacology Division, National Cancer Center Research Institute, Tokyo, Japan.
Usuda
J
J
Iwamoto
Y
Y
Fukumoto
H
H
Nakamura
T
T
Yoneda
T
T
Narita
N
N
Saijo
N
N
Nishio
K
K
D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung; D002453:Cell Cycle; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms; D010766:Phosphorylation; D016160:Retinoblastoma Protein / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; C439829:N-(3-chloro-7-indolyl)-1,4-benzenedisulphonamide; D016160:Retinoblastoma Protein; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D018844:Cyclin-Dependent Kinases