Isolation of a mitomycin-resistant human lung adenocarcinoma cell subline to investigate the modulation by sodium butyrate of cell growth and drug resistance.
We developed a mitomycin C (MMC)-resistant human lung adenocarcinoma cell subline, SPC-A1/DM4, from cloned SPC-A1/D13 parent cells by 1 h exposures to escalating concentrations of the drug over 17 months. A 5.9-fold resistance to MMC and a 3.8-fold cross-resistance to cisplatin were present in resistant cells compared with parent cells. This phenotype was stable in the absence of drug exposure for at least 6 months. Sodium butyrate (NaBu), a widely used differentiating agent, was shown to inhibit cell proliferation in a dose-dependent manner, with the cytostatic concentration of 2 mM. This NaBu-induced growth inhibition was reversible. However, SPC-A1/DM4 cells, after recovery from the cytostasis induced by 2 days treatment with 2 mM NaBu, became 2-fold more sensitive to MMC than the cells not exposed to the agent. Meanwhile, the cisplatin response of these treated cells reached a level comparable to the parent cells. This modulation by NaBu of drug resistance could be retained for at least 1 month. Treatment with 2 mM NaBu for 2 days caused inhibition of DNA synthesis and accumulation of cells in the G1 and G2/M-phases of the cell cycle. Correlated with these were a marked increase of protein content in these cell subpopulations and an enhanced RNA synthesis. In addition, NaBu-treated cells acquired development of endoplasmic reticulum and accumulated lipid droplets. These morphological alterations were accompanied by a significant decrease in the ratio of nuclear to cytoplasmic areas. These findings suggest that NaBu is potentially useful in the treatment of drug-resistant non-small cell lung cancer. Information about the NaBu-induced phenotypic alterations may offer a clue to the understanding of its long-term effect on drug resistance.
Dong
Q G
QG
Lung Cancer Research Center, Shanghai Chest Hospital, PRC.
Gong
L L
LL
Wang
H J
HJ
Wang
E Z
EZ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D002087:Butyrates / Q000494:pharmacology*; D020148:Butyric Acid; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004351:Drug Resistance; D005434:Flow Cytometry; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016685:Mitomycin / Q000494:pharmacology*; D010641:Phenotype; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000494:pharmacology
D002087:Butyrates; D004273:DNA, Neoplasm; D020148:Butyric Acid; D016685:Mitomycin; D014750:Vincristine; D002945:Cisplatin