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 adenorcarcinoma 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.