Induction of metallothionein isoforms in rat hepatoma cells by various anticancer drugs.
The induction of metallothionein (MT) isoforms (MT-1, -2) by anticancer drugs was investigated in cultured rat hepatoma H4 II E C3 cells. The steady-state expression of MT-1 mRNAs was higher than that of MT-2 mRNAs. During incubation of the cells with various anticancer drugs, namely, adriamycin, epirubicin, cis-diamminedichloroplatinum(II) (CDDP), and cis-diammine(1, 1-cyclobutyldicarboxylato)platinum(II), both MT-1 and MT-2 mRNAs were coordinately inducible: the levels of isoMT mRNA reached a maxim of approximate by 6-fold at 3 h. Immunofluorescent studies revealed that the cytosolic fluorescence in the cells exposed to 1 microM CDDP for 48 h was more intensified than that in the untreated cells. Transfer of antisense oligonucleotides resulted in marked reduction of isoMT mRNA, and upon exposure to 5 microM CDDP for 48 h, the viabilities of these cells dropped to 25.8% of the controls. These results indicate that anticancer drugs are potent inducers of MT isoforms in hepatoma cells and that a decrease in cellular MTs enhances the susceptibility of hepatoma cells to CDDP. Thus, we conclude that endogenous MTs play a role in determining the sensitivity or resistance of cancer cells to clinically important anticancer agents.
Miyazaki
H
H
Third Department of Internal Medicine, Kansai Medical University, Moriguchi, Osaka, 570-8506, Japan.
Naitoh
Y
Y
Nakahashi
Y
Y
Yanagitani
S
S
Kuno
K
K
Ueno
Y
Y
Okajima
A
A
Inoue
K
K
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019084:Fluorescent Antibody Technique, Indirect; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D008668:Metallothionein / Q000096:biosynthesis* / Q000235:genetics; D009841:Oligonucleotides / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D014162:Transfection; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D009841:Oligonucleotides; D012333:RNA, Messenger; D008668:Metallothionein