Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12-o-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance
✍ Scribed by Yuichiro Takeda; Kazuto Nishio; Yoshikazu Sugimoto; Kazuo Kasahara; Sachiyo Kubo; Yasuhiro Fujiwara; Nagahiro Saijo; Hisanobu Niitani
- Publisher
- John Wiley and Sons
- Year
- 1991
- Tongue
- French
- Weight
- 903 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant t o the growth-inhibitory effect of I 2 -0tetradecanoylphorbol I 3-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of crossresistance to tumor promoters in K562/ADM, we have established a K562 subline resistant t o TPA-induced growth inhibition by exposing K562 cells t o N-methyl-N'-nitro-Nnitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562iTPA, was selected by a limiting dilution technique. K56UTPA was more than 500-fold resistant t o TPA compared with parental K562 cells. K56UTPA showed cross-resistance t o etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5pyrimidinyl)] methyl-I -(2-chloroethyl)-I -nitrosourea, but showed collateral sensitivity to cisplatin. Although K56WADM was not cross-resistant t o 3'-deamino-3'-morpholino-13deoxo-10-hydroxycarminomycin (MXZ), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K56UTPA did not express MDR-I. Accumulation of ADM by K562/TPA was no lower than that of K562 although that of K562/ADM was 5-fold lower than K562. We examined the subcellular distribution of ADM by fluorescence microscopy. The fluorescence of ADM was located in the nucleus of K562 and mainly in the cytoplasm of K562/TPA and K562/ADM. The distribution of ADM in K562/TPA, however, was different from that in K562/ADM. These results suggested that K562iTPA had a non-P-glycoprotein-mediated multidrug-resistance phenotype and that the mechanism of drugresistance in this cell line might be explained by an alteration in the intracellular drug distribution.