Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance

Y. Takeda, K. Nishio, Yoshikazu Sugimoto, K. Kasahara, S. Kubo, Y. Fujiwara, H. Niitani, N. Saijo

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Abstract

We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of cross-resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA-induced growth inhibition by exposing K562 cells to N-methyl-N'-nitro-N-nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500-fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross-resistance to etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5-pyrimidinyl)] methyl-1-(2-chloroethyl)-1-nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K562/TPA 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 K562/TPA had a non-P-glycoprotein-mediated multi-drug-resistance phenotype and that the mechanism of drug-resistance in this cell line might be explained by an alteration in the intracellular drug distribution.

Original languageEnglish
Pages (from-to)931-937
Number of pages7
JournalInternational Journal of Cancer
Volume48
Issue number6
Publication statusPublished - 1991
Externally publishedYes

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Multiple Drug Resistance
Tetradecanoylphorbol Acetate
Glycoproteins
Leukemia
Doxorubicin
Growth
K562 Cells
Carcinogens
Teniposide
Vindesine
Methylnitronitrosoguanidine
Indicator Dilution Techniques
Cell Line
Morpholinos
Anthracyclines
P-Glycoprotein
Vincristine
Etoposide
Fluorescence Microscopy
Drug Resistance

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance. / Takeda, Y.; Nishio, K.; Sugimoto, Yoshikazu; Kasahara, K.; Kubo, S.; Fujiwara, Y.; Niitani, H.; Saijo, N.

In: International Journal of Cancer, Vol. 48, No. 6, 1991, p. 931-937.

Research output: Contribution to journalArticle

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abstract = "We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of cross-resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA-induced growth inhibition by exposing K562 cells to N-methyl-N'-nitro-N-nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500-fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross-resistance to etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5-pyrimidinyl)] methyl-1-(2-chloroethyl)-1-nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K562/TPA 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 K562/TPA had a non-P-glycoprotein-mediated multi-drug-resistance phenotype and that the mechanism of drug-resistance in this cell line might be explained by an alteration in the intracellular drug distribution.",
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T1 - Establishment of a human leukemia subline resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and showing non-P-glycoprotein-mediated multi-drug resistance

AU - Takeda, Y.

AU - Nishio, K.

AU - Sugimoto, Yoshikazu

AU - Kasahara, K.

AU - Kubo, S.

AU - Fujiwara, Y.

AU - Niitani, H.

AU - Saijo, N.

PY - 1991

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N2 - We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of cross-resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA-induced growth inhibition by exposing K562 cells to N-methyl-N'-nitro-N-nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500-fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross-resistance to etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5-pyrimidinyl)] methyl-1-(2-chloroethyl)-1-nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K562/TPA 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 K562/TPA had a non-P-glycoprotein-mediated multi-drug-resistance phenotype and that the mechanism of drug-resistance in this cell line might be explained by an alteration in the intracellular drug distribution.

AB - We have previously reported that K562/ADM, a typical P-glycoprotein-mediated multi-drug-resistant cell line, is cross-resistant to the growth-inhibitory effect of 12-0-tetradecanoylphorbol 13-acetate (TPA) and non-TPA type tumor promoters. To elucidate the mechanism of cross-resistance to tumor promoters in K562/ADM, we have established a K562 subline resistant to TPA-induced growth inhibition by exposing K562 cells to N-methyl-N'-nitro-N-nitrosoguanidine for 24 hr followed by continuous exposure to TPA. A K562 subline resistant to the TPA-induced growth inhibition, termed K562/TPA, was selected by a limiting dilution technique. K562/TPA was more than 500-fold resistant to TPA compared with parental K562 cells. K562/TPA showed cross-resistance to etoposide, teniposide, adriamycin (ADM), vincristine, vindesine and 3-[(4-amino-2-methyl-5-pyrimidinyl)] methyl-1-(2-chloroethyl)-1-nitrosourea, but showed collateral sensitivity to cisplatin. Although K562/ADM was not cross-resistant to 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin (MX2), an anthracycline derivative, K562/TPA was cross-resistant to MX2. By Northern blot analysis, K562/TPA 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 K562/TPA had a non-P-glycoprotein-mediated multi-drug-resistance phenotype and that the mechanism of drug-resistance in this cell line might be explained by an alteration in the intracellular drug distribution.

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