Resistance to taxanes is induced by c-erbB-2 overexpression in human MCF-10A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type I protein kinase A

Fortunato Ciardiello, Rosa Caputo, Grazia Pomatico, Michelino De Laurentiis, Sabino De Placido, A. Raffaele Bianco, Giampaolo Tortora

Research output: Contribution to journalArticle

Abstract

We have tested the sensitivity of human MCF-10A mammary epithelial cells and of their transformed derivatives overexpressing an activated c-Ha-ras gene (MCF-10A Ha-ras cells), the c-erbB-2 gene (MCF-10A c-erbB-2 cells) or both genes (MCF-10A HE cells) to different cytotoxic drugs. As compared with parental MCF-10A cells, the transformed cells exhibited an increased sensitivity to topoisomerase I-and topoisomerase II-inhibitors, and to platinum-derivatives with a 2- to 10-fold reduction in IC50 values. A remarkable difference in sensitivity was observed following treatment with taxanes. While MCF-10A Ha-ras cells showed an increased sensitivity, MCF-10A c-erbB-2 and MCF-10A HE cells exhibited a relative resistance to taxol and taxotere, with an approximately 3.5- to 6.5-fold higher IC50 as compared with MCF-10A cells suggesting that c-erbB-2 overexpression has a dominant effect compared with an activated c-Ha-ras gene. The type 1 cAMP-dependent protein kinase (PKAI) is overexpressed in cancer cells. Inhibition of PKAI by antisense oligonucleotides targeting its RIα regulatory subunit results in canter cell growth inhibition. To evaluate the effect of blocking PKAI on MCF-10A cell sensitivity to taxanes, we treated these cells with taxol or taxotere in combination with a PKAI antisense oligonucleotide. Treatment with this agent, but not with a control scramble sequence, was able to overcome the effect of c-erbB-2 overexpression on MCF-10A cell sensitivity to taxol and taxotere, with a 20- to 40-fold shift in the IC50 values for the 2 drugs. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)710-715
Number of pages6
JournalInternational Journal of Cancer
Volume85
Issue number5
DOIs
Publication statusPublished - 2000

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Cyclic AMP-Dependent Protein Kinase Type I
Taxoids
Antisense Oligonucleotides
Breast
Epithelial Cells
docetaxel
Paclitaxel
Inhibitory Concentration 50
ras Genes
Topoisomerase II Inhibitors
erbB-2 Genes
Type I DNA Topoisomerase

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Resistance to taxanes is induced by c-erbB-2 overexpression in human MCF-10A mammary epithelial cells and is blocked by combined treatment with an antisense oligonucleotide targeting type I protein kinase A. / Ciardiello, Fortunato; Caputo, Rosa; Pomatico, Grazia; De Laurentiis, Michelino; De Placido, Sabino; Bianco, A. Raffaele; Tortora, Giampaolo.

In: International Journal of Cancer, Vol. 85, No. 5, 2000, p. 710-715.

Research output: Contribution to journalArticle

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abstract = "We have tested the sensitivity of human MCF-10A mammary epithelial cells and of their transformed derivatives overexpressing an activated c-Ha-ras gene (MCF-10A Ha-ras cells), the c-erbB-2 gene (MCF-10A c-erbB-2 cells) or both genes (MCF-10A HE cells) to different cytotoxic drugs. As compared with parental MCF-10A cells, the transformed cells exhibited an increased sensitivity to topoisomerase I-and topoisomerase II-inhibitors, and to platinum-derivatives with a 2- to 10-fold reduction in IC50 values. A remarkable difference in sensitivity was observed following treatment with taxanes. While MCF-10A Ha-ras cells showed an increased sensitivity, MCF-10A c-erbB-2 and MCF-10A HE cells exhibited a relative resistance to taxol and taxotere, with an approximately 3.5- to 6.5-fold higher IC50 as compared with MCF-10A cells suggesting that c-erbB-2 overexpression has a dominant effect compared with an activated c-Ha-ras gene. The type 1 cAMP-dependent protein kinase (PKAI) is overexpressed in cancer cells. Inhibition of PKAI by antisense oligonucleotides targeting its RIα regulatory subunit results in canter cell growth inhibition. To evaluate the effect of blocking PKAI on MCF-10A cell sensitivity to taxanes, we treated these cells with taxol or taxotere in combination with a PKAI antisense oligonucleotide. Treatment with this agent, but not with a control scramble sequence, was able to overcome the effect of c-erbB-2 overexpression on MCF-10A cell sensitivity to taxol and taxotere, with a 20- to 40-fold shift in the IC50 values for the 2 drugs. (C) 2000 Wiley-Liss, Inc.",
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AU - Ciardiello, Fortunato

AU - Caputo, Rosa

AU - Pomatico, Grazia

AU - De Laurentiis, Michelino

AU - De Placido, Sabino

AU - Bianco, A. Raffaele

AU - Tortora, Giampaolo

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