Enhancement of anthracycline growth inhibition in parent and multidrug-resistant Chinese hamster ovary cells by cyclosporin A and its analogues

Setsuko K Chambers, W. N. Hait, B. M. Kacinski, S. R. Keyes, R. E. Handschumacher

Research output: Contribution to journalArticle

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Abstract

Cyclosporins have been shown to sensitize multidrug-resistant cells to chemotherapeutic agents but, generally, have minimal effect on sensitive lines. We studied the effect of cyclosporin A (CsA) and two nonimmunosuppressive analogues, 11-methyl-leucine (11-Me-Leu-CsA) and 6-methyl-alanine-cyclosporin A (6-Me-Ala-CsA), and the action of doxorubicin (DOX) and 4'-epidoxorubicin against parent (AuXB1) and multidrug-resistant (CH(R)C5) Chinese hamster ovary cells. CsA and its two analogues reduced the IC50 values for DOX in sensitive AuXB1 cells from 0.1 to 0.01-0.02 μM. Cyclosporins reduced the IC50 of DOX in resistant CH(R)C5 cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 μM (11-Me-Leu-CsA). Similar results were seen when cyclosporins were combined with 4'-epidoxorubicin. The cyclosporins alone had no effect at these concentrations (1-2.0 μg/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CH(R)C5 cells. The ability of the cyclosporins to enhance anthracycline growth inhibition in parent AuXB1 cells may be related to an increase in drug uptake and an increase in anthracycline-induced DNA damage. CsA increased DOX accumulation as well as DOX-associated DNA single-strand breaks in AuXB1 cells over those seen in cells exposed to DOX alone. The degree of increase in DNA breaks paralleled the degree of growth inhibition seen in cells exposed to the same concentrations of drugs. In contrast, CsA had no effect on DOX accumulation or DNA single-strand breaks in CH(R)C5 cells. These findings imply that, in the resistant cell line, the enhanced anthracycline growth inhibition in the presence of CsA is independent of DOX accumulation and single-strand DNA breaks. These studies demonstrate that CsA and tow nonimmunosuppressive analogues can sensitize both sensitive and resistant Chinese hamster ovary cells to anthracyclines. Furthermore, the mechanisms underlying this effect may differ between sensitive and multidrug-resistant cells.

Original languageEnglish (US)
Pages (from-to)6275-6279
Number of pages5
JournalCancer Research
Volume49
Issue number22
StatePublished - 1989
Externally publishedYes

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Anthracyclines
Cricetulus
Cyclosporine
Ovary
Cyclosporins
Growth
Doxorubicin
Single-Stranded DNA Breaks
Epirubicin
Inhibitory Concentration 50
DNA Breaks
Alanine
Pharmaceutical Preparations
DNA Damage

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Enhancement of anthracycline growth inhibition in parent and multidrug-resistant Chinese hamster ovary cells by cyclosporin A and its analogues. / Chambers, Setsuko K; Hait, W. N.; Kacinski, B. M.; Keyes, S. R.; Handschumacher, R. E.

In: Cancer Research, Vol. 49, No. 22, 1989, p. 6275-6279.

Research output: Contribution to journalArticle

Chambers, Setsuko K ; Hait, W. N. ; Kacinski, B. M. ; Keyes, S. R. ; Handschumacher, R. E. / Enhancement of anthracycline growth inhibition in parent and multidrug-resistant Chinese hamster ovary cells by cyclosporin A and its analogues. In: Cancer Research. 1989 ; Vol. 49, No. 22. pp. 6275-6279.
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abstract = "Cyclosporins have been shown to sensitize multidrug-resistant cells to chemotherapeutic agents but, generally, have minimal effect on sensitive lines. We studied the effect of cyclosporin A (CsA) and two nonimmunosuppressive analogues, 11-methyl-leucine (11-Me-Leu-CsA) and 6-methyl-alanine-cyclosporin A (6-Me-Ala-CsA), and the action of doxorubicin (DOX) and 4'-epidoxorubicin against parent (AuXB1) and multidrug-resistant (CH(R)C5) Chinese hamster ovary cells. CsA and its two analogues reduced the IC50 values for DOX in sensitive AuXB1 cells from 0.1 to 0.01-0.02 μM. Cyclosporins reduced the IC50 of DOX in resistant CH(R)C5 cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 μM (11-Me-Leu-CsA). Similar results were seen when cyclosporins were combined with 4'-epidoxorubicin. The cyclosporins alone had no effect at these concentrations (1-2.0 μg/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CH(R)C5 cells. The ability of the cyclosporins to enhance anthracycline growth inhibition in parent AuXB1 cells may be related to an increase in drug uptake and an increase in anthracycline-induced DNA damage. CsA increased DOX accumulation as well as DOX-associated DNA single-strand breaks in AuXB1 cells over those seen in cells exposed to DOX alone. The degree of increase in DNA breaks paralleled the degree of growth inhibition seen in cells exposed to the same concentrations of drugs. In contrast, CsA had no effect on DOX accumulation or DNA single-strand breaks in CH(R)C5 cells. These findings imply that, in the resistant cell line, the enhanced anthracycline growth inhibition in the presence of CsA is independent of DOX accumulation and single-strand DNA breaks. These studies demonstrate that CsA and tow nonimmunosuppressive analogues can sensitize both sensitive and resistant Chinese hamster ovary cells to anthracyclines. Furthermore, the mechanisms underlying this effect may differ between sensitive and multidrug-resistant cells.",
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T1 - Enhancement of anthracycline growth inhibition in parent and multidrug-resistant Chinese hamster ovary cells by cyclosporin A and its analogues

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AU - Keyes, S. R.

AU - Handschumacher, R. E.

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N2 - Cyclosporins have been shown to sensitize multidrug-resistant cells to chemotherapeutic agents but, generally, have minimal effect on sensitive lines. We studied the effect of cyclosporin A (CsA) and two nonimmunosuppressive analogues, 11-methyl-leucine (11-Me-Leu-CsA) and 6-methyl-alanine-cyclosporin A (6-Me-Ala-CsA), and the action of doxorubicin (DOX) and 4'-epidoxorubicin against parent (AuXB1) and multidrug-resistant (CH(R)C5) Chinese hamster ovary cells. CsA and its two analogues reduced the IC50 values for DOX in sensitive AuXB1 cells from 0.1 to 0.01-0.02 μM. Cyclosporins reduced the IC50 of DOX in resistant CH(R)C5 cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 μM (11-Me-Leu-CsA). Similar results were seen when cyclosporins were combined with 4'-epidoxorubicin. The cyclosporins alone had no effect at these concentrations (1-2.0 μg/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CH(R)C5 cells. The ability of the cyclosporins to enhance anthracycline growth inhibition in parent AuXB1 cells may be related to an increase in drug uptake and an increase in anthracycline-induced DNA damage. CsA increased DOX accumulation as well as DOX-associated DNA single-strand breaks in AuXB1 cells over those seen in cells exposed to DOX alone. The degree of increase in DNA breaks paralleled the degree of growth inhibition seen in cells exposed to the same concentrations of drugs. In contrast, CsA had no effect on DOX accumulation or DNA single-strand breaks in CH(R)C5 cells. These findings imply that, in the resistant cell line, the enhanced anthracycline growth inhibition in the presence of CsA is independent of DOX accumulation and single-strand DNA breaks. These studies demonstrate that CsA and tow nonimmunosuppressive analogues can sensitize both sensitive and resistant Chinese hamster ovary cells to anthracyclines. Furthermore, the mechanisms underlying this effect may differ between sensitive and multidrug-resistant cells.

AB - Cyclosporins have been shown to sensitize multidrug-resistant cells to chemotherapeutic agents but, generally, have minimal effect on sensitive lines. We studied the effect of cyclosporin A (CsA) and two nonimmunosuppressive analogues, 11-methyl-leucine (11-Me-Leu-CsA) and 6-methyl-alanine-cyclosporin A (6-Me-Ala-CsA), and the action of doxorubicin (DOX) and 4'-epidoxorubicin against parent (AuXB1) and multidrug-resistant (CH(R)C5) Chinese hamster ovary cells. CsA and its two analogues reduced the IC50 values for DOX in sensitive AuXB1 cells from 0.1 to 0.01-0.02 μM. Cyclosporins reduced the IC50 of DOX in resistant CH(R)C5 cells from 9 to 0.1 (CsA), 0.7 (6-Me-Ala-CsA), and 1.2 μM (11-Me-Leu-CsA). Similar results were seen when cyclosporins were combined with 4'-epidoxorubicin. The cyclosporins alone had no effect at these concentrations (1-2.0 μg/ml). Dose-response curves suggested that CsA was a more potent modifying agent than 11-Me-Leu-CsA towards resistant CH(R)C5 cells. The ability of the cyclosporins to enhance anthracycline growth inhibition in parent AuXB1 cells may be related to an increase in drug uptake and an increase in anthracycline-induced DNA damage. CsA increased DOX accumulation as well as DOX-associated DNA single-strand breaks in AuXB1 cells over those seen in cells exposed to DOX alone. The degree of increase in DNA breaks paralleled the degree of growth inhibition seen in cells exposed to the same concentrations of drugs. In contrast, CsA had no effect on DOX accumulation or DNA single-strand breaks in CH(R)C5 cells. These findings imply that, in the resistant cell line, the enhanced anthracycline growth inhibition in the presence of CsA is independent of DOX accumulation and single-strand DNA breaks. These studies demonstrate that CsA and tow nonimmunosuppressive analogues can sensitize both sensitive and resistant Chinese hamster ovary cells to anthracyclines. Furthermore, the mechanisms underlying this effect may differ between sensitive and multidrug-resistant cells.

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