Skip to main content

Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex.

Publication ,  Journal Article
Gamcsik, MP; Kasibhatla, MS; Adams, DJ; Flowers, JL; Colvin, OM; Manikumar, G; Wani, M; Wall, ME; Kohlhagen, G; Pommier, Y
Published in: Mol Cancer Ther
November 2001

Depletion of glutathione (GSH) in MCF-7 and MDA-MB-231 cell lines by pretreatment with the GSH synthesis inhibitor buthionine sulfoximine potentiated the activity of 10,11-methylenedioxy-20(S)-camptothecin, SN-38 [7-ethyl-10-hydroxy-20(S)-camptothecin], topotecan, and 7-chloromethyl-10,11-methylenedioxy-20(S)-camptothecin (CMMDC). The greatest potentiation was observed with the alkylating camptothecin CMMDC. Buthionine sulfoximine pretreatment also increased the number of camptothecin-induced DNA-protein crosslinks, indicating that GSH affects the mechanism of action of camptothecin. We also report that GSH interacts with CMMDC to form a stable conjugate, 7-(glutathionylmethyl)-10,11-methylenedioxy-20(S)-camptothecin (GSMMDC), which is formed spontaneously in buffered solutions and in MCF-7 cells treated with CMMDC. GSMMDC was synthesized and found to be nearly as active as 10,11-methylenedioxy-20(S)-camptothecin in a topoisomerase (topo) I-mediated DNA nicking assay. The resulting topo I cleavage complexes were remarkably stable. In cell culture, GSMMDC displayed potent growth-inhibitory activity against U937 and P388 leukemia cell lines. GSMMDC was not active against a topo I-deficient P388 cell line, indicating that topo I is its cellular target. Peptide-truncated analogues of GSMMDC were prepared and evaluated. All three derivatives [7-(gamma-glutamylcysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, 7-(cysteinylglycylmethyl)-10,11-methylenedioxy-20(S)-camptothecin, and 7-(cysteinylmethyl)-10,11-methylenedioxy-20(S)-camptothecin] displayed topo I and cell growth-inhibitory activity. These results suggest that 7-peptidyl derivatives represent a new class of camptothecin analogues.

Duke Scholars

Published In

Mol Cancer Ther

ISSN

1535-7163

Publication Date

November 2001

Volume

1

Issue

1

Start / End Page

11 / 20

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Oncology & Carcinogenesis
  • Mass Spectrometry
  • Magnetic Resonance Spectroscopy
  • Humans
  • Glutathione
  • Female
  • Drug Synergism
  • DNA, Neoplasm
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Gamcsik, M. P., Kasibhatla, M. S., Adams, D. J., Flowers, J. L., Colvin, O. M., Manikumar, G., … Pommier, Y. (2001). Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex. Mol Cancer Ther, 1(1), 11–20.
Gamcsik, M. P., M. S. Kasibhatla, D. J. Adams, J. L. Flowers, O. M. Colvin, G. Manikumar, M. Wani, M. E. Wall, G. Kohlhagen, and Y. Pommier. “Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex.Mol Cancer Ther 1, no. 1 (November 2001): 11–20.
Gamcsik MP, Kasibhatla MS, Adams DJ, Flowers JL, Colvin OM, Manikumar G, et al. Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex. Mol Cancer Ther. 2001 Nov;1(1):11–20.
Gamcsik MP, Kasibhatla MS, Adams DJ, Flowers JL, Colvin OM, Manikumar G, Wani M, Wall ME, Kohlhagen G, Pommier Y. Dual role of glutathione in modulating camptothecin activity: depletion potentiates activity, but conjugation enhances the stability of the topoisomerase I-DNA cleavage complex. Mol Cancer Ther. 2001 Nov;1(1):11–20.

Published In

Mol Cancer Ther

ISSN

1535-7163

Publication Date

November 2001

Volume

1

Issue

1

Start / End Page

11 / 20

Location

United States

Related Subject Headings

  • Tumor Cells, Cultured
  • Structure-Activity Relationship
  • Oncology & Carcinogenesis
  • Mass Spectrometry
  • Magnetic Resonance Spectroscopy
  • Humans
  • Glutathione
  • Female
  • Drug Synergism
  • DNA, Neoplasm