Sensitization of drug resistant human ovarian cancer cells to cyanomorpholino doxorubicin (MRA-CN) by modulation of glutathione metabolism

Alexander D. Lewis, George E. Durán, Derick H Lau, Branimir I. Sikic

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

MRA-CN, the alkylating cyanomorpholino derivative of doxorubicin (DOX), is extremely potent (100 to 1000 fold increase in cytotoxicity in vitro and in vivo), more lipophilic, non-cardiotoxic, and non-cross-resistant in multidrug resistant cells compared to DOX. We have developed an ovarian carcinoma cell line ES-2R that is 4-fold resistant to MRA-CN, compared to the parental ES-2 cells. This resistant cell line exhibits cross-resistance to alkylators and ionizing radiation. Glutathione (GSH) and GSH-dependent enzymes were found to be altered in the resistant cells with 1.5-fold increase in GSH, and 2- to 3-fold increase in the pi-class glutathione-s-transferase (GST) protein. Both D,L buthionine-S,R-sulfoximine (BSO) and ethacrynic acid (EA), inhibitors of GSH biosynthesis and pi-class GST activity, respectively, could sensitize the ES-2R cells to MRA-CN. These findings implicate a role for GSH metabolism in resistance of ES-2R cells to MRA-CN. The data also indicates the potential utility of EA to modulate GST activity and sensitize tumor cells toward alkylators.

Original languageEnglish (US)
Pages (from-to)821-824
Number of pages4
JournalInternational Journal of Radiation Oncology, Biology, Physics
Volume22
Issue number4
DOIs
StatePublished - 1992
Externally publishedYes

Fingerprint

3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin
glutathione
metabolism
Ovarian Neoplasms
Glutathione
drugs
cancer
modulation
Glutathione Transferase
cells
Pharmaceutical Preparations
Ethacrynic Acid
cultured cells
Alkylating Agents
acids
biosynthesis
Cell Line
ionizing radiation
inhibitors
enzymes

Keywords

  • Cyanomorpholino doxorubicin
  • Ethacrynic acid
  • Glutathione-s-transferase
  • GSH depletion
  • Modulation of resistance

ASJC Scopus subject areas

  • Oncology
  • Radiology Nuclear Medicine and imaging
  • Radiation

Cite this

Sensitization of drug resistant human ovarian cancer cells to cyanomorpholino doxorubicin (MRA-CN) by modulation of glutathione metabolism. / Lewis, Alexander D.; Durán, George E.; Lau, Derick H; Sikic, Branimir I.

In: International Journal of Radiation Oncology, Biology, Physics, Vol. 22, No. 4, 1992, p. 821-824.

Research output: Contribution to journalArticle

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AB - MRA-CN, the alkylating cyanomorpholino derivative of doxorubicin (DOX), is extremely potent (100 to 1000 fold increase in cytotoxicity in vitro and in vivo), more lipophilic, non-cardiotoxic, and non-cross-resistant in multidrug resistant cells compared to DOX. We have developed an ovarian carcinoma cell line ES-2R that is 4-fold resistant to MRA-CN, compared to the parental ES-2 cells. This resistant cell line exhibits cross-resistance to alkylators and ionizing radiation. Glutathione (GSH) and GSH-dependent enzymes were found to be altered in the resistant cells with 1.5-fold increase in GSH, and 2- to 3-fold increase in the pi-class glutathione-s-transferase (GST) protein. Both D,L buthionine-S,R-sulfoximine (BSO) and ethacrynic acid (EA), inhibitors of GSH biosynthesis and pi-class GST activity, respectively, could sensitize the ES-2R cells to MRA-CN. These findings implicate a role for GSH metabolism in resistance of ES-2R cells to MRA-CN. The data also indicates the potential utility of EA to modulate GST activity and sensitize tumor cells toward alkylators.

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