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Superoxide Enhances the Antitumor Combination of AdMnSOD Plus BCNU in Breast Cancer

Wenqing G Sun1, Christine J Weydert, Yuping Zhang

  • 1Free Radical and Radiation Biology Program, Department of Radiation Oncology, Holden Comprehensive Cancer Center, Iowa City, Iowa.

Cancers
|June 10, 2010
PubMed

Insights

Overexpressing manganese superoxide dismutase (MnSOD) enhances cancer cell killing when combined with BCNU and agents that increase superoxide. This approach boosts intracellular peroxide levels and sensitizes tumors to treatment.

Area of Science:

  • Biochemistry
  • Oncology
  • Molecular Biology

Background:

  • Overexpression of manganese superoxide dismutase (MnSOD) sensitizes cancer cells to anticancer drugs.
  • Elevating peroxide levels by increasing MnSOD and inhibiting peroxide removal enhances cancer cell killing.
  • BCNU, an anticancer drug, inhibits glutathione reductase (GR), impairing peroxide removal.

Purpose of the Study:

  • To determine if anticancer modalities producing superoxide radicals can enhance the antitumor effect of MnSOD overexpression combined with BCNU.
  • To investigate the combined effects of AdMnSOD, BCNU, and superoxide-generating agents on cancer cell cytotoxicity.

Main Methods:

  • Adenoviral construct (AdMnSOD) introduced into human breast cancer cells (ZR-75-1) to enhance MnSOD.
  • Glutathione reductase (GR) inhibition using BCNU or siRNA.
  • Combination treatments with AdMnSOD, BCNU, and superoxide-generating agents (TNF-α, antimycin, adriamycin, photosensitizers, ionizing radiation).

Main Results:

  • AdMnSOD infection alone did not increase cell killing.
  • Inhibiting GR with BCNU or siRNA significantly increased cytotoxicity in AdMnSOD-infected cells.
  • Combining AdMnSOD + BCNU with superoxide-generating agents increased cell cytotoxicity and intracellular peroxide levels.

Conclusions:

  • Anticancer effects of AdMnSOD combined with BCNU can be enhanced by agents that increase superoxide generation.
  • This strategy shows potential for increasing cancer cell killing through elevated peroxide levels.

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