Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas

Irina V. Lebedeva, Ilyas Washington, Devanand Sarkar, Jennifer A. Clark, Robert L. Fine, Paul Dent, David T. Curiel, Nicholas J. Turro, Paul B. Fisher

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

Effective therapies for most solid cancers, especially those that have progressed to metastasis, remain elusive because of inherent and acquired resistance of tumor cells to conventional treatments. Additionally, the effective therapeutic window for many protocols can be very narrow, frequently resulting in toxicity. The present study explores an anticancer strategy that effectively eliminates resistant cancer cells without exerting deleterious effects on normal cells. This approach employs melanoma differentiation-induced gene-7/interleukin-24 (mda-7/IL-24), a cancer-specific, apoptosis-inducing cytokine, in combination with nontoxic doses of a chemical compound from the endoperoxide class that decomposes in water generating singlet oxygen. This combinatorial regimen specifically induced in vitro apoptosis in prostate carcinoma cells, with innate resistance to chemotherapy or engineered resistance to mda-7/IL-24, as well as pancreatic carcinoma cells inherently resistant to any treatment modality, including mda-7/IL-24. Apoptosis induction correlated with increased cellular reactive oxygen species production and was prevented by general antioxidants, such as N-acetyl-L-cysteine or Tiron. Induction of apoptosis in combination-treated cancer cells correlated with a reduction in the antiapoptotic protein BCL-XL. In contrast, both normal prostate and pancreatic epithelial cells were unaffected by the single or combination treatment. These provocative findings suggest that this combinatorial strategy might provide a platform for developing effective treatments for therapy-resistant cancers.

Original languageEnglish
Pages (from-to)3484-3489
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number9
DOIs
StatePublished - Feb 27 2007
Externally publishedYes

Keywords

  • BCL-x
  • Cancer-selective apoptosis
  • Endoperoxide
  • Reactive oxygen species
  • mda-7/IL-24

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