title: Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas.
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-x(L). 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.
authors.affiliation: Department of Urology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Lebedeva
authors.forename: Ilyas
authors.initials: I
authors.lastname: Washington
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Clark
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fine
authors.forename: Paul
authors.initials: P
authors.lastname: Dent
authors.forename: David T
authors.initials: DT
authors.lastname: Curiel
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Turro
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002264:Carboxylic Acids / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004359:Drug Therapy, Combination; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007378:Interleukins / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010190:Pancreatic Neoplasms / Q000188:drug therapy*; D010545:Peroxides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D017382:Reactive Oxygen Species / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism; D000099180:Interleukin-24
chemical_list: D002264:Carboxylic Acids; D007378:Interleukins; D009281:Naphthalenes; D010545:Peroxides; D017382:Reactive Oxygen Species; D051020:bcl-X Protein; D000099180:Interleukin-24; C494811:BCL2L1 protein, human; C520285:EPX compound