Strategy for reversing resistance to a single anticancer agent in human prostate and pancreatic carcinomas
Authors: Jennifer A Clark
David T Curiel
Ilyas Washington
Nicholas J Turro
Devanand Sarkar
Paul Dent
Paul B Fisher
Irina V Lebedeva
Robert L Fine
Journal: Proceedings of the National Academy of Sciences of the United States of America (2007)
Discipline: Multidisciplinary
Keywords: solid cancers; metastasis; resistance; tumor cells; conventional treatments
Affiliations: Department of Urology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.

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. 

Retracted: No

PubPeer comments:
 Figure 4. Much more similar and different than you would expect. https: imgur.com gr4MzEY , 
  The present study explores an anticancer strategy that effectively eliminates resistant cancer cells without exerting deleterious effects on normal cells.  Is the holy grail. , 
 #2 Thank you for your email. I am referring this to the first author who developed the data and figures for the paper- Dr. Lebedeva (Columbia University). She will be able to address your concern. , 
 #3 Dr. Fisher: I appreciate your response. Might you peruse the other papers posted on PubPeer which have not yet been addressed to see if any other concerns can be cleared up? https: pubpeer.com search?q=Paul+B+Fisher , 
 #1 The data in this paper is now ~14 years since the work was completed and submitted, reviewed and accepted in PNAS. It is possible, although not definitive, that there might have been issues in preparing the western blots you question in this paper. Unfortunately, the original data is no longer available. These studies have been repeated by others and the hypothesis we proposed in the paper has been confirmed in multiple external laboratories. We thank you for bringing this issue to our attention. Sincerely yours, Dr. Lebedeva. ,