Apoptosis-inducing effect of erlotinib is potentiated by 3,3'-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer
Authors: Shadan Ali
Fazlul H Sarkar
Philip A Philip
Aamir Ahmad
Sanjeev Banerjee
Bassel F El-Rayes
Journal: Molecular cancer therapeutics (2008)
Discipline: CLINICAL MEDICINE
Keywords: EGFR; tyrosine kinase inhibitors; survival pathways; 3,3'-diindolylmethane; B-DIM
Affiliations: Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA.

Abstract:  Blockade of epidermal growth factor receptor (EGFR) by EGFR tyrosine kinase inhibitors is insufficient for effective antitumor activity because of independently activated survival pathways. A multitargeted approach may therefore improve the outcome of anti-EGFR therapies. In the present study, we determined the effects of 3,3'-diindolylmethane (Bioresponse BR-DIM referred to as B-DIM), a formulated DIM with greater bioavailability on cell viability and apoptosis with erlotinib in vitro and in vivo using an orthotopic animal tumor model. BxPC-3 and MIAPaCa cells with varying levels of EGFR and nuclear factor-kappaB (NF-kappaB) DNA-binding activity were treated with B-DIM (20 micromol/L), erlotinib (2 micromol/L), and the combination. Cell survival and apoptosis was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and histone-DNA ELISA. Electrophoretic mobility shift assay was used to evaluate NF-kappaB DNA-binding activity. We found significant reduction in cell viability by both 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and clonogenic assays, induction of apoptosis, down-regulation of EGFR phosphorylation, NF-kappaB DNA-binding activity, and expression of antiapoptotic genes in BxPC-3 cells when treated with the combination of erlotinib and B-DIM compared with either agent alone. In contrast, no such effect was observed in MIAPaCa cells by similar treatment. Most importantly, these in vitro results were recapitulated in animal model showing that B-DIM in combination with erlotinib was much more effective as an antitumor agent compared with either agent alone. These results suggest that the utilization of B-DIM could be a useful strategy for achieving better treatment outcome in patients with activated status of EGFR and NF-kappaB in their tumors. 

Retracted: Yes

PubPeer comments:
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 2018 retraction. https: mct.aacrjournals.org content 17 10 2266 This article (1) has been retracted at the request of the editors. Following an institutional review by Wayne State University (Detroit, MI), the primary institution for several of the authors, it was determined that the article (1) included falsification and or fabrication of multiple Western blot bands in Fig. 3 and inappropriate cutting and pasting of the u201cN NFu03baB,u201d u201ccyto NFu03baBu201d and u03b2-actin bands in the BxPC-3 cell blots of Fig. 5A. As a result of these findings, the institution recommended retraction and, upon internal review, the editors agree with this recommendation. A copy of this retraction notice was sent to the last known email addresses for five of the six authors. Two authors (B.F. El-Rayes and P.A. Philip) agreed to the retraction; three authors (S. Banerjee, A. Ahmad, and F.H. Sarkar) did not respond; the remaining author (S. Ali) could not be located. Reference 1.u21b5Ali S, Banerjee S, Ahmad A, El-Rayes BF, Philip PA, Sarkar FH. Apoptosis-inducing effect of erlotinib is potentiated by 3,3u2032-diindolylmethane in vitro and in vivo using an orthotopic model of pancreatic cancer. Mol Cancer Ther 2008;7:1708u201319. ,