The Akt Inhibitor ISC-4 Synergizes with Cetuximab in 5-FU-Resistant Colon Cancer

Joshua E. Allen, Jean Nicolas Gallant, David T. Dicker, Shantu Amin, Rosalyn B. Irby, Arun K. Sharma, Wafik S. El-Deiry

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Phenylbutyl isoselenocyanate (ISC-4) is an Akt inhibitor with demonstrated preclinical efficacy against melanoma and colon cancer. In this study, we sought to improve the clinical utility of ISC-4 by identifying a synergistic combination with FDA-approved anti-cancer therapies, a relevant and appropriate disease setting for testing, and biomarkers of response. We tested the activity of ISC-4 and 19 FDA-approved anticancer agents, alone or in combination, against the SW480 and RKO human colon cancer cell lines. A synergistic interaction with cetuximab was identified and validated in a panel of additional colon cancer cell lines, as well as the kinetics of synergy. ISC-4 in combination with cetuximab synergistically reduced the viability of human colon cancer cells with wild-type but not mutant KRAS genes. Further analysis revealed that the combination therapy cooperatively decreased cell cycle progression, increased caspase-dependent apoptosis, and decreased phospho-Akt in responsive tumor cells. The synergism between ISC-4 and cetuximab was retained independently of acquired resistance to 5-FU in human colon cancer cells. The combination demonstrated synergistic anti-tumor effects in vivo without toxicity and in the face of resistance to 5-FU. These results suggest that combining ISC-4 and cetuximab should be explored in patients with 5-FU-resistant colon cancer harboring wild-type KRAS.

Original languageEnglish (US)
Article numbere59380
JournalPloS one
Volume8
Issue number3
DOIs
StatePublished - Mar 12 2013

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colorectal neoplasms
Fluorouracil
Colonic Neoplasms
Cells
Tumors
cell lines
Cell Line
Neoplasms
therapeutics
neoplasms
antineoplastic agents
caspases
synergism
Biomarkers
melanoma
Caspases
Antineoplastic Agents
Toxicity
Cetuximab
Melanoma

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Allen, Joshua E. ; Gallant, Jean Nicolas ; Dicker, David T. ; Amin, Shantu ; Irby, Rosalyn B. ; Sharma, Arun K. ; El-Deiry, Wafik S. / The Akt Inhibitor ISC-4 Synergizes with Cetuximab in 5-FU-Resistant Colon Cancer. In: PloS one. 2013 ; Vol. 8, No. 3.
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The Akt Inhibitor ISC-4 Synergizes with Cetuximab in 5-FU-Resistant Colon Cancer. / Allen, Joshua E.; Gallant, Jean Nicolas; Dicker, David T.; Amin, Shantu; Irby, Rosalyn B.; Sharma, Arun K.; El-Deiry, Wafik S.

In: PloS one, Vol. 8, No. 3, e59380, 12.03.2013.

Research output: Contribution to journalArticle

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