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Novel Combination Therapy: Monensin Potentiates Erlotinib-Induced Cytotoxicity

Receptor Tyrosine Kinase (RTK) inhibitors, such as erlotinib/tarceva, have been introduced
in the past decade as a promising therapeutic option in Head and Neck Squamous Cell
Carcinoma (HNSCC), however, they lack significant efficacy as single agents. As a result,
RTK inhibitors require a combination based therapeutic approach with other treatment
modalities. To uncover such a combination of agents, we performed a high throughput
Prestwick library screen that included 1200 compounds approved by the FDA on HNSCC
cell lines and found that monensin, a coccidial antibiotic, synergistically enhanced the
cytotoxicity of erlotinib. RT-PCR revealed that monensin induced the expression of
Activation of Transcription Factor (ATF) 3 and its downstream target C/EBP homologous
protein (CHOP) which are key regulators of apoptosis. Furthermore, RNA-Seq analysis
suggests that monensin augments erlotinib cytotoxicity by disturbing lipid and sterol
biosynthesis. Therefore, identifying the mechanism of action exerted by monensin may open alternative avenues of cancer treatment.

Identiferoai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/24405
Date January 2013
CreatorsKhalil, Dayekh
ContributorsDimitroulakos, Jim
PublisherUniversité d'Ottawa / University of Ottawa
Source SetsUniversité d’Ottawa
LanguageEnglish
Detected LanguageEnglish
TypeThesis

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