Study of the effect of novel anticancer agent oncamex on gene expression profiles of preclinical breast cancer models.

Carlos Martinez-Perez, Arran Turnbull, Carol Ward, Peter Mullen, James Meehan, Edward J Jarman, Graeme Cook, Patrick I T Thomson, Colin J Campbell, Donald McPhail, David Harrison, Simon Langdon

Research output: Contribution to journalMeeting abstractpeer-review

Abstract

e14071Background: Clinical trials now underway will assess the use of flavonoids (natural polyphenols) as anticancer agents. Previous work has shown the promising antitumor activity of Oncamex (a novel myricetin-derived flavonoid with redox properties and mitochondrial targeting) on preclinical breast cancer models and suggested the role of reactive oxygen species (ROS) modulation in these effects. Methods: We evaluated the effect at gene level of Oncamex treatment (10µM for 6 h) in cell lines representing ER+, antiestrogen-resistant and triple negative breast cancers. RNA was extracted, amplified, labeled and hybridised to Illumina microarrays for gene expression analysis (GEA). Results: Oncamex produced a strong induction of apoptosis in all models through caspase activation and modulation of the Bcl-2 family: down-regulating antiapoptotic genes (BCL2, BIRC6) and up-regulating proapoptotic genes (BNIP3, BNIP3L, CRADD). Oncamex also up-regulated caspase co-activator APAF1 and proapoptotic transcription factor FOXO3. Cell cycle was inhibited at gene level by down-regulating expression of cyclins (CCND1, CCNB1) and up-regulating checkpoint genes (CDK7, RAS1). Interestingly, Oncamex also reduced expression of mitochondrial transmembrane proteins (TOMM40, TIMM23) and NFkB-related genes linked to proliferation and progression (BCL3, IL1A, IL1R1, AKT1). These novel results have led us to a new mechanistic model: due to its mitochondrial targeting, Oncamex disrupts mitochondrial redox homeostasis and membrane integrity, leading to initiation of intrinsic apoptosis through cytochrome C release and caspase activation. Conclusions: New GEA results have shown the proapoptotic and antiproliferative effect of Oncamex at gene expression level. We have formulated a novel mechanistic model by which Oncamex effectively induces intrinsic mitochondria-dependent apoptosis. GEA results suggest Oncamex works not only at protein level, but also induces transcriptional changes. Other mechanisms may be involved which directly inhibit proliferation at gene expression level, possibly through NFkB modulation. Current work will validate and expand this model using RT-PCR and western blot.
Original languageEnglish
Pages (from-to)e14071-e14071
JournalJournal of Clinical Oncology
Volume34
Issue number15suppl
DOIs
Publication statusPublished - 2016

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