Investigation of potential pro-apoptotic and differentiating therapeutic modalities in breast cancer cells

Abstract

Firstly investigation addressed the ability of the anti-apoptotic protein BAG-1, which potentiates the oestrogen receptor in breast cancer, to also modulate PPARγ (peroxisome proliferator activated receptor γ), a nuclear hormone receptor important for lipid and glucose homeostasis.  PPARγ agonists represent a potential therapeutic approach for breast cancer, inducing cell cycle arrest, apoptosis and differentiation.  Prostaglandin J2 (PGJ2) stimulated PPARγ mediated expression of HSP70, a BAG-1 binding partner, but not BAG-1 isoform expression.  BAG-1 over expression did not alter PGJ2 dependent transcription, or interfere with PGJ2-induced cell cycle arrest or differentiation.  However, BAG-1 did not interfere with induction of cell death by PGJ2. Thus, BAG-1 is unlikely to directly modulate PPAR, but its known over expression in some breast cancers might limit potential clinical efficacy of PPARγ agonists, by suppression of PPARγ-induced cell death pathways.

Secondly, a depsipeptide natural compound, Spiruchostatin A, was characterised with respect to its histone deacetylase (HDAC) activity and ability to induce cell cycle arrest, differentiation and cell death in breast cancer cells.  Differences in potency, cell cycle arrest characteristics and induction of cell death were detected for Spiruchostatin A in breast cancer versus normal cells.  Comparative investigation of the depsipeptide HDAC inhibitors Spiruchostatin A and FK-228 demonstrated class I HDAC selectivity in distinction to hydroxamate pan HDAC class I and II inhibitors.  Class I HDAC selectivity allowed for the retention of anti breast cancer cell histone acetylation pharmacodynamics with implications for in-vivo surrogate markers of downstream biological effects of these compounds.

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