new hopeful lead in treating her2+ brain mets

[Lani]

performed in animals so far, but should be possible to test quickly in humans as all medications already fda approved and

the HDACinhibitor used in these experiments is actually an antiseizure medicine.

Cancer Biol Ther. 2013 Aug 22;14(10). [Epub ahead of print]
Histone deacetylase inhibitors restore toxic BH3 domain protein expression in anoikis resistant mammary and brain cancer stem cells thereby enhancing the response to anti-ERBB1/ERBB2 therapy.
Cruickshanks N, Hamed HA, Booth L, Tavallai S, Syed J, Sajithlal GB, Grant S, Poklepovic A, Dent P.
Source
Department of Neurosurgery; Virginia Commonwealth University; Richmond, VA USA.
Abstract
The present studies focused on defining the mechanisms by which anoikis resistant (AR) mammary carcinoma cells can be reverted to a therapy-sensitive phenotype. AR mammary carcinoma cells had reduced expression of the toxic BH3 domain proteins BAX, BAK, NOXA, and PUMA. In AR cells expression of the protective BCL-2 family proteins BCL-XL and MCL-1 was increased. AR cells were resistant to cell killing by multiple anti-tumor cell therapies, including ERBB1/2 inhibitor + MCL-1 inhibitor treatment, and had a reduced autophagic flux response to these therapies, despite similarly exhibiting increased levels of LC3II processing. Knock down of MCL-1 and BCL-XL caused necro-apoptosis in AR cells to a greater extent than in parental cells. Pre-treatment of anoikis-resistant cells with histone deacetylase inhibitors (HDACIs) for 24 h increased the levels of toxic BH3 domain proteins, reduced MCL-1 levels, and restored/re-sensitized the cell death response of AR tumor cells to multiple toxic therapies. In vivo, pre-treatment of AR breast tumors in the brain with valproate restored the chemo-sensitivity of the tumors and prolonged animal survival. These data argue that one mechanism to enhance the anti-tumor effect of chemotherapy could be HDACI pre-treatment.
KEYWORDS:
BAK, BH3 domain, ERBB1, MCL-1, NOXA, anoikis, autophagy, necrosis, signaling, tumor

PMID: 24025251