gx-15-070 and Brain-Neoplasms

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. Knockdown 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.

Topics: Animals; Anoikis; Antineoplastic Agents, Hormonal; Apoptosis Regulatory Proteins; bcl-2 Homologous Antagonist-Killer Protein; bcl-2-Associated X Protein; bcl-X Protein; Brain Neoplasms; Breast Neoplasms; Cell Survival; Drug Resistance, Neoplasm; Epigenesis, Genetic; ErbB Receptors; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Gene Knockdown Techniques; Histone Deacetylase Inhibitors; Humans; Indoles; Lapatinib; Mice; Mice, Nude; Myeloid Cell Leukemia Sequence 1 Protein; Neoplastic Stem Cells; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-bcl-2; Pyrroles; Quinazolines; Receptor, ErbB-2; RNA, Small Interfering; Valproic Acid; Xenograft Model Antitumor Assays