Background: Despite aggressive treatment, including surgical resection, radiation and chemotherapy, over 90% of glioblastoma (GB) patients experience tumor recurrence. This may be due to high migratory potential, angiogenesis, molecular heterogeneity and a strong immunosuppressive environment. GB expresses high levels of carbohydrate-binding galectin proteins and histone deacetylase (HDAC) activity. The aim of this study was: 1) identify the differential expressions of galectin 1-15 protein levels in human GB patient samples as compared to normal tissue (obtained from Institutional Tissue Bank) and (2) modulate the galectin functions with and without a HDAC inhibitor (DATS: Dially Triisulfide and SAHA: Suberoylanilide Hydroxamic Acid ) or bevacizumab in in vitro GB models.
Methods: The effects of TMZ, ionizing radiation, or combined chemoradiation on galectin protein secretion and expression were assessed in human GB cells and human umbilical vein endothelial cells (HUVECs).
Results: We found increased galectin-1 protein expression in human GB tissue. We also observed that HUVEC co-culture with GB cells increased galectin-1 protein expression by 14 - 20% following bevacizumab, and conferred a bevacizumab protective benefit to GB cells. Our in vitro models promisingly demonstrated that 72 hr treatments with 25 µM of galectin 1 inhibitor + HDAC inhibitor induce antitumor activity in GB cells. Western blot and activities assay results also demonstrated that combination blockade of HDAC activity and galectin-1 augmented apoptosis in GB cells, which mechanistically involves activation of caspase-3 and inhibition of anti-apoptotic protein (survivin, p-Akt, and Mcl-1 expression).
Conclusion: Our in vitro culture results suggest possible benefit in combining a galectin inhibitor with an HDAC inhibitor in GB. Further studies in different animal models are warranted.
Citation Format: David Cachia, Arindam Rano Chatterjee, William Alexander Vandergrift, Sunil J. Patel, Gabriel A. Rabinovich, Arabinda Das. Galectins in glioblastoma: opportunities for combined therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1. doi:10.1158/1538-7445.AM2017-1