Curcumin and 2-DG synergistically target the glio-oncogenesis trigger IL-6 and down-regulate the stemness in glioblastoma model in-vitro

Glioblastoma is the most lethal brain tumor; despite available multimodal therapies. This poor survival is an outcome of many contributing factors the major is resistance due to inflammation and the presence of a subset of cells called glial stem-cells (GSCs). A rationale combination of drugs which act by targeting multiple mechanisms to inhibit cancer cells and GSCs would be more potent in abrogating chemoresistance. In this study, we aimed to target cancer hallmarks using a natural polyphenol in combination with 2-deoxyglucose, a glycolytic inhibitor on the heterogeneous human U-87 Glioblastoma model. The U-87 glioblastoma cells were treated with curcumin, 2-deoxyglucose and combination of both. Cell proliferation was determined by MTT assay and combination index was analyzed. Cell cycle inhibition and apoptosis were assessed by flow cytometry. The tumorigenicity of the cells was evaluated by clonogenic and soft agar assay. Migration efficacy of the cells was assessed by wound healing assay while the inflammation trigger Il-6 was assessed by ELISA. The changes in expression of molecular marker of stemness were analyzed by immuno-cytochemistry. Curcumin enhanced the cytotoxic effect of 2-deoxyglucose in GB cancer cells. The combination of CUR (20µM) and 2-DG (4mM) showed a synergistic effect in reducing cell viability with a combination index of less than 0.9. The polyphenol induced apoptosis, arrested the cells in S and G2/M phase of the cell cycle, inhibited anchorage dependent, anchorage independent clone forming efficacy, cell migration capacity as well as stemness while 2-DG downregulated IL-6 expression potently. Our novel combination exhibited the potential to reduce glio-oncogenesis trigger Il-6 and inhibit GSCs responsible for relapse and resistance. The study suggests that our tailor-made combination using established drugs can target multiple cancer signaling molecules to yield optimal therapeutic outcome and is the right approach to address stemness attributed resistance.