Curcuminoid analogs, a novel class of drugs for the treatment of Glioblastoma multiforme

Abstract

Glioblastoma multiforme is one of the glial‐derived malignant primary brain tumors in adults with a poor prognosis. The average survival period still remains between 14–16 months despite various treatment modalities involving combination of surgery, radiotherapy and chemotherapy with temozolomide, an imidazotetrazine derivative. Curcumin (#1) is a plant derived dietary constituent, and has been shown to play a role in preventing many cancers. We investigated for the first time the potencies and the molecular mechanisms of action of #1 and its three synthetic analogs (#7, #20, and #32) that were prepared through an acid catalyzed condensation with various hydrazine derivatives. Cultures of grade IV glioblastoma multiforme (GBM) MG118 cells (5,000/cm2) were treated with various concentrations (0.01–100μmole) of #1, #7, #20 or #32 for 24 hr. along with temozolomide (0.1–300μmole) as positive control. Cell viability/toxicity was assessed by Cell Titer Glo 2.0 Assay, and by the fluorescent dyes Hoechst 33342/Propidium iodide‐based live‐dead cell assay. Apoptosis was directly assessed by TACS Annexin V‐FITC Apoptosis detection kit. Concurrently, we measured the effects of these analogs on the expression of pro‐angiogenic HIF1α, VEGF, and chemokine receptor 4 (CXCR4) by western blotting analyses and quantitated using GAPDH loading controls. Additionally, we formulated curcuminoid‐loaded nanoparticles & optimized it using Design Expert (DoE) software and then evaluated the prepared formulation for determining the cytotoxic effects in GBM. Our results show that the tested analogs dose‐dependently caused apoptosis, decreased cell viability and inhibited cell proliferation in the order #32> #20> #7> #1>>temozolamide, suggesting that synthetic cucuminoids 32 and 20 are more potent than their parent compound and the current drug temozolomide. Additionally, we noted that these two analogs down‐regulated the expression of VEGF, and anti‐hypoxic HIF1α, and the chemokine receptor CXCR4 a known mediator of cancer cell proliferation and invasion. Thus our preclinical results demonstrate that compounds 32 and 20 may be two novel class of drugs for the treatment of GBM by down‐regulation of key targets that are critical for GBM survival and metastasis.Support or Funding InformationPartial support from an Institutional grant (ACS), and a grant from NIMHD/NIH #2G12MD007605 (KR).