Roberto A. Martin, OMS-II: No financial relationships to disclose
Introduction/Purpose: Glioblastoma multiforme (GBM) is the most lethal and common primary malignant brain tumor in adults. These tumors are known to grow rapidly and invade far into the normal brain parenchyma. Current treatments include aggressive surgical resection, radiation therapy and chemotherapy. Despite this, the five-year survival rate remains under 10%. Contributing to the dismal outcome of these patients is the presence of treatment-resistant glioblastoma stem cells (GSCs), which are responsible forthe tumor's heterogeneity and post-therapy recurrence. Effective elimination of these cells, therefore, is necessary to prevent recurrence and improve patient outcomes. Due to its strong electron-withdrawing capabilities, nitro group (-NO2) containing compounds are being explored as potential anti-cancer compounds. As such, this study's purpose was to examine the cytotoxic effects of a series of nitro compounds on GSCs to identify a lead compound for adjuvant GBM therapy.
Methods or Case Description: 42 nitro-containing chalcones and cyclic C5-curcumin analogs, including several novel compounds, were synthesized via the Claisen-Schmidt reaction, purified and characterized by NMR. Cytotoxicity was tested against GSC lines developed in our laboratory from resected tumors of patients including one derived from a recurrent tumor. Briefly, GSCs were treated with 0.1-10 µM of each compound and viability examined 72 hours later by MTS assay. Active compounds, defined as those demonstratingan IC50valueof< 10 µM, were subsequently tested against two human non-tumor cell lines, mesenchymal stem cells and brain derived vascular smooth muscle cells. Computational target prediction models were used to determine the most probable target for the active compounds.
Outcomes: Of the 42 compounds tested, 25 had an average GSC IC50valueof 10 µM or below, and of these, 4 compounds had an IC50 value in the lower nanomolar range. The most effective compounds were the cyclic C5-curcumin analogs. Molecular targets of the active compounds included heat shock proteins and 5-lipoxygenases. While several compounds demonstrated toxicity toward the normal cell lines, a few were non-toxic suggesting promising leads for further development.
Conclusion: The nitro-group is a potent and versatile functional group known to induce cancer cell death by a variety of mechanisms. Here we identified several promising lead compounds with potent anti-GSC activity. To minimize their toxicity, ongoing studies are evaluating their potential to selectively deliver these to GBM tumors using non-toxic carbon dots as a nanocarrier.
Learning Objectives:
Upon completion, participants will be able to understand the importance of targeting Glioblastoma Stem Cells for Glioblastoma treatment.
Upon completion, participants will be able to describe the role of the nitro functional group in chemotherapy.
Upon completion, participants will be able to understand the potential of targeting STAT3 for Glioblastoma treatment.
