Despite the success of genomics in identifying new essential oncogenic signaling pathways, there have been a limited number of sustainable leads in anticancer drug discovery to address increasing chemoresistance. To improve progress in this area, our lab synthesized several novel benzisoxazoloazinium tetrafluoroborates (1-3) with structural characteristics similar to clinically effective DNA binding drugs. From a series of eight tricyclic pyridinium compounds with various substituents, Compound 1a effectively inhibits proliferation in colon cancer cell lines (IC50 = 2.95 µM) and shows significant in silico and in vitro DNA binding affinity. Incorporation of a fourth ring generated quinolinium derivatives (2) that recapitulate DNA binding activity of ellipticine. Preliminary IC50 values range from 52 µM for 2b to 202 µM for 2a. To evaluate the impact of second nitrogen, we synthesized and evaluated a quinoxalinium analog (3); results for this compound (IC50 of 18 µM) show increased cytotoxicity compared to 2b. All compounds induce cell death via non-apoptotic pathways. Future work will involve the synthesis and evaluation of other quinoxalinium analogs, as well as evaluation of their activity against PC3 human prostate cancer cells.
Biomedical imaging is an important technique that can be used for several applications such as cancer research and cardiology. A range of imaging technology, such as PET, SPECT, micro-CT and optical X-ray, is available for imaging. However, many research institutes use rats and mice for preclinical experiments. The purpose of this study was to determine if Zebrafish are compatible for use in pre-clinical imaging, and which modalities and probes work best. Different Zebrafish specimens were tested using five different modalities and four probes. In order to assess with twodimensional modalities, both fluorescence and planar X-Ray were performed on the specimens. The fluorescence imaging was acquired using OsteoSense 750x and ProSense 750x as the probes. Through the results, we discovered that OsteoSense did not work as well as the ProSense. The next three modalities represented three-dimensional imaging. These modalities consist of X-ray Computed Tomography (CT), Positron Emission Tomography (PET), and Single Photon Emission Computed Tomography (SPECT). The standard settings of high dosage and low voltage were used to assess with X-ray Computed Tomography. Sodium Fluoride (NaF) and Fludeoxyglucose (FDG) were the two probes tested with PET imaging, while MDP with technetium-99 was used for SPECT. The majority of the probes were detected in the specimens, but not at the correct target.
Aberrant expression of high mobility group A1 (hmga1), resulting from inactivating defects in upstream tumor suppressor genes or upregulation of oncogenic transactivators, induces the initiation of cancer progression pathways. The protein products of hmga1, HMGA1a and HMGA1b, are characterized by the presence of three DNA-binding motifs that possess a central RGR sequence and preferentially bind to the minor-groove of AT-rich stretches of target DNA. Importantly, R25 of the RGR sequence within the first DNA-binding motif bears covalent modifications that may recruit or repel specific transcriptional regulators in cancer cells. Despite the implication of hmga1 and arginine methylation in oncogenic function, the role of epigenetic regulation of hmga1 by arginine methylation has not been evaluated. Here, we investigate the impact of R25 substitutions on HMGA1b binding DNA targets using fluorescence spectroscopy and functional cellular assays. R25 substitutions disrupt DNA binding to various targets and suppress HMGA1-dependent oncogenic transformation. Together, our data reveals new potential anti-cancer strategies by targeting HMGA1 protein methylation and downstream targets.
