IDENTIFICATION OF A NOVEL AGENT THAT CAN SUPPRESS PROLIFERATION, INDUCE APOPTOSIS AND OVERCOME CHEMORESISTANCE IN MULTIPLE MYELOMA

Ph.DDOCTOR OF PHILOSOPH

Plumbagin inhibits invasion and migration of breast and gastric cancer cells by downregulating the expression of chemokine receptor CXCR4

<p>Abstract</p> <p>Background</p> <p>Increasing evidence indicates that the interaction between the CXC chemokine receptor-4 (CXCR4) and its ligand CXCL12 is critical in the process of metastasis that accounts for more than 90% of cancer-related deaths. Thus, novel agents that can downregulate the CXCR4/CXCL12 axis have therapeutic potential in inhibiting cancer metastasis.</p> <p>Methods</p> <p>In this report, we investigated the potential of an agent, plumbagin (5-hydroxy-2-methyl-1, 4-naphthoquinone), for its ability to modulate CXCR4 expression and function in various tumor cells using Western blot analysis, DNA binding assay, transient transfection, real time PCR analysis, chromatin immunoprecipitation, and cellular migration and invasion assays.</p> <p>Results</p> <p>We found that plumbagin downregulated the expression of CXCR4 in breast cancer cells irrespective of their HER2 status. The decrease in CXCR4 expression induced by plumbagin was not cell type-specific as the inhibition also occurred in gastric, lung, renal, oral, and hepatocellular tumor cell lines. Neither proteasome inhibition nor lysosomal stabilization had any effect on plumbagin-induced decrease in CXCR4 expression. Detailed study of the underlying molecular mechanism(s) revealed that the regulation of the downregulation of CXCR4 was at the transcriptional level, as indicated by downregulation of mRNA expression, inhibition of NF-κB activation, and suppression of chromatin immunoprecipitation activity. In addition, using a virtual, predictive, functional proteomics-based tumor pathway platform, we tested the hypothesis that NF-κB inhibition by plumbagin causes the decrease in CXCR4 and other metastatic genes. Suppression of CXCR4 expression by plumbagin was found to correlate with the inhibition of CXCL12-induced migration and invasion of both breast and gastric cancer cells.</p> <p>Conclusions</p> <p>Overall, our results indicate, for the first time, that plumbagin is a novel blocker of CXCR4 expression and thus has the potential to suppress metastasis of cancer.</p

A Comparative Analysis of Tumors and Plasma Circulating Tumor DNA in 145 Advanced Cancer Patients Annotated by 3 Core Cellular Processes

Matched-targeted and immune checkpoint therapies have improved survival in cancer patients, but tumor heterogeneity contributes to drug resistance. Our study categorized gene mutations from next generation sequencing (NGS) into three core processes. This annotation helps decipher complex biologic interactions to guide therapy. We collected NGS data on 145 patients who have failed standard therapy (2016 to 2018). One hundred and forty two patients had data for tissue (Caris MI/X) and plasma cell-free circulating tumor DNA (Guardant360) platforms. The mutated genes were categorized into cell fate (CF), cell survival (CS), and genome maintenance (GM). Comparative analysis was performed for concordance and discordance, unclassified mutations, trends in TP53 alterations, and PD-L1 expression. Two gene mutation maps were generated to compare each NGS platform. Mutated genes predominantly matched to CS with concordance between Guardant360 (64.4%) and Caris (51.5%). TP53 alterations comprised a significant proportion of the mutation pool in Caris and Guardant360, 14.7% and 13.1%, respectively. Twenty-six potentially actionable gene alterations were detected from matching ctDNA to Caris unclassified alterations. The CS core cellular process was the most prevalent in our study population. Clinical trials are warranted to investigate biomarkers for the three core cellular processes in advanced cancer patients to define the next best therapies.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Celastrol suppresses growth and induces apoptosis of human hepatocellular carcinoma through the modulation of STAT3/JAK2 signaling cascade In Vitro and In Vivo

10.1158/1940-6207.CAPR-11-0420Cancer Prevention Research54631-64

Suppression of essential pro-inflammatory signaling pathways by natural agents for the therapy of multiple myeloma

10.1007/s11101-013-9287-3Phytochemistry Reviews13179-106PRHE