Butein downregulates chemokine receptor CXCR4 expression and function through suppression of NF-κB activation in breast and pancreatic tumor cells

Determining chemokine receptor CXCR4 expression is significant in multiple diseases due to its role in promoting inflammation, cell migration and tumorigenesis. [68Ga]Pentixafor is a promising ligand for imaging CXCR4 expression in multiple tumor types, but its utility is limited by the physical properties of 68Ga. We screened a library of >200 fluorine-containing structural derivatives of AMD-3465 to identify promising candidates for in vivo imaging of CXCR4 expression by positron emission tomography (PET). Compounds containing fluoroethyltriazoles consistently achieved higher docking scores. Six of these higher scoring compounds were radiolabeled by click chemistry and evaluated in PC3-CXCR4 cells and BALB/c mice bearing bilateral PC3-WT and PC3-CXCR4 xenograft tumors. The apparent CXCR4 affinity of the ligands was relatively low, but tumor uptake was CXCR4-specific. The tumor uptake of [18F]RPS-534 (7.2 ± 0.3 %ID/g) and [18F]RPS-547 (3.1 ± 0.5 %ID/g) at 1 h p.i. was highest, leading to high tumor-to-blood, tumor-to-muscle, and tumor-to-lung ratios. Total cell-associated activity better predicted in vivo tumor uptake than did the docking score or apparent CXCR4 affinity. By this metric, and on the basis of their high yielding radiosynthesis, high tumor uptake, and good contrast to background, [18F]RPS-547, and especially [18F]RPS-534, are promising 18F-labeled candidates for imaging CXCR4 expression.

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Clinical significance of nuclear kappa B and chemokine receptor CXCR4 expression in patients with diffuse large B-cell lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18533 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18533-e18533

Author(s):

Byung Woog Kang ◽

Jong Gwang Kim ◽

Yee Soo Chae ◽

Soo Jung Lee ◽

Sang Kyun Sohn ◽

...

Keyword(s):

B Cell ◽

Prognostic Marker ◽

Chemokine Receptor ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Cxcr4 Expression ◽

Chemokine Receptor Cxcr4 ◽

Large B Cell Lymphoma ◽

Significant Difference ◽

Large B Cell

e18533 Background: This study investigated the activation of nuclear factor kB (NFkB) and the chemokine receptor CXCR4 co-expression in patients with diffuse large B-cell lymphoma (DLBCL) who received rituximab-based therapy. Methods: Seventy patients with DLBCL and treated with rituximab-CHOP (RCHOP) were included. Tissue microarray blocks were created from 70 cases of DLBCL. Sections were stained with antibodies to IKKα, p-IkB, p50, p52, and CXCR4. To classify cases of DLBCL into GCB (germinal center B-cell-like) and non-GCB, additional immunohistochemical expression of CD10, bcl-6, or MUM1 has been used in this study. A numeric intensity score of 0-3 was assigned each case. Negative was scored if 0/+1 and positive was scored if 2+/3+. Results: The median age was 66.5 years (range, 17-87) and 58.6% were male. Twenty-seven patients (38.6%) had stage III and IV at diagnosis. Twenty-three patients (32.9%) were categorized as high or high-intermediate risk according to their IPI. The overall incidence of BM involvement was 5.7%. Positive expression for NFkB and CXCR4 were more than 80%. In NFkB and CXCR4 status, there are no significant difference between GCB and non-GCB. High NFkB expression is associated with CXCR4 expression and they are co-expressed in about two thirds of patients. With a median follow-up duration of 28.7 months (range, 0.1-76.1), the 5-year overall survival (OS) and event-free survival (EFS) rate was 67.4% and 79.8%, respectively. Neither NFkB nor CXCR4 were associated with DLBCL outcomes. Conclusions: In concolusion, none of the NFkB and CXCR4 expression profiles investigated in this study was found to be an independent prognostic marker for Korean patients with DLBCL. However, further studies on a larger scale are warranted to clarify the role of NFkB and CXCR4 as a prognostic marker.

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