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Abstract: Chemokines (chemotactic cytokines) are a family of proteins associated with the trafficking and activation of leukocytes and other cell types in immune surveillance and inflammatory response. Besides their roles in the immune system, they play pleiotropic roles in tumor initiation, promotion, and progression. Chemokines can be classified into four subfamilies of chemokines, CXC, CC, C, or CX3C, based on their number and spacing of conserved cysteine residues near the N-terminus. This CXC subfamily can be further subclassified into two groups, depending on the presence or absence of a tripeptide motif glutamic acid–leucine–arginine (ELR) in the N-terminal domain. ELR−CXCL12, which binds to CXCR4 has been frequently implicated in various cancers. Over the past several years, studies have increasingly shown that the CXCR4/CXCL12 axis plays critical roles in tumor progression, such as invasion, angiogenesis, survival, homing to metastatic sites. This review focuses on involvement of CXCR4/CXCL12 interaction in neuroectodermal cancers and their therapeutic potentials. As an attractive therapeutic target of CXCR4/CXCL12 axis for cancer chemotherapy, development history and application of CXCR4 antagonists are described. [Copyright &y& Elsevier]

Abstract: Stromal-derived factor-1 (SDF-1) is a unique ligand of the CXC chemokine receptor 4 (CXCR4), which is critically involved in the metastasis of breast cancer. High levels of SDF-1 in the common destination organs of metastasis, such as the lymph nodes, lungs, liver, and bones, attract CXCR4-positive tumor cells. The interaction between SDF-1 and CXCR4 leads to the activation of specific signaling pathways, allowing for homing and metastatic progression. However, regulation of CXCR4 expression at the metastatic organ site is not well-documented. We detected the expression of CXCR4 and hypoxia inducible factor (HIF)-1α in breast tumor tissues by immunohistochemical staining and analyzed SDF-1 in primary tumors and lymph nodes using real-time RT-PCR. Compared to the corresponding metastasized tumors in the lymph nodes, primary invasive carcinomas showed more intense staining for CXCR4, particularly on the cellular membrane. Both primary tumors and lymph node metastases exhibited higher levels of CXCR4 expression compared to non-neoplastic breast tissues. Therefore, we hypothesized that the tumor environment in the lymph nodes may cause the reduction of CXCR4 levels in the metastatic tumor cells because of: (1) high SDF-1 levels and (2) lower levels of HIF-1α. Our in vitro data demonstrated that high levels of SDF-1 can induce the internalization and degradation of CXCR4 through the lysosome pathway. In addition, lower levels of HIF-1α in the lymph node metastases, probably induced by the less hypoxic environment, further lowered CXCR4 levels. These results indicate that ligand-dependent degradation and lower HIF-1α levels may be potential causes of lowered levels of CXCR4 in the lymph nodes compared to the primary tumors. Our study suggests that CXCR4 levels in tumor cells are regulated by its microenvironment. These findings may enhance our ability to understand the biological behavior of breast cancers. [Copyright &y& Elsevier]

Abstract: DU145 human prostatic carcinoma cells were treated with the differentiating agents phenylacetate (PA) and phenylbutyrate (PB) and examined in perfused cultures by diffusion-weighted 1H and 31P nuclear magnetic resonance spectroscopy (NMR). PA and PB (10 mM) induced significant (>3-fold) time-dependent increases in the level of NMR-visible lipids and total choline in 1H spectra, and glycerophosphocholine levels in the 31P spectra, with the increases being greater for PB. These effects were accompanied by significant increases in cytoplasmic lipid droplets and intracellular lipid volume fraction as observed by morphometric analysis of Oil Red O-stained cells. PB treatment caused cell cycle arrest in the G1 phase and induction of apoptosis. In contrast, PA-treated DU145 cells showed an accumulation of cells in G2/M and no evidence of apoptosis. These results demonstrate that significant differences exist in the mechanism of PA and PB activity, although both compounds cause similar, but graded alterations in lipid metabolism. The simultaneous accumulation of mobile lipid and glycerophosphocholine suggests that PB and PA induce phospholipid catabolism via a phospholipase-mediated pathway. The mobile lipid accumulation following the induction of either apoptosis and cytostasis by related differentiating agents indicate that the presence of NMR-visible lipids may not be a specific event causally resulting from the induction of apoptosis. [Copyright &y& Elsevier]

Presents a study on glucose-dependent apoptotic pathway induced by c-Myc, a lactate dehydrogenase gene. Discussion on the effect of glucose deprivation in c-Myc transformed and nontransformed cells; Indication that frequent increase of c-Myc in human cancers; Discussion on observation of c-Myc in rat cells.

Looks at the molecular basis of tumor aerobic glycolysis, focusing on a study in which the lactate dehydrogenase-A gene (LDH-A) was identified as a c-Myc-responsive gene using representational difference analysis. Description of the LDH-A gene; Methodology of the experiments conducted; Results obtained; Implications of these results for tumor metabolism and growth.

Purpose: Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the mechanism of HDAC9's contribution to chemoresistance remains poorly understood. The aim of this study was to investigate the role of miR-30c-regulated HDAC9 in chemoresistance of breast cancer and to determine the potential of selective inhibition of HDAC9 in sensitizing resistant breast cancer cells to chemotherapy.Methods: Expression levels of HDAC9 and miR-30c were measured in breast cancer cells and tissues using quantitative PCR analysis. The effect of selective inhibition of HDAC9 on sensitizing MDR cells to chemotherapy was assessed. MiR-30c/HDAC9 pathways' potential to mediate chemoresistance was analyzed.Results: Our studies show that HDAC9 was significantly up-regulated in chemoresistant breast cancer cell lines compared to a chemosensitive cell line and was inversely correlated with the levels of miR-30c. MiR-30c mimics and HDAC9 inhibitors reversed the chemoresistance of multidrug-resistant breast cancer cells.Conclusions: These results indicate that the mechanism of chemoresistance reversal with selective HDAC inhibition was partially realized by regulating miR-30c via directly targeting HDAC9. Our findings suggest that the miR-30c/HDAC9 signaling axis could be a novel and potential therapeutic target in chemoresistant breast cancer. [ABSTRACT FROM AUTHOR]

Modern radiation therapy is delivered with great precision, in part by relying on high-resolution multidimensional anatomic imaging to define targets in space and time. The development of quantitative imaging (QI) modalities capable of monitoring biologic parameters could provide deeper insight into tumor biology and facilitate more personalized clinical decision-making. The Quantitative Imaging Network (QIN) was established by the National Cancer Institute to advance and validate these QI modalities in the context of oncology clinical trials. In particular, the QIN has significant interest in the application of QI to widen the therapeutic window of radiation therapy. QI modalities have great promise in radiation oncology and will help address significant clinical needs, including finer prognostication, more specific target delineation, reduction of normal tissue toxicity, identification of radioresistant disease, and clearer interpretation of treatment response. Patient-specific QI is being incorporated into radiation treatment design in ways such as dose escalation and adaptive replanning, with the intent of improving outcomes while lessening treatment morbidities. This review discusses the current vision of the QIN, current areas of investigation, and how the QIN hopes to enhance the integration of QI into the practice of radiation oncology. [ABSTRACT FROM AUTHOR]

Simple Summary: With several previous efforts to segment pre-surgical brain tumor lesions from MRI, we sought to shine a different light on the problem. Radiation treatment planning post-surgery still relies heavily on manual contouring of T1-weighted contrast-enhanced and T2-weighted fluid-attenuated inversion recovery MRI. This is one of the first attempts to segment post-surgical brain lesions through deep learning approaches for radiation treatment planning and longitudinal tracking. Our best-performing model segments an overwhelming majority of lesions with at least 70% accuracy and has already been integrated into a web application heavily used by physicians and researchers for longitudinal tracking. Glioblastoma (GBM) has a poor survival rate even with aggressive surgery, concomitant radiation therapy (RT), and adjuvant chemotherapy. Standard-of-care RT involves irradiating a lower dose to the hyperintense lesion in T2-weighted fluid-attenuated inversion recovery MRI (T2w/FLAIR) and a higher dose to the enhancing tumor on contrast-enhanced, T1-weighted MRI (CE-T1w). While there have been several attempts to segment pre-surgical brain tumors, there have been minimal efforts to segment post-surgical tumors, which are complicated by a resection cavity and postoperative blood products, and tools are needed to assist physicians in generating treatment contours and assessing treated patients on follow up. This report is one of the first to train and test multiple deep learning models for the purpose of post-surgical brain tumor segmentation for RT planning and longitudinal tracking. Post-surgical FLAIR and CE-T1w MRIs, as well as their corresponding RT targets (GTV1 and GTV2, respectively) from 225 GBM patients treated with standard RT were trained on multiple deep learning models including: Unet, ResUnet, Swin-Unet, 3D Unet, and Swin-UNETR. These models were tested on an independent dataset of 30 GBM patients with the Dice metric used to evaluate segmentation accuracy. Finally, the best-performing segmentation model was integrated into our longitudinal tracking web application to assign automated structured reporting scores using change in percent cutoffs of lesion volume. The 3D Unet was our best-performing model with mean Dice scores of 0.72 for GTV1 and 0.73 for GTV2 with a standard deviation of 0.17 for both in the test dataset. We have successfully developed a lightweight post-surgical segmentation model for RT planning and longitudinal tracking. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to the infiltrative nature of glioblastoma, standard MRI techniques, such as T1-weighted contrast-enhanced (T1w-CE) and T2-weighted fluid-attenuated inversion recovery (FLAIR), imperfectly delineate radiation-targeted tumor volume. With spectroscopic MRI, the ratio of choline elevation, a tumor biomarker and N-acetylaspartate reduction, a healthy neuronal biomarker, can better determine the extent of the tumor. The aim of our secondary analysis was to determine if there was a relationship between survival outcomes and biomarkers identified by spectroscopic MRI for a cohort of 28 glioblastoma patients who received high-dose radiation guided by spectroscopic MRI. We determined that the volume of post-surgical spectroscopically abnormal tissue was a biomarker of overall and progression-free survival, whereas the volume of residual contrast enhancement, determined by T1w-CE MRI, was not. Our results suggest that accurate delineation and treatment of an infiltrative tumor not identified by contrast is a critical component of glioblastoma management and patient survival. Despite aggressive treatment, glioblastoma has a poor prognosis due to its infiltrative nature. Spectroscopic MRI-measured brain metabolites, particularly the choline to N-acetylaspartate ratio (Cho/NAA), better characterizes the extent of tumor infiltration. In a previous pilot trial (NCT03137888), brain regions with Cho/NAA ≥ 2x normal were treated with high-dose radiation for newly diagnosed glioblastoma patients. This report is a secondary analysis of that trial where spectroscopic MRI-based biomarkers are evaluated for how they correlate with progression-free and overall survival (PFS/OS). Subgroups were created within the cohort based on pre-radiation treatment (pre-RT) median cutoff volumes of residual enhancement (2.1 cc) and metabolically abnormal volumes used for treatment (19.2 cc). We generated Kaplan–Meier PFS/OS curves and compared these curves via the log-rank test between subgroups. For the subgroups stratified by metabolic abnormality, statistically significant differences were observed for PFS (p = 0.019) and OS (p = 0.020). Stratification by residual enhancement did not lead to observable differences in the OS (p = 0.373) or PFS (p = 0.286) curves. This retrospective analysis shows that patients with lower post-surgical Cho/NAA volumes had significantly superior survival outcomes, while residual enhancement, which guides high-dose radiation in standard treatment, had little significance in PFS/OS. This suggests that the infiltrating, non-enhancing component of glioblastoma is an important factor in patient outcomes and should be treated accordingly. [ABSTRACT FROM AUTHOR]

Triple negative breast tumors don’t respond to Tamoxifen and Herceptin, two of the most effective medications for treating breast cancer. Additionally, triple negative breast cancer (TNBC) intrinsically resists or will eventually acquire resistance to chemotherapy. The purpose of this study is to understand better the molecular basis of TNBC as well as develop new therapeutic strategies against it. Here, we analyzed miRNA-206 expression levels in breast cancer cell lines and tissues. In addition, we investigated whether miR-206 mimics inhibited TNBC tumor invasion and angiogenesis. The results showed that miR-206 was downregulated in TNBC compared to non-TNBC cell lines and tissues. Additionally, the decreased levels of miR-206 were inversely consistent with expression levels of VEGF. Furthermore, the forced expression of miR-206 in the mimic-transfected TNBC cells downregulated VEGF, MAPK3, and SOX9 expression levels. The miR-206 mimics inhibited TNBC breast cell invasion and angiogenesis. These findings demonstrate for the first time the involvement of miRNA-206 in TNBC invasion and angiogenesis and suggest that miR-206 may be an efficient agent for therapy of TNBC. [ABSTRACT FROM AUTHOR]

Retraction Note to: MicroRNA-30c-regulated HDAC9 mediates chemoresistance of breast cancer Retraction to: Cancer Chemotherapy and Pharmacology (2020) 85:413-423 https://doi.org/10.1007... The Editors-in-Chief have retracted this article. 3b, 4a and 4c. The corresponding author confirmed that the western blot backgrounds have been altered but stated that the original unedited images were no longer available. [Extracted from the article]

Abstract: Lysophosphatidic acids (LPA) exert growth factor-like effects through specific G protein-coupled receptors. The presence of different LPA receptors often determines the specific signaling mechanisms and the physiological consequences of LPA in different environments. Among the four members of the LPA receptor family, LPA2 has been shown to be overexpressed in colon cancer suggesting that the signaling by LPA2 may potentiate growth and survival of tumor cells. In this study, we examined the effect of LPA on survival of colon cancer cells using Caco-2 cells as a cell model system. LPA rescued Caco-2 cells from apoptosis elicited by the chemotherapeutic drug, etoposide. This protection was accompanied by abrogation of etoposide-induced stimulation of caspase activity via a mechanism dependent on Erk and PI3K. In contrast, perturbation of cellular signaling mediated by the LPA2 receptor by knockdown of a scaffold protein NHERF2 abrogated the protective effect of LPA. Etoposide decreased the expression of Bcl-2, which was reversed by LPA. Etoposide decreased the phosphorylation level of the proapoptotic protein Bad in an Erk-dependent manner, without changing Bad expression. We further show that LPA treatment resulted in delayed activation of Erk. These results indicate that LPA protects Caco-2 cells from apoptotic insult by a mechanism involving Erk, Bad, and Bcl-2. [Copyright &y& Elsevier]

Secondary glioblastoma is a rare brain tumor characterized by a mutation in isocitrate dehydrogenase, which is reported to lead to epigenetic modification. Patients with secondary glioblastoma experience poor survival and quality-of-life outcomes due to the disease's aggressiveness and a lack of targeted therapies. In this report, a patient with a secondary glioblastoma was treated with a histone deacetylase inhibitor, an epigenetic drug with potent anti-inflammatory properties, in addition to the standard regimen. The patient showed very favorable survival and quality-of-life measures, and a restoration of several neuro-metabolites as measured by spectroscopic magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

The CXCR4/CXCL12 axis plays prominent roles in tumor metastasis and inflammation. CXCR4 has been shown to be involved in a variety of inflammation-related diseases. Therefore, CXCR4 is a promising potential target to develop novel anti-inflammatory agents. Taking our previously discovered CXCR4 modulator RB-108 as the lead compound, a series of derivatives were synthesized structurally modifying and optimizing the amide and sulfamide side chains. The derivatives successfully maintained potent CXCR4 binding affinity. Furthermore, compounds IIb , IIc , IIIg , IIIj , and IIIm were all efficacious in inhibiting the invasion of CXCR4-positive cells, displaying a much more potent effect than the lead compound RB-108. Notably, compound IIIm significantly decreased carrageenan-induced swollen volume and paw thickness in a mouse paw edema model. More importantly, IIIm exhibited satisfying PK profiles with a half-life of 4.77 h in an SD rat model. In summary, we have developed compound IIIm as a new candidate for further investigation based on the lead compound RB-108. Image 1 • A series of CXCR4 inhibitors were synthesized based on the lead compound RB-108. • Compound IIIm significantly inhibited the invasion of CXCR4+ cells by 83%. • IIIm significantly attenuated mouse paw edema and tissue damage. • IIIm exhibited satisfying PK profiles with a T 1/2 of 4.77 h. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A series of pyridine derivatives were synthesized as potential CXCR4 antagonists. • Thirteen compounds have a potent effective concentration in a binding affinity assay. • Nine compounds have at least 75% inhibition of invasion in Matrigel binding assay. • These compounds show potential for further optimization as CXCR4 antagonist. Abstract CXCR4 and its cognate ligand CXCL12 has been linked to various pathways such as cancer metastasis, inflammation, HIV-1 proliferation, and auto-immune diseases. Small molecules have shown potential as CXCR4 inhibitors and modulators, and therefore can mitigate diseases related to the CXCR4-CXCL12 pathway. We have designed and synthesized a series of 2,5-diamino and 2,5-dianilinomethyl pyridine derivatives as potential CXCR4 antagonists. Thirteen compounds have an effective concentration (EC) of 100 nM or less in a binding affinity assay and nine of these have at least 75% inhibition of invasion in Matrigel binding assay. Compounds 3l , 7f , 7j , and 7p show a minimal reduction in inflammation when carrageenan paw edema test is conducted. Overall, these compounds show potential as CXCR4 antagonist. [ABSTRACT FROM AUTHOR]

Deriving accurate attenuation maps for PET/MRI remains a challenging problem because MRI voxel intensities are not related to properties of photon attenuation and bone/air interfaces have similarly low signal. This work presents a learning-based method to derive patient-specific computed tomography (CT) maps from routine T1-weighted MRI in their native space for attenuation correction of brain PET. We developed a machine-learning-based method using a sequence of alternating random forests under the framework of an iterative refinement model. Anatomical feature selection is included in both training and predication stages to achieve optimal performance. To evaluate its accuracy, we retrospectively investigated 17 patients, each of which has been scanned by PET/CT and MR for brain. The PET images were corrected for attenuation on CT images as ground truth, as well as on pseudo CT (PCT) images generated from MR images. The PCT images showed mean average error of 66.1 ± 8.5 HU, average correlation coefficient of 0.974 ± 0.018 and average Dice similarity coefficient (DSC) larger than 0.85 for air, bone and soft tissue. The side-by-side image comparisons and joint histograms demonstrated very good agreement of PET images after correction by PCT and CT. The mean differences of voxel values in selected VOIs were less than 4%, the mean absolute difference of all active area is around 2.5%, and the mean linear correlation coefficient is 0.989 ± 0.017 between PET images corrected by CT and PCT. This work demonstrates a novel learning-based approach to automatically generate CT images from routine T1-weighted MR images based on a random forest regression with patch-based anatomical signatures to effectively capture the relationship between the CT and MR images. Reconstructed PET images using the PCT exhibit errors well below accepted test/retest reliability of PET/CT indicating high quantitative equivalence. [ABSTRACT FROM AUTHOR]

Triple negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes with poor prognosis. The purpose of this study is to better understand the molecular basis of TNBC as well as develop new therapeutic strategies. Our results demonstrate that HDAC9 is overexpressed in TNBC compared to non-TNBC cell lines and tissues and is inversely proportional with miR-206 expression levels. We show that HDAC9 selective inhibition blocked the invasion of TNBC cells in vitro and repressed the angiogenesis shown via in vivo Matrigel plug assays. Subsequent HDAC9 siRNA knockdown was then shown to restore miR-206 while also decreasing VEGF and MAPK3 levels. Furthermore, the inhibition of miR-206 neutralized the action of HDAC9 siRNA on decreasing VEGF and MAPK3 levels. This study highlights HDAC9 as a mediator of cell invasion and angiogenesis in TNBC cells through VEGF and MAPK3 by modulating miR-206 expression and suggests that selective inhibition of HDAC9 may be an efficient route for TNBC therapy. [ABSTRACT FROM AUTHOR]

The CXCR4/CXCL12 chemokine axis can chemotactically accumulate inflammatory cells to local tissues and regulate the release of inflammatory factors. Developing novel CXCR4 modulators may provide a desirable strategy to control the development of inflammation. A series of novel hybrids were designed by integrating the key pharmacophores of three CXCR4 modulators. The majority of compounds displayed potent CXCR4 binding affinity. Compound 7a exhibited 1000-fold greater affinity than AMD3100 and significantly inhibited invasion of CXCR4-positive tumor cells. Additionally, compound 7a blocked mice ear inflammation by 67% and suppressed the accumulation of inflammatory cells in an in vivo mouse ear edema evaluation. Western blot analyses revealed that 7a inhibited the CXCR4/CXCL12-mediated phosphorylation of Akt and p44 in a dose-dependent manner. Moreover, compound 7a had no observable cytotoxicity and displayed a favorable plasma stability in our preliminary pharmacokinetic study. These results confirmed that this is a feasible method to develop CXCR4 modulators for the regulation and reduction of inflammation. [ABSTRACT FROM AUTHOR]

Although histone deacetylase (HDAC) inhibitors have been shown to effectively induce the inhibition of proliferation and migration in breast cancer, the anticancer mechanism remains poorly understood. Our studies show that miR-200c was significantly downregulated in breast cancer cell lines compared to normal cell lines and inversely correlated with the levels of class IIa HDACs and CRKL. HDAC inhibitors and the ectopic expression of miR-200c as tumor suppressors inhibited the proliferation, invasion, and migration of breast cancer cells by downregulating CRKL. These results indicate that the anticancer mechanism of HDAC inhibitor was realized partially by regulating miR-200c via CRKL targeting. Our findings suggest that the HDAC-miR200c-CRKL signaling axis could be a novel diagnostic marker and potential therapeutic target in breast cancer. [ABSTRACT FROM AUTHOR]

CXCR4 plays a crucial role in the inflammatory disease process, providing an attractive means for drug targeting. A series of novel amide-sulfamide derivatives were designed, synthesized and comprehensively evaluated. This new scaffold exhibited much more potent CXCR4 inhibitory activity, with more than 70% of the compounds showed notably better binding affinity than the reference drug AMD3100 in the binding assay. Additionally, in the Matrigel invasion assay, most of our compounds significantly blocked the tumor cell invasion, demonstrating superior efficacy compared to AMD3100. Furthermore, compound IIj blocked mice ear inflammation by 75% and attenuated ear edema and damage substantially in an in vivo model of inflammation. Western blot analyses revealed that CXCR4 modulator IIj significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, compound IIj had no observable cytotoxicity and displayed a favourable plasma stability in our preliminary pharmacokinetic study. The preliminary structure-activity relationships were also summarized. In short, this novel amide-sulfamide scaffold exhibited potent CXCR4 inhibitory activity both in vitro and in vivo . These results also confirmed that developing modulators targeting CXCR4 provides an exciting avenue for treatment of inflammation. [ABSTRACT FROM AUTHOR]

CXCR4 plays a crucial role in recruitment of inflammatory cells to inflammation sites at the beginning of the disease process. Modulating CXCR4 functions presents a new avenue for anti-inflammatory strategies. However, using CXCR4 antagonists for a long term usage presents potential serious side effect due to their stem cell mobilizing property. We have been developing partial CXCR4 antagonists without such property. A new computer-aided drug design program, the FRESH workflow, was used for anti-CXCR4 lead compound discovery and optimization, which coupled both compound library building and CXCR4 docking screens in one campaign. Based on the designed parent framework, 30 prioritized amide-sulfamide structures were obtained after systemic filtering and docking screening. Twelve compounds were prepared from the top-30 list. Most synthesized compounds exhibited good to excellent binding affinity to CXCR4. Compounds Ig and Im demonstrated notable in vivo suppressive activity against xylene-induced mouse ear inflammation (with 56% and 54% inhibition). Western blot analyses revealed that Ig significantly blocked CXCR4/CXCL12-mediated phosphorylation of Akt. Moreover, Ig attenuated the amount of TNF-α secreted by pathogenic E. coli-infected macrophages. More importantly, Ig had no observable cytotoxicity. Our results demonstrated that FRESH virtual high throughput screening program of targeted chemical class could successfully find potent lead compounds, and the amide-sulfamide pharmacophore was a novel and effective framework blocking CXCR4 function. [ABSTRACT FROM AUTHOR]

Targeting the interaction between G-Protein Coupled Receptor, CXCR4, and its natural ligand CXCL12 is a leading strategy to mitigate cancer metastasis and reduce inflammation. Several pyridine-based compounds modeled after known small molecule CXCR4 antagonists, AMD3100 and WZ811, were synthesized. Nine hit compounds were identified. These compounds showed lower binding concentrations than AMD3100 (1000 nM) and six of the nine compounds had an effective concentration (EC) less than or equal to WZ811 (10 nM). Two of the hit compounds ( 2g and 2w ) inhibited invasion of metastatic cells at a higher rate than AMD3100 (62%). Compounds 2g and 2w also inhibit inflammation in the same range as WZ811 in the paw edema test at 40% reduction in inflammation. These preliminary results are the promising foundation of a new class of pyridine-based CXCR4 antagonists. [ABSTRACT FROM AUTHOR]

CXCR4 inhibitors are promising agents for the treatment of cancer metastasis and inflammation. A series of novel tertiary amine derivatives targeting CXCR4 were designed, synthesized, and evaluated. The central benzene ring linker and side chains were modified and optimized to study the structure–activity relationship. Seven compounds displayed much more potent activity than the reference drug, AMD3100, in both the binding affinity assay and the blocking of Matrigel invasion functional assay. These compounds exhibited effective concentration ranging from 1 to 100 nM in the binding affinity assay and inhibited invasion from 65.3% to 100% compared to AMD3100 at 100 nM. Compound IIn showed a 50% suppressive effect against carrageenan-induced paw inflammation in a mouse model, which was as effective as the peptidic antagonist, TN14003 (48%). These data demonstrate that symmetrical bis-tertiary amines are unique CXCR4 inhibitors with high potency. [ABSTRACT FROM AUTHOR]

Purpose: Glioblastoma (GBM) neurosurgical resection relies on contrast-enhanced MRI-based neuronavigation. However, it is well-known that infiltrating tumor extends beyond contrast enhancement. Fluorescence-guided surgery (FGS) using 5-aminolevulinic acid (5-ALA) was evaluated to improve extent of resection (EOR) of GBMs. Preoperative morphological tumor metrics were also assessed.Procedures: Thirty patients from a phase II trial evaluating 5-ALA FGS in newly diagnosed GBM were assessed. Tumors were segmented preoperatively to assess morphological features as well as postoperatively to evaluate EOR and residual tumor volume (RTV).Results: Median EOR and RTV were 94.3 % and 0.821 cm(3), respectively. Preoperative surface area to volume ratio and RTV were significantly associated with overall survival, even when controlling for the known survival confounders.Conclusions: This study supports claims that 5-ALA FGS is helpful at decreasing tumor burden and prolonging survival in GBM. Moreover, morphological indices are shown to impact both resection and patient survival. [ABSTRACT FROM AUTHOR]

A series of pyridine derivatives were synthesized as potential inhibitors of chemokine receptor type 4. This chemokine receptor has been linked to various disease pathways including HIV-1 proliferation, autoimmune disorders, inflammatory diseases, and cancer metastasis. The compounds were tested for activity using an affinity binding assay and an assay that tests the ability to inhibit cell invasion. Two hit compounds ( 2b and 2j) have been identified for further evaluation that inhibit cell invasion by at least 50% and have an effective concentration of less than 100 n m in the binding affinity assay. The structures of the synthesized compounds were confirmed by spectral data. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Renal scintigraphy is an important imaging modality for the diagnosis and management of a variety of renal diseases including obstruction and renovascular hypertension as well as the evaluation of absolute and relative kidney function. The goal of this work was to evaluate Al18F-NODA-butyric acid (Al18F-1) as a potential PET tracer to image the kidneys and monitor renal function by comparing its pharmacokinetic properties with those of 131I-o-iodohippurate (131I-OIH), the radioactive standard for the measurement of effective renal plasma flow. Methods: Al18F-1 was prepared in aqueous conditions using a one-pot Al18F-radiofluorination method and its radiochemical purity was determined by HPLC. Biodistribution studies, using 131I-OIH as an internal control, were performed in normal rats and in rats with renal pedicle ligation. In vitro stability and metabolism of Al18F-1 were analyzed by HPLC. Dynamic microPET/CT studies were conducted in normal rats. Results: Al18F-1 showed excellent stability in vitro and in vivo. Biodistribution studies in normal rats and in rats with simulated renal failure confirmed that Al18F-1 was exclusively cleared through the renal–urinary pathway and that the hepatic/gastrointestinal activity was less for Al18F-1 than for 131I-OIH both at 10 and 60min. Dynamic PET showed a rapid transit of Al18F-1 through the kidneys into the bladder. Conclusion: These results suggest that the easily labeled Al18F-based compounds provide a highly promising approach for the development of a PET renal radiotracer that combines superior imaging qualities with a reliable measure of effective renal plasma flow. [Copyright &y& Elsevier]

Curcumin is a biologically activecomponent of curry powder. Astructurally related class of mimetics possesses similar anti-inflammatoryand anticancer properties. Mechanism has been examined by exploringkinase inhibition trends. In a screen of 50 kinases relevant to manyforms of cancer, one member of the series (4, EF31) showed≥85% inhibition for 10 of the enzymes at 5 μM, while22 of the proteins were blocked at ≥40%. IC50valuesfor an expanded set of curcumin analogues established a rank orderof potencies, and analyses of IKKβ and AKT2 enzyme kineticsfor 4revealed a mixed inhibition model, ATP competitiondominating. Our curcumin mimetics are generally selective for Ser/Thrkinases. Both selectivity and potency trends are compatible with proteinsequence comparisons, while modeled kinase binding site geometriesdeliver a reasonable correlation with mixed inhibition. Overall, theseanalogues are shown to be pleiotropic inhibitors that operate at multiplepoints along cell signaling pathways. [ABSTRACT FROM AUTHOR]

Purpose: Solid tumors can be resistant or develop resistance to radiotherapy. The purpose of this study is to explore whether microRNA-302 is involved in radioresistance and can be exploited as a sensitizer to enhance sensitivity of breast cancer cells to radiation therapy. Methods: MiR-302 expression levels in radioresistant cell lines were analyzed in comparison with their parent cell lines. Furthermore, we investigated whether enforced expression of miR-302 sensitized radioresistant breast cancer cells to ionizing radiation in vitro and in vivo. Results: MiR-302 was downregulated in irradiated breast cancer cells. Additionally, the expression levels of miR-302a were inversely correlated with those of AKT1 and RAD52, two critical regulators of radioresistance. More promisingly, miR-302a sensitized radioresistant breast cancer cells to radiation therapy in vitro and in vivo and reduced the expression of AKT1 and RAD52. Conclusion: Our findings demonstrated that decreased expression of miR-302 confers radioresistance and restoration of miR-302 baseline expression sensitizes breast cancer cells to radiotherapy. These data suggest that miR-302 is a potential sensitizer to radiotherapy. [ABSTRACT FROM AUTHOR]

Abstract: Nuclear factor kappa B (NF-κB) is a key signaling molecule in the elaboration of the inflammatory response. Data indicate that curcumin, a natural ingredient of the curry spice turmeric, acts as a NF-κB inhibitor and exhibits both anti-inflammatory and anti-cancer properties. Curcumin analogs with enhanced activity on NF-κB and other inflammatory signaling pathways have been developed including the synthetic monoketone compound 3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24). 3,5-Bis(2-pyridinylmethylidene)-4-piperidone (EF31) is a structurally-related curcumin analog whose potency for NF-κB inhibition has yet to be determined. To examine the activity of EF31 compared to EF24 and curcumin, mouse RAW264.7 macrophages were treated with EF31, EF24, curcumin (1–100μM) or vehicle (DMSO 1%) for 1h. NF-κB pathway activity was assessed following treatment with lipopolysaccharide (LPS) (1μg/mL). EF31 (IC50 ~5μM) exhibited significantly more potent inhibition of LPS-induced NF-κB DNA binding compared to both EF24 (IC50 ~35μM) and curcumin (IC50 >50μM). In addition, EF31 exhibited greater inhibition of NF-κB nuclear translocation as well as the induction of downstream inflammatory mediators including pro-inflammatory cytokine mRNA and protein (tumor necrosis factor-α, interleukin-1β, and interleukin-6). Regarding the mechanism of these effects on NF-κB, EF31 (IC50 ~1.92μM) exhibited significantly greater inhibition of IκB kinase β compared to EF24 (IC50 ~131μM). Finally, EF31 demonstrated potent toxicity in NF-κB-dependent cancer cell lines while having minimal and reversible toxicity in RAW264.7 macrophages. These data indicate that EF31 is a more potent inhibitor of NF-κB activity than either EF24 or curcumin while exhibiting both anti-inflammatory and anticancer activities. Thus, EF31 represents a promising curcumin analog for further therapeutic development. [Copyright &y& Elsevier]

Purpose: To explore whether miR-19 is involved in the regulation of multidrug resistance (MDR), one of the main causes of breast cancer mortality, and modulates sensitivity of tumor cells to chemotherapeutic agents. Methods: We analyzed miRNA expression levels in three MDR cell lines in comparison with their parent cell line, MCF-7, using a miRNA microarray. We investigated whether inhibitor of miR-19 sensitized MDR cells to chemotherapeutic agents in vitro and in vivo. Results: MiR-19 was overexpressed in all three MDR cell lines compared to their parental cell line, MCF-7. Expression levels of miR-19 in MDR cells were inversely consistent with those of PTEN. Inhibitor of miR-19a restored sensitivity of MDR cells to cytotoxic agents; administration of LNA-antimiR-19a, a chemo-modified miR-19a inhibitor, sensitized MDR cells to chemotherapeutic agents in vivo. Conclusion: Our findings demonstrate, for the first time, involvement of miR-19 in multidrug resistance through modulation of PTEN and suggest that miR-19 may be a potential target for preventing and reversing MDR in tumor cells. [ABSTRACT FROM AUTHOR]

The C-X-C chemokine receptor type 4 (CXCR4)/stromal cell derived factor-1 (SDF-1 or CXCL12) interaction and the resulting cell signaling cascade play a key role in metastasis and inflammation. On the basis of the previously published CXCR4 antagonist 5 (WZ811), a series of novel nonpeptidic anti-CXCR4 small molecules have been designed and synthesized to improve potency. Following a structure−activity profile around 5, more advanced compounds in the N,N′-(1, 4-phenylenebis(methylene)) dipyrimidin-2-amines series were discovered and shown to possess higher CXCR4 binding potential and specificity than 5. Compound 26 (508MCl) is the lead compound and exhibits subnanomolar potency in three in vitro assays including competitive binding, Matrigel invasion and Gαi cyclic adenosine monophosphate (cAMP) modulation signaling. Furthermore, compound 26 displays promising effects by interfering with CXCR4 function in three mouse models: paw inflammation, Matrigel plug angiogenesis, and uveal melanoma micrometastasis. These data demonstrate that dipyrimidine amines are unique CXCR4 antagonists with high potency and specificity. [ABSTRACT FROM AUTHOR]

Abstract: Multidrug resistance-associated protein (MRP-1/ABCC1) transports a wide range of therapeutic agents and may play a critical role in the development of multidrug resistance (MDR) in tumor cells. However, the regulation of MRP-1 remains controversial. To explore whether miRNAs are involved in the regulation of MRP-1 expression and modulate the sensitivity of tumor cells to chemotherapeutic agents, we analyzed miRNA expression levels in VP-16-resistant MDR cell line, MCF-7/VP, in comparison with its parent cell line, MCF-7, using a miRNA microarray. MCF-7/VP overexpressed MRP-1 mRNA and protein not MDR-1 and BCRP. miR-326 was downregulated in MCF-7/VP compared to MCF-7. Additionally, miR-326 was downregulated in a panel of advanced breast cancer tissues and consistent reversely with expression levels of MRP-1. Furthermore, the elevated levels of miR-326 in the mimics-transfected VP-16-resistant cell line, MCF-7/VP, downregulated MRP-1 expression and sensitized these cells to VP-16 and doxorubicin. These findings demonstrate for the first time the involvement of miRNAs in multidrug resistance mediated by MRP-1 and suggest that miR-326 may be an efficient agent for preventing and reversing MDR in tumor cells. [Copyright &y& Elsevier]

Background: Long-term success in lung transplantation is limited by obliterative bronchiolitis (OB), yet the mechanism for this disease is not well understood. Chemokine SDF-1 and its receptor, CXCR4, have been reported to be involved in several fibrogenic processes by recruiting inflammatory and fibroblast progenitor cells into injured tissues. We hypothesized that the SDF-1/CXCR4 axis also plays a role in the pathogenesis of OB. Methods: Using the mouse heterotopic allogeneic airway transplant model, we transplanted mouse tracheas from BALB/c donors into C57BL/6 recipients. At Day 10 after transplant, we found high expression of SDF-1 in cells in the sub-epithelial layers of the allograft. Approximately 26% of cells infiltrating the allograft were CD45+CXCR4+, as determined by flow cytometry analysis. Results: Treatment of the recipients with a CXCR4 antagonist, TN14003, decreased cell infiltration into the grafts at Day 10 post-implantation. At Day 42, a significant reduction in luminal occlusion was found in the TN14003-treated animals compared with controls (57.40% vs 98.21%, p < 0.01). To demonstrate the relevance of the SDF-1/CXCR4 axis in OB, sections of lung tissue obtained from lung transplant patients with OB were examined for SDF-1 and CXCR4 expression. We found a higher number of CXCR4- and SDF-1–positive cells in samples from patients with OB as compared with normal lungs. Conclusions: These findings provide new insights into the mechanisms of lung chronic rejection and may lead to new intervention tools for the treatment of OB. [Copyright &y& Elsevier]

Tissue factor (TF) is aberrantly expressed on tumor vascular endothelial cells (VECs) and on cancer cells in many malignant tumors, but not on normal VECs, making it a promising target for cancer therapy. As a transmembrane receptor for coagulation factor VIIa (fVIIa), TF forms a high-affinity complex with its cognate ligand, which is subsequently internalized through receptor-mediated endocytosis. Accordingly, we developed a method for selectively delivering EF24, a potent synthetic curcumin analog, to TF-expressing tumor vasculature and tumors using fVIIa as a drug carrier. EF24 was chemically conjugated to fVIIa through a tripeptide-chloromethyl ketone. After binding to TF-expressing targets by fVIIa, EF24 will be endocytosed along with the drug carrier and will exert its cytotoxicity. Our results showed that the conjugate inhibits vascular endothelial growth factor-induced angiogenesis in a rabbit cornea model and in a Matrigel model in athymic nude mice. The conjugate-induced apoptosis in tumor cells and significantly reduced tumor size in human breast cancer xenografts in athymic nude mice as compared with the unconjugated EF24. By conjugating potent drugs to fVIIa, this targeted drug delivery system has the potential to enhance therapeutic efficacy, while reducing toxic side effects. It may also prove to be useful for treating drug-resistant tumors and micro-metastases in addition to primary tumors. [ABSTRACT FROM AUTHOR]

Abstract: miRNAs have been shown to function as regulatory molecules and to play an important role in cancer progression. Very little is currently known about the increasing invasion and metastasis of breast cancer due to the loss of expressive levels of certain miRNAs in breast tumor cells. In order to determine whether the CXCR4/SDF-1 pathway is regulated by expression of miRNAs, we designed and synthesized pre-miRNA against CXCR4. This double-stranded miRNA gene was ligated with a miR-155-based Block-iT Pol II miR RNAi Expression Vector (Invitrogen). Expression levels of CXCR4 in CXCR4–miRNA-transfected breast tumor cells had significantly declined. These cells exhibited reduced migration and invasion in vitro. Furthermore, they formed fewer lung metastases in vivo compared to ctrl-miRNA-transfected cells. These data support the conclusion that miRNA against CXCR4 can serve as an alterative means of therapy to lower CXCR4 expression and to block the invasion and metastasis of breast cancer cells. [Copyright &y& Elsevier]

Abstract: CXC chemokine receptor 4 (CXCR4) has been shown to play a critical role in chemotaxis and homing, which are key steps in cancer metastasis. There is also increasing evidence that links this receptor to angiogenesis; however, its molecular basis remains elusive. Vascular endothelial growth factor (VEGF), one of the major angiogenic factors, promotes the formation of leaky tumor vasculatures that are the hallmarks of tumor progression. Here, we investigated whether CXCR4 induces the expression of VEGF through the PI3K/Akt pathway. Our results showed that CXCR4/CXCL12 induced Akt phosphorylation, which resulted in upregulation of VEGF at both the mRNA and protein levels. Conversely, blocking the activation of Akt signaling led to a decrease in VEGF protein levels; blocking CXCR4/CXCL12 interaction with a CXCR4 antagonist suppressed tumor angiogenesis and growth in vivo. Furthermore, VEGF mRNA levels correlated well with CXCR4 mRNA levels in patient tumor samples. In summary, our study demonstrates that the CXCR4/CXCL12 signaling axis can induce angiogenesis and progression of tumors by increasing expression of VEGF through the activation of PI3K/Akt pathway. Our findings suggest that targeting CXCR4 could provide a potential new anti-angiogenic therapy to suppress the formation of both primary and metastatic tumors. [Copyright &y& Elsevier]

The C-X-C chemokine receptor type 4 (CXCR4) is a potential therapeutic target for HIV infection, metastatic cancer, and inflammatory autoimmune diseases. In this study, we screened the ZINC chemical database for novel CXCR4 modulators through a series of in silico guided processes. After evaluating the screened compounds for their binding affinities to CXCR4 and inhibitory activities against the chemoattractant CXCL12, we identified a hit compound (ZINC 72372983) showing 100 nM affinity and 69% chemotaxis inhibition at the same concentration (100 nM). To increase the potency of our hit compound, we explored the protein-ligand interactions at an atomic level using molecular dynamics simulation which enabled us to design and synthesize a novel compound (Z7R) with nanomolar affinity (IC 50 = 1.25 nM) and improved chemotaxis inhibition (78.5%). Z7R displays promising anti-inflammatory activity (50%) in a mouse edema model by blocking CXCR4-expressed leukocytes, being supported by our immunohistochemistry study. Image 1 • New CXCR4 ligands were identified by in silico screenings and in vitro assays. • A novel compound was rationally designed from the hit compound using MD simulation. • Z7R displayed nanomolar binding affinity (1 nM) and inhibited 79% of chemotaxis. • Z7R demonstrated 50% anti-inflammatory activity in a mouse edema model. [ABSTRACT FROM AUTHOR]

• A novel small molecular CXCR4-targeted PET tracer without chelating moiety is designed based on benzenesulfonamide scaffold via chemoinformatic and molecular modeling approach. • In vitro binding assay and chemotaxis inhibition assay affirm the affinity and functional activity of the novel agent with CXCR4. • The novel CXCR4-targeted F-18 PET agent demonstrates the ability to visualize acute inflammation, head and neck cancer, and cancer lung metastasis in mouse models. CXCR4 is involved in various diseases such as inflammation, tumor growth, and cancer metastasis through the interaction with its natural endogenous ligand, chemokine CXCL12. In an effort to develop imaging probes for CXCR4, we developed a novel small molecule CXCR4-targeted PET agent (compound 5) by combining our established benzenesulfonamide scaffold with a labeling component by virtue of click chemistry. 5 shows nanomolar affinity (IC 50 = 6.9 nM) against a known CXCR4 antagonist (TN14003) and inhibits more than 65% chemotaxis at 10 nM in vitro assays. Radiofluorinated compound 5 ([18F] 5) demonstrates a competitive cellular uptake against CXCL12 in a dose-dependent manner. Further, microPET images of [18F] 5 exhibits preferential accumulation of radioactivity in the lesions of λ-carrageenan-induced paw edema, human head and neck cancer orthotopic xenograft, and metastatic lung cancer of each mouse model. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequently diagnosed malignancy and the second common cause of death in women worldwide. High mortality in breast cancer is frequently associated with metastatic progression rather than the primary tumor itself. It has been recently identified that the CXCR4/CXCL12 axis plays a pivotal role in breast cancer metastasis, especially in directing metastatic cancer cells to CXCL12-riched organs and tissues. Herein, taking the amide-sulfamide as the lead structure, the second-round structural modifications to the sulfamide structure were performed to obtain more active CXCR4 modulators against tumor metastasis. Both in vivo and in vitro experiments illustrated that compound IIIe possessed potent CXCR4 binding affinity, excellent anti-metastatic and anti-angiogenetic activity against breast cancer. More importantly, in a mouse breast cancer lung metastasis model, compound IIIe exerted a significant inhibitory effect on breast cancer metastasis. Taken together, all these positive results demonstrated that developing of CXCR4 modulators is a promising strategy to mediate breast cancer metastasis. Image 1 • CXCR4/CXCL12 axis plays a pivotal role in breast cancer metastasis. • New derivatives were obtained by second-round structural modifications. • Compound IIIe exerted a significant inhibition on breast cancer metastasis. • CXCR4 modulator is a promising strategy to mediate tumor metastasis. [ABSTRACT FROM AUTHOR]

The interaction between G-Protein coupled receptor CXCR4 and its natural ligand CXCL12 has been linked to inflammation experienced by patients with Irritable Bowel Disease (IBD). Blocking this interaction could potentially reduce inflammatory symptoms in IBD patients. In this work, several thiophene-based and furan-based compounds modeled after AMD3100 and WZ811—two known antagonists that interrupt the CXCR4-CXCL12 interaction—were synthesized and analyzed. Fifteen hit compounds were identified; these compounds exhibited effective concentrations (EC) lower than 1000 nM (AMD3100) and inhibited invasion of metastatic cells by at least 45%. Selected compounds (2d , 2j , 8a) that inhibited metastatic invasion at a higher rate than WZ811 (62%) were submitted for a carrageenan inflammation test, where both 8a and 2j reduced inflammation in the same range as WZ811 (40%) but did not reduce inflammation more than 40%. Select compounds were also modeled in silic o to show key residue interactions. These preliminary results with furan-based and thiophene-based analogues contribute to the new class on heterocyclic aromatic-based CXCR4 antagonists. Image 1 • Fifty-six potential furan and thiophene based CXCR4/CXCL12 modulators synthesized. • Sixteen hit compounds inhibited metastasis of breast cancer cells by 50% or more. • Two hit compounds reduced carrageenan induced inflammation by 30%. • In silico analysis suggests hit compounds interact with key CXCR4/CXCL12 residues. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most aggressive primary brain tumor in adults. Limited treatment options and the intense nature of therapy make determining the appropriate treatment course for each patient difficult. The appearance of transient worsening of imaging findings, known as treatment effect, after chemoradiation further complicates clinical decision-making. Accurately differentiating treatment effects from true progression is critical as subsequent treatment decisions are based largely on radiographic evidence of tumor progression. As chemoradiation can cause worsening of imaging findings, it is possible that the use of new treatments and modified chemoradiation regimens may alter the presentation of treatment effect. Therefore, physicians should be aware that atypical presentations of treatment effects can occur, and may be more likely, when treatment regimens are modified. Here, we present the case of a patient with isocitrate dehydrogenase 1 wild type, O-6-methylguanine-DNA methyltransferase-methylated glioblastoma who underwent dose-escalation radiation therapy (to 75 Gy) and exhibited worsened imaging findings at 8 months post-radiation. [ABSTRACT FROM AUTHOR]

The standard treatment for patients diagnosed with glioblastoma is surgical resection of tumor followed by high dose radiation and chemotherapy with temozolomide. For patients who experience allergic reactions to temozolomide despite desensitization protocols, alternative therapies must be considered. In this report, we present such a patient who then received treatment with an epidermal growth factor receptor inhibitor, erlotinib, concurrent with a tumor-treating field device, Optune. Through this combination of a targeted molecular therapy and the Optune device, the patient has been able to achieve stable disease 9 months after completing radiation. [ABSTRACT FROM AUTHOR]

Background:A devastating late injury caused by radiation is pulmonary fibrosis. This risk may limit the volume of irradiation and compromise potentially curative therapy. Therefore, development of a therapy to prevent this toxicity can be of great benefit for this patient population. Activation of the chemokine receptor CXCR4 by its ligand stromal cell-derived factor 1 (SDF-1/CXCL12) may be important in the development of radiation-induced pulmonary fibrosis. Here, we tested whether MSX-122, a novel small molecule and partial CXCR4 antagonist, can block development of this fibrotic process. Methodology/Principal Findings:The radiation-induced lung fibrosis model used was C57BL/6 mice irradiated to the entire thorax or right hemithorax to 20 Gy. Our parabiotic model involved joining a transgenic C57BL/6 mouse expressing GFP with a wild-type mouse that was subsequently irradiated to assess for migration of GFP+ bone marrow-derived progenitor cells to the irradiated lung. CXCL12 levels in the bronchoalveolar lavage fluid (BALF) and serum after irradiation were determined by ELISA. CXCR4 and CXCL12 mRNA in the irradiated lung was determined by RNase protection assay. Irradiated mice were treated daily with AMD3100, an established CXCR4 antagonist; MSX-122; and their corresponding vehicles to determine impact of drug treatment on fibrosis development. Fibrosis was assessed by serial CTs and histology. After irradiation, CXCL12 levels increased in BALF and serum with a corresponding rise in CXCR4 mRNA within irradiated lungs consistent with recruitment of a CXCR4+ cell population. Using our parabiotic model, we demonstrated recruitment of CXCR4+ bone marrow-derived mesenchymal stem cells, identified based on marker expression, to irradiated lungs. Finally, irradiated mice that received MSX-122 had significant reductions in development of pulmonary fibrosis while AMD3100 did not significantly suppress this fibrotic process. Conclusions/Significance:CXCR4 inhibition by drugs such as MSX-122 may alleviate potential radiation-induced lung injury, presenting future therapeutic opportunities for patients requiring chest irradiation. [ABSTRACT FROM AUTHOR]