Curcumin Chemosensitizes 5-Fluorouracil Resistant MMR-Deficient Human Colon Cancer Cells in High Density Cultures

Objective

Treatment of colorectal cancer (CRC) remains a clinical challenge, as more than 15% of patients are resistant to 5-Fluorouracil (5-FU)-based chemotherapeutic regimens, and tumor recurrence rates can be as high as 50–60%. Cancer stem cells (CSC) are capable of surviving conventional chemotherapies that permits regeneration of original tumors. Therefore, we investigated the effectiveness of 5-FU and plant polyphenol (curcumin) in context of DNA mismatch repair (MMR) status and CSC activity in 3D cultures of CRC cells.

Methods

High density 3D cultures of CRC cell lines HCT116, HCT116+ch3 (complemented with chromosome 3) and their corresponding isogenic 5-FU-chemo-resistant derivative clones (HCT116R, HCT116+ch3R) were treated with 5-FU either without or with curcumin in time- and dose-dependent assays.

Results

Pre-treatment with curcumin significantly enhanced the effect of 5-FU on HCT116R and HCR116+ch3R cells, in contrast to 5-FU alone as evidenced by increased disintegration of colonospheres, enhanced apoptosis and by inhibiting their growth. Curcumin and/or 5-FU strongly affected MMR-deficient CRC cells in high density cultures, however MMR-proficient CRC cells were more sensitive. These effects of curcumin in enhancing chemosensitivity to 5-FU were further supported by its ability to effectively suppress CSC pools as evidenced by decreased number of CSC marker positive cells, highlighting the suitability of this 3D culture model for evaluating CSC marker expression in a close to vivo setting.

Conclusion

Our results illustrate novel and previously unrecognized effects of curcumin in enhancing chemosensitization to 5-FU-based chemotherapy on DNA MMR-deficient and their chemo-resistant counterparts by targeting the CSC sub-population. (246 words in abstract).     

Antiproliferative Effects and Mechanisms of Liver X Receptor Ligands in Pancreatic Ductal Adenocarcinoma Cells

Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation, and LXR agonists have been developed to regulate LXR function in these processes. Intriguingly, these compounds also exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC.     

Neuropsychological Correlates of Brain Perfusion SPECT in Patients with Macrophagic Myofasciitis

Background

Patients with aluminum hydroxide adjuvant-induced macrophagic myofasciitis (MMF) complain of arthromyalgias, chronic fatigue and cognitive deficits. This study aimed to characterize brain perfusion in these patients.

Methods

Brain perfusion SPECT was performed in 76 consecutive patients (aged 49±10 y) followed in the Garches-Necker-Mondor-Hendaye reference center for rare neuromuscular diseases. Images were acquired 30 min after intravenous injection of 925 MBq ^99mTc-ethylcysteinate dimer (ECD) at rest. All patients also underwent a comprehensive battery of neuropsychological tests, within 1.3±5.5 mo from SPECT. Statistical parametric maps (SPM12) were obtained for each test using linear regressions between each performance score and brain perfusion, with adjustment for age, sex, socio-cultural level and time delay between brain SPECT and neuropsychological testing.

Results

SPM analysis revealed positive correlation between neuropsychological scores (mostly exploring executive functions) and brain perfusion in the posterior associative cortex, including cuneus/precuneus/occipital lingual areas, the periventricular white matter/corpus callosum, and the cerebellum, while negative correlation was found with amygdalo-hippocampal/entorhinal complexes. A positive correlation was also observed between brain perfusion and the posterior associative cortex when the time elapsed since last vaccine injection was investigated.

Conclusions

Brain perfusion SPECT showed a pattern of cortical and subcortical changes in accordance with the MMF-associated cognitive disorder previously described. These results provide a neurobiological substrate for brain dysfunction in aluminum hydroxide adjuvant-induced MMF patients.     

Diagnostic Accuracy of PET/CT-Guided Percutaneous Biopsies for Malignant Peripheral Nerve Sheath Tumors in Neurofibromatosis Type 1 Patients

Background

Malignant peripheral nerve sheath tumors (MPNST) are one of the most frequent causes of death in patients with neurofibromatosis type 1 (NF1). Early detection is crucial because complete surgical resection is the only curative treatment. It has been previously reported that an ¹⁸F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) image with a T/L (Tumor/Liver) SUV_max ratio > 1.5 provides a high negative predictive value; however, it is not specific enough to make a NF1-related MPNST diagnosis. A formal proof of malignant transformation from a histological analysis is necessary before surgical excision because the procedure can cause mutilation. The objective of the present work was to investigate the effectiveness of and complications associated with PET/CT-guided percutaneous biopsies for an NF1-related MPNST diagnosis.

Methods

PET/CT-guided percutaneous biopsy procedures performed on 26 NF1 patients with a clinical suspicion of MPNST and a suspect lesion from a PET/CT scan (T/L SUV_max ratio > 1.5) were retrospectively evaluated. The localization of the suspected malignant site was determined using PET/CT. A stereotactic (ultrasonic and CT control) core biopsy technique was used with a local anesthesia.

Results

The first PET/CT-guided percutaneous biopsies enabled a pathological diagnosis for all of the patients (no "inconclusive " results were obtained), and no secondary procedures were needed. Among the 26 patients, the histopathological results from the biopsy were malignant in 17 cases and benign (BPNST with atypical cells) in nine cases. No complications from the diagnostic procedure were observed. A surgical resection was performed in 18 patients (seven benign and 11 malignant biopsies), removing the fine needle biopsy scar. In addition, six locally advanced/metastatic MPNST were treated with chemo/radiotherapy, and two BPNST had no progression after a follow-up of 14 and 39 months, respectively. The PET/CT-guided percutaneous biopsy gave 25 accurate diagnoses and one false negative (BPNST with atypical cells on the biopsy and MPNST on the operated tumor), resulting in a diagnostic accuracy rate of 96%. This false negative case may be explained by the high heterogeneity of the tumor: benign areas were contiguous with the malignant ones and associated with inflammation.

Conclusions

PET/CT-guided percutaneous biopsies are an effective and relatively non-traumatic procedure for diagnosis of NF1-related MPNST. It is the most reliable approach for early detection of MPNST.     

Fabrication and evaluation of aptamer-conjugated paclitaxel-loaded magnetic nanoparticles for targeted therapy on breast cancer cells

Molecular Biology Reports - Targeted drug delivery vehicles make it possible to deliver anti-cancer drugs to the cells or tissues of interest. Aptamers are peptide or oligonucleotide molecules that...     

Clavulanic Acid Attenuating Effect on the Diabetic Neuropathic Pain in Rats

Neurochemical Research - Diabetic neuropathy is one of the most common complications of diabetes mellitus. Excess glutamate release and oxidative stress are hypothesized to be involved in the...     

Magnetic nanoparticle-based immunosensor for electrochemical detection of hepatitis B surface antigen

An electrochemical immunosensor was developed for the detection of hepatitis B surface antigen (HBsAg). The biotinylated hepatitis B surface antibody was immobilized on streptavidin magnetic nanoparticles and used for targeting the HBsAg. By the addition of horseradish peroxidase conjugated with secondary antibody (HRP–HBsAb), a sandwich-type immunoassay format was formed. Aminophenol as substrate for conjugated HRP was enzymatically changed into 3-aminophenoxazone (3-APZ). This electroactive enzymatic production (3-APZ) was transferred into an electrochemical cell and monitored by cyclic voltammetry. Under optimal conditions, the cathodic current response of 3-APZ, which was proportional to the HBsAg concentration, was measured by a glassy carbon electrode. The immunosensor response was linear toward HBsAg in the concentration range from 0.001 to 0.015 ng/ml with a detection limit of 0.9 pg/ml at a signal/noise ratio of 3.