Attributes for a discrete-choice experiment on preferences of patients for oncology pharmacy consultations.

PURPOSE: To ensure the safe use of oral anticancer drugs, oncology pharmacy consultations (OPCs) have been established in France. They are conditioned by the needs, expectations, and involvement of the patients in their care. Thus, it is essential to elicit their preferences. The discrete-choice experiment (DCE) is a method recommended by the ISPOR for such a task. The "selection and validation of attributes and their values" step is fundamental in this process. In this context, the aim of this study was to present our research approach to identify and validate the attributes that characterize an OPC and their values. METHODS: Due to the lack of relevant published data in the literature, the focus-group method was used in accordance with good research practices for the application of conjoint-analysis of the ISPOR. The two-round Delphi method was used to validate the attributes and their values identified by the focus-group method. RESULTS: The focus-group method enabled identification of nine attributes. Thirty-seven healthcare professionals at a national level, including 30 pharmacists and seven physicians, were selected to take part in the Delphi procedure. Seven attributes (frequency, planification, operation mode, duration, content, written support, and report) and their values were thus validated. CONCLUSION: Based on these results, the next step will be to elicit patient preferences for OPCs and to then shed light on the issues of pharmaceutical support for patients by comparing their preferences with those of informal caregivers and, in particular, those of the healthcare professionals involved in their care.

Blocking EREG/GPX4 Sensitizes Head and Neck Cancer to Cetuximab through Ferroptosis Induction.

(1) Background: Epiregulin (EREG) is a ligand of EGFR and ErB4 involved in the development and the progression of various cancers including head and neck squamous cell carcinoma (HNSCC). Its overexpression in HNSCC is correlated with short overall survival and progression-free survival but predictive of tumors responding to anti-EGFR therapies. Besides tumor cells, macrophages and cancer-associated fibroblasts shed EREG in the tumor microenvironment to support tumor progression and to promote therapy resistance. Although EREG seems to be an interesting therapeutic target, no study has been conducted so far on the consequences of EREG invalidation regarding the behavior and response of HNSCC to anti-EGFR therapies and, more specifically, to cetuximab (CTX); (2) Methods: EREG was silenced in various HNSCC cell lines. The resulting phenotype (growth, clonogenic survival, apoptosis, metabolism, ferroptosis) was assessed in the absence or presence of CTX. The data were confirmed in patient-derived tumoroids; (3) Results: Here, we show that EREG invalidation sensitizes cells to CTX. This is illustrated by the reduction in cell survival, the alteration of cell metabolism associated with mitochondrial dysfunction and the initiation of ferroptosis characterized by lipid peroxidation, iron accumulation and the loss of GPX4. Combining ferroptosis inducers (RSL3 and metformin) with CTX drastically reduces the survival of HNSCC cells but also HNSCC patient-derived tumoroids; (4) Conclusions: The loss of EREG might be considered in clinical settings as a predictive biomarker for patients that might undergo ferroptosis in response to CTX and that might benefit the most from the combination of ferroptosis inducers and CTX.

Comparative analysis of rituximab or obinutuzumab combined with CHOP in first-line treatment of follicular lymphoma.

PURPOSE: Rituximab (R) or obinutuzumab (G) combined with CHOP chemotherapy are used in previously untreated follicular lymphoma (FL). The aim is to compare in real life setting the efficacy and safety of these therapeutic strategies and assess the economic impact of introducing G. METHODS: This retrospective study, performed in 3 centers, included data from all patients who received R-CHOP or G-CHOP for previous untreated FL from June 1st, 2016 to December 31st, 2020. Progression-Free Survival (PFS) were estimated according to the Kaplan-Meier method. A budgetary impact model was performed from the French health care system's perspective. RESULTS: N = 124 patients were included (58 G-CHOP; 66 R-CHOP). Fifty-one and 57 patients achieved a complete response at the end of induction in the G-CHOP and R-CHOP group, respectively. PFS was not significantly longer in the G-CHOP group (HR 0.28; 95% CI 0.08-0.97; p value = 0.14). Hematological toxicity occurred more frequently with G-CHOP than R-CHOP during induction treatment (n = 58; 100% vs. n = 61; 92%), including higher severe neutropenia (grade ≥ 3) (n = 26; 45% vs. n = 23; 35%). Infusion-related reactions during the first infusion occurred more frequently with G-CHOP (n = 19; 33% vs. n = 16; 24%). The introduction of a completed G treatment (induction and maintenance) results in an additional cumulative cost per patient estimated at more than €30,000. CONCLUSION: Similar results were found in the GALLIUM subgroup analysis study, suggesting that at this time there is no absolute benefit to administer G-CHOP instead of R-CHOP in all patients with previously untreated FL and may encourage clinical and economic trials including quality of life data.

Bioimaging Nucleic-Acid Aptamers with Different Specificities in Human Glioblastoma Tissues Highlights Tumoral Heterogeneity.

Nucleic-acid aptamers are of strong interest for diagnosis and therapy. Compared with antibodies, they are smaller, stable upon variations in temperature, easy to modify, and have higher tissue-penetration abilities. However, they have been little described as detection probes in histology studies of human tissue sections. In this study, we performed fluorescence imaging with two aptamers targeting cell-surface receptors EGFR and integrin α5ß1, both involved in the aggressiveness of glioblastoma. The aptamers' cell-binding specificities were confirmed using confocal imaging. The affinities of aptamers for glioblastoma cells expressing these receptors were in the 100-300 nM range. The two aptamers were then used to detect EGFR and integrin α5ß1 in human glioblastoma tissues and compared with antibody labeling. Our aptafluorescence assays proved to be able to very easily reveal, in a one-step process, not only inter-tumoral glioblastoma heterogeneity (differences observed at the population level) but also intra-tumoral heterogeneity (differences among cells within individual tumors) when aptamers with different specificities were used simultaneously in multiplexing labeling experiments. The discussion also addresses the strengths and limitations of nucleic-acid aptamers for biomarker detection in histology.

Temozolomide-Acquired Resistance Is Associated with Modulation of the Integrin Repertoire in Glioblastoma, Impact of α5ß1 Integrin.

Despite extensive treatment, glioblastoma inevitably recurs, leading to an overall survival of around 16 months. Understanding why and how tumours resist to radio/chemotherapies is crucial to overcome this unmet oncological challenge. Primary and acquired resistance to Temozolomide (TMZ), the standard-of-care chemotherapeutic drug, have been the subjects of several studies. This work aimed to evaluate molecular and phenotypic changes occurring during and after TMZ treatment in a glioblastoma cell model, the U87MG. These initially TMZ-sensitive cells acquire long-lasting resistance even after removal of the drug. Transcriptomic analysis revealed that profound changes occurred between parental and resistant cells, particularly at the level of the integrin repertoire. Focusing on α5ß1 integrin, which we proposed earlier as a glioblastoma therapeutic target, we demonstrated that its expression was decreased in the presence of TMZ but restored after removal of the drug. In this glioblastoma model of recurrence, α5ß1 integrin plays an important role in the proliferation and migration of tumoral cells. We also demonstrated that reactivating p53 by MDM2 inhibitors concomitantly with the inhibition of this integrin in recurrent cells may overcome the TMZ resistance. Our results may explain some integrin-based targeted therapy failure as integrin expressions are highly switchable during the time of treatment. We also propose an alternative way to alter the viability of recurrent glioblastoma cells expressing a high level of α5ß1 integrin.

Expression Analysis of α5 Integrin Subunit Reveals Its Upregulation as a Negative Prognostic Biomarker for Glioblastoma.

Integrin α5ß1 was suggested to be involved in glioblastoma (GBM) aggressiveness and treatment resistance through preclinical studies and genomic analysis in patients. However, further protein expression data are still required to confirm this hypothesis. In the present study, we investigated by immunofluorescence the expression of integrin α5 and its prognostic impact in a glioblastoma series of patients scheduled to undergo the Stupp protocol as first-line treatment for GBM. The integrin α5 protein expression level was estimated in each tumor by the mean fluorescence intensity (MFI) and allowed us to identify two subpopulations showing either a high or low expression level. The distribution of patients in both subpopulations was not significantly different according to age, gender, recursive partitioning analysis (RPA) prognostic score, molecular markers or surgical and medical treatment. A high integrin α5 protein expression level was associated with a high risk of recurrence (HR = 1.696, 95% CI 1.031-2.792, p = 0.0377) and reduced overall survival (OS), even more significant in patients who completed the Stupp protocol (median OS: 15.6 vs. 22.8 months; HR = 2.324; 95% CI 1.168-4.621, p = 0.0162). In multivariate analysis, a high integrin α5 protein expression level was confirmed as an independent prognostic factor in the subpopulation of patients who completed the temozolomide-based first-line treatment for predicting OS over age, extent of surgery, RPA score and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation (p = 0.029). In summary, for the first time, our study validates that a high integrin α5 protein expression level is associated with poor prognosis in GBM and confirms its potential as a therapeutic target implicated in the Stupp protocol resistance.

Cav1/EREG/YAP Axis in the Treatment Resistance of Cav1-Expressing Head and Neck Squamous Cell Carcinoma.

The EGFR-targeting antibody cetuximab (CTX) combined with radiotherapy is the only targeted therapy that has been proven effective for the treatment of locally advanced head and neck squamous cell carcinoma (LA-HNSCC). Recurrence arises in 50% of patients with HNSCC in the years following treatment. In clinicopathological practice, it is difficult to assign patients to classes of risk because no reliable biomarkers are available to predict the outcome of HPV-unrelated HNSCC. In the present study, we investigated the role of Caveolin-1 (Cav1) in the sensitivity of HNSCC cell lines to CTX-radiotherapy that might predict HNSCC relapse. Ctrl- and Cav-1-overexpressing HNSCC cell lines were exposed to solvent, CTX, or irradiation, or exposed to CTX before irradiation. Growth, clonogenicity, cell cycle progression, apoptosis, metabolism and signaling pathways were analyzed. Cav1 expression was analyzed in 173 tumor samples and correlated to locoregional recurrence and overall survival. We showed that Cav1-overexpressing cells demonstrate better survival capacities and remain proliferative and motile when exposed to CTX-radiotherapy. Resistance is mediated by the Cav1/EREG/YAP axis. Patients whose tumors overexpressed Cav1 experienced regional recurrence a few years after adjuvant radiotherapy ± chemotherapy. Together, our observations suggest that a high expression of Cav1 might be predictive of locoregional relapse of LA-HNSCC.

A Systematic Review of Glioblastoma-Targeted Therapies in Phases II, III, IV Clinical Trials.

Glioblastoma (GBM), the most frequent and aggressive glial tumor, is currently treated as first line by the Stupp protocol, which combines, after surgery, radiotherapy and chemotherapy. For recurrent GBM, in absence of standard treatment or available clinical trials, various protocols including cytotoxic drugs and/or bevacizumab are currently applied. Despite these heavy treatments, the mean overall survival of patients is under 18 months. Many clinical studies are underway. Based on clinicaltrials.org and conducted up to 1 April 2020, this review lists, not only main, but all targeted therapies in phases II-IV of 257 clinical trials on adults with newly diagnosed or recurrent GBMs for the last twenty years. It does not involve targeted immunotherapies and therapies targeting tumor cell metabolism, that are well documented in other reviews. Without surprise, the most frequently reported drugs are those targeting (i) EGFR (40 clinical trials), and more generally tyrosine kinase receptors (85 clinical trials) and (ii) VEGF/VEGFR (75 clinical trials of which 53 involving bevacizumab). But many other targets and drugs are of interest. They are all listed and thoroughly described, on an one-on-one basis, in four sections related to targeting (i) GBM stem cells and stem cell pathways, (ii) the growth autonomy and migration, (iii) the cell cycle and the escape to cell death, (iv) and angiogenesis.

[Impact of patient testimony in the education of medicine and pharmacy students]. / Patients acteurs et formation en oncologie pour futurs médecins et pharmaciens.

The initiative from patients suffering from cancer or having had the disease in speaking about their illness to medical students during an internship in a cancer control center of the faculty of medicine and to pharmacy students at the university of Strasbourg was implemented in 2014. This action was coordinated by the French Cancer League as part of the National French cancer plan 3. After training, ten patients teachers were able to freely and spontaneously explain their diagnostic and therapeutic journey as well as their feelings about the disease and their relationship with their oncologists in front of 187 medical students and 131 pharmacy students. A moderator, often a former cancer teacher, helped coordinate the discussions. Questionnaires were given to students, patients teachers and moderators in order to assess the merits of the action and the expected benefits at the end of the training. A second questionnaire was sent to the students six months after the interviews. The assessment was made by an independent firm. The students' responses were very favorable and this training met their expectations in almost 98% of the cases and 1/3 of the students were destabilized by this training. Patients teacher were very satisfied with their intervention and felt that they were able to convey a message. Six months later, the 30% of student respondents said that these testimonies had or could have an impact on their practices. This is the first assessment of the interest of resource patients in teaching cancer patients about medical and pharmacy students.

Gefitinib induces EGFR and α5ß1 integrin co-endocytosis in glioblastoma cells.

Overexpression of EGFR drives glioblastomas (GBM) cell invasion but these tumours remain resistant to EGFR-targeted therapies such as tyrosine kinase inhibitors (TKIs). Endocytosis, an important modulator of EGFR function, is often dysregulated in glioma cells and is associated with therapy resistance. However, the impact of TKIs on EGFR endocytosis has never been examined in GBM cells. In the present study, we showed that gefitinib and other tyrosine kinase inhibitors induced EGFR accumulation in early-endosomes as a result of an increased endocytosis. Moreover, TKIs trigger early-endosome re-localization of another membrane receptor, the fibronectin receptor alpha5beta1 integrin, a promising therapeutic target in GBM that regulates physiological EGFR endocytosis and recycling in cancer cells. Super-resolution dSTORM imaging showed a close-proximity between beta1 integrin and EGFR in intracellular membrane compartments of gefitinib-treated cells, suggesting their potential interaction. Interestingly, integrin depletion delayed gefitinib-mediated EGFR endocytosis. Co-endocytosis of EGFR and alpha5beta1 integrin may alter glioma cell response to gefitinib. Using an in vitro model of glioma cell dissemination from spheroid, we showed that alpha5 integrin-depleted cells were more sensitive to TKIs than alpha5-expressing cells. This work provides evidence for the first time that EGFR TKIs can trigger massive EGFR and alpha5beta1 integrin co-endocytosis, which may modulate glioma cell invasiveness under therapeutic treatment.

Biological Relevance of RGD-Integrin Subtype-Specific Ligands in Cancer.

Integrins are heterodimeric transmembrane proteins able to connect cells with the micro-environment. They represent a family of receptors involved in almost all the hallmarks of cancer. Integrins recognizing the Arg-Gly-Asp (RGD) peptide in their natural extracellular matrix ligands have been particularly investigated as tumoral therapeutic targets. In the last 30 years, intense research has been dedicated to designing specific RGD-like ligands able to discriminate selectively the different RGD-recognizing integrins. Chemists' efforts have led to the proposition of modified peptide or peptidomimetic libraries to be used for tumor targeting and/or tumor imaging. Here we review, from the biological point of view, the rationale underlying the need to clearly delineate each RGD-integrin subtype by selective tools. We describe the complex roles of RGD-integrins (mainly the most studied αvß3 and α5ß1 integrins) in tumors, the steps towards selective ligands and the current usefulness of such ligands. Although the impact of integrins in cancer is well acknowledged, the biological characteristics of each integrin subtype in a specific tumor are far from being completely resolved. Selective ligands might help us to reconsider integrins as therapeutic targets in specific clinical settings.

Exposure to Endocrine Disrupting Chemicals and Risk of Breast Cancer.

Breast cancer (BC) is the second most common cancer and the fifth deadliest in the world. Exposure to endocrine disrupting pollutants has been suggested to contribute to the increase in disease incidence. Indeed, a growing number of researchershave investigated the effects of widely used environmental chemicals with endocrine disrupting properties on BC development in experimental (in vitro and animal models) and epidemiological studies. The complex effects of endocrine disrupting chemicals (EDCs) on hormonal pathways, involving carcinogenic effects and an increase in mammary gland susceptibility to carcinogenesis-together with the specific characteristics of the mammary gland evolving over the course of life and the multifactorial etiology of BC-make the evaluation of these compounds a complex issue. Among the many EDCs suspected of increasing the risk of BC, strong evidence has only been provided for few EDCs including diethylstilbestrol, dichlorodiphenyltrichloroethane, dioxins and bisphenol A. However, given the ubiquitous nature and massive use of EDCs, it is essential to continue to assess their long-term health effects, particularly on carcinogenesis, to eradicate the worst of them and to sensitize the population to minimize their use.

Preferential Response of Basal-Like Head and Neck Squamous Cell Carcinoma Cell Lines to EGFR-Targeted Therapy Depending on EREG-Driven Oncogenic Addiction.

The management of locally advanced head and neck squamous cell carcinoma (HNSCC) with Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), achieves only moderate response rates, and clinical trials that evaluated EGFR-blockade with tyrosine kinase inhibitors (TKI) yielded disappointing results. Inter-tumor heterogeneity may hinder the therapeutic efficiency of anti-EGFR treatments. HNSCC heterogeneity was addressed in several studies, which all converged towards the definition of molecular subgroups. They include the basal subgroup, defined by the deregulated expression of factors involved in the EGFR signaling pathway, including the epiregulin EGFR ligand encoded by the EREG gene. These observations indicate that basal tumors could be more sensitive to anti-EGFR treatments. To test this hypothesis, we performed a screen of a representative collection of basal versus non-basal HNSCC cell lines for their sensitivity to several anti-EGFR drugs (Cetuximab, Afatinib, and Gefitinib), tested as monotherapy or in combination with drugs that target closely-linked pathways [Mitogen-activated protein kinase kinase/ extracellular signal-regulated kinases (MEK), mammalian Target of Rapamycine (mTOR) or Human Epidermal growth factor Receptor 2 (HER2)]. Basal-like cell lines were found to be more sensitive to EGFR blockade alone or in combination with treatments that target MEK, mTOR, or HER2. Strikingly, the basal-like status was found to be a better predictor of cell response to EGFR blockade than clinically relevant mutations [e.g., cyclin-dependent kinase Inhibitor 2A (CDKN2A)]. Interestingly, we show that EGFR blockade inhibits EREG expression, and that EREG knock-down decreases basal cell clonogenic survival, suggesting that EREG expression could be a predictive functional marker of sensitivity to EGFR blockade in basal-like HNSCC.

Expression/activation of α5ß1 integrin is linked to the ß-catenin signaling pathway to drive migration in glioma cells.

The Wnt/beta catenin pathway has been highlighted as an important player of brain tumors aggressiveness and resistance to therapies. Increasing knowledges of the regulation of beta-catenin transactivation point out its hub position in different pathophysiological outcomes in glioma such as survival and migration. Crosstalks between integrins and beta-catenin pathways have been suggested in several tumor tissues. As we demonstrated earlier that α5ß1 integrin may be considered as a therapeutic target in high grade glioma through its contribution to glioma cell migration and resistance to chemotherapy, we addressed here the potential relationship between α5ß1 integrin and beta-catenin activation in glioma cells. We demonstrated that overexpression and activation by fibronectin of α5ß1 integrin allowed the transactivation of beta-catenin gene targets included in an EMT-like program that induced an increase in cell migration. Hampering of beta catenin activation and cell migration could be similarly achieved by a specific integrin antagonist. In addition we showed that α5ß1 integrin/AKT axis is mainly involved in these processes. However, blockade of beta-catenin by XAV939 (tankyrase inhibitor leading to beta-catenin degradation) did not synergize with p53 activation aiming to cell apoptosis as was the case with integrin antagonists. We therefore propose a dual implication of α5ß1 integrin/AKT axis in glioma cell resistance to therapies and migration each supported by different signaling pathways. Our data thus suggest that α5ß1 integrin may be added to the growing list of beta-catenin modulators and provide new evidences to assign this integrin as a valuable target to fight high grade glioma.

Glioma cell dispersion is driven by α5 integrin-mediated cell-matrix and cell-cell interactions.

Glioblastoma multiform (GBM) is the most common and most aggressive primary brain tumor. The fibronectin receptor, α5 integrin is a pertinent novel therapeutic target. Despite numerous data showing that α5 integrin support tumor cell migration and invasion, it has been reported that α5 integrin can also limit cell dispersion by increasing cell-cell interaction. In this study, we showed that α5 integrin was involved in cell-cell interaction and gliomasphere formation. α5-mediated cell-cell cohesion limited cell dispersion from spheroids in fibronectin-poor microenvironment. However, in fibronectin-rich microenvironment, α5 integrin promoted cell dispersion. Ligand-occupied α5 integrin and fibronectin were distributed in fibril-like pattern at cell-cell junction of evading cells, forming cell-cell fibrillar adhesions. Activated focal adhesion kinase was not present in these adhesions but was progressively relocalized with α5 integrin as cell migrates away from the spheroids. α5 integrin function in GBM appears to be more complex than previously suspected. As GBM overexpressed fibronectin, it is most likely that in vivo, α5-mediated dissemination from the tumor mass overrides α5-mediated tumor cell cohesion. In this respect, α5-integrin antagonists may be useful to limit GBM invasion in brain parenchyma.

A Chinese 2-herb formula (NF3) promotes hindlimb ischemia-induced neovascularization and wound healing of diabetic rats.

Diabetic foot ulcer is closely associated with peripheral vascular disease. Enhancement of tissue oxidative stress, reduction of nitric oxide (NO) and angiogenic growth factors, and abnormal matrix metalloproteinase (MMP) activity are pathophysiological factors in post-ischemic neovascularization and diabetic wound healing. Our previous study demonstrated that the Chinese 2-herb formula, NF3, showed significant wound healing effects on diabetic foot ulcer rats. A novel rat diabetic foot ulcer with hindlimb ischemia model was established in order to strengthen our claims on the diabetic wound healing and post-ischemic neovascularization effects of NF3. Our results demonstrate that NF3 can significantly reduce the wound area of the diabetic foot ulcer rat with hindlimb ischemia by 21.6% (p<0.05) compared with the control group. In addition, flow cytometric analysis revealed that NF3 could boost circulating EPC levels for local wound vessel incorporation. Immunohistochemical analysis showed that NF3 could significantly augment blood vessel density, VEGF and eNOS expression, and attenuate tissue oxidative stress of ischemic muscles (p<0.001). NF3 significantly stimulated MMP activity involved in angiogenesis. Our study shows, for the first time, the beneficial effects of NF3 in wound healing and post-ischemic neovascularization in diabetes.

Molecular mechanisms of the cardiovascular protective effects of polyphenols.

Epidemiological studies have reported a greater reduction in cardiovascular risk and metabolic disorders associated with diets rich in polyphenols. The antioxidant effects of polyphenols are attributed to the regulation of redox enzymes by reducing reactive oxygen species production from mitochondria, NADPH oxidases and uncoupled endothelial NO synthase in addition to also up-regulating multiple antioxidant enzymes. Although data supporting the effects of polyphenols in reducing oxidative stress are promising, several studies have suggested additional mechanisms in the health benefits of polyphenols. Polyphenols from red wine increase endothelial NO production leading to endothelium-dependent relaxation in conditions such as hypertension, stroke or the metabolic syndrome. Numerous molecules contained in fruits and vegetables can activate sirtuins to increase lifespan and silence metabolic and physiological disturbances associated with endothelial NO dysfunction. Although intracellular pathways involved in the endothelial effects of polyphenols are partially described, the molecular targets of these polyphenols are not completely elucidated. We review the novel aspects of polyphenols on several targets that could trigger the health benefits of polyphenols in conditions such as metabolic and cardiovascular disturbances.

Aronia melanocarpa juice induces a redox-sensitive p73-related caspase 3-dependent apoptosis in human leukemia cells.

Polyphenols are natural compounds widely present in fruits and vegetables, which have antimutagenic and anticancer properties. The aim of the present study was to determine the anticancer effect of a polyphenol-rich Aronia melanocarpa juice (AMJ) containing 7.15 g/L of polyphenols in the acute lymphoblastic leukemia Jurkat cell line, and, if so, to clarify the underlying mechanism and to identify the active polyphenols involved. AMJ inhibited cell proliferation, which was associated with cell cycle arrest in G(2)/M phase, and caused the induction of apoptosis. These effects were associated with an upregulation of the expression of tumor suppressor p73 and active caspase 3, and a downregulation of the expression of cyclin B1 and the epigenetic integrator UHRF1. AMJ significantly increased the formation of reactive oxygen species (ROS), decreased the mitochondrial membrane potential and caused the release of cytochrome c into the cytoplasm. Treatment with intracellular ROS scavengers prevented the AMJ-induced apoptosis and upregulation of the expression of p73 and active caspase 3. The fractionation of the AMJ and the use of identified isolated compounds indicated that the anticancer activity was associated predominantly with chlorogenic acids, some cyanidin glycosides, and derivatives of quercetin. AMJ treatment also induced apoptosis of different human lymphoblastic leukemia cells (HSB-2, Molt-4 and CCRF-CEM). In addition, AMJ exerted a strong pro-apoptotic effect in human primary lymphoblastic leukemia cells but not in human normal primary T-lymphocytes. Thus, the present findings indicate that AMJ exhibits strong anticancer activity through a redox-sensitive mechanism in the p53-deficient Jurkat cells and that this effect involves several types of polyphenols. They further suggest that AMJ has chemotherapeutic properties against acute lymphoblastic leukemia by selectively targeting lymphoblast-derived tumor cells.

Down-regulation of UHRF1, associated with re-expression of tumor suppressor genes, is a common feature of natural compounds exhibiting anti-cancer properties.

Over-expressed in numerous cancers, Ubiquitin-like containing PHD Ring Finger 1 (UHRF1, also known as ICBP90 or Np95) is characterized by a SRA domain (Set and Ring Associated) which is found only in the UHRF family. UHRF1 constitutes a complex with histone deacetylase 1 (HDAC1) and DNA methyltransferase 1 (DNMT1) via its SRA domain and represses the expression of several tumour suppressor genes (TSGs) including p16INK4A, hMLH1, BRCA1 and RB1. Conversely, UHRF1 is regulated by other TSGs such as p53 and p73. UHRF1 is hypothetically involved in a macro-molecular protein complex called "ECREM" for "Epigenetic Code Replication Machinery". This complex would be able to duplicate the epigenetic code by acting at the DNA replication fork and by activating the right enzymatic activity at the right moment. There are increasing evidence that UHRF1 is the conductor of this replication process by ensuring the crosstalk between DNA methylation and histone modifications via the SRA and Tandem Tudor Domains, respectively. This cross-talk allows cancer cells to maintain the repression of TSGs during cell proliferation. Several studies showed that down-regulation of UHRF1 expression in cancer cells by natural pharmacological active compounds, favors enhanced expression or re-expression of TSGs, suppresses cell growth and induces apoptosis. This suggests that hindering UHRF1 to exert its role in the duplication of the methylation patterns (DNA + histones) is responsible for inducing apoptosis. In this review, we present UHRF1 expression as a target of several natural products and we discuss their underlying molecular mechanisms and benefits for chemoprevention and chemotherapy.

Vascular protection by natural product-derived polyphenols: in vitro and in vivo evidence.

Epidemiological studies have indicated that regular intake of fruit and vegetables and beverages such as red wine and tea, which contain high levels of polyphenols, is associated with a reduced risk of cardiovascular diseases. The beneficial effect of polyphenol-rich natural products has been attributable, at least in part, to their direct effect on blood vessels, and in particular on endothelial cells. Indeed, polyphenols from tea, grapes, berries, and plants have been shown to activate endothelial cells to increase the formation of potent vasoprotective factors including nitric oxide (NO) and endothelium-derived hyperpolarizing factor. Experimental and clinical studies have also indicated that chronic intake of several polyphenol-rich natural products is able to improve endothelial dysfunction and to decrease vascular oxidative stress associated with major cardiovascular diseases such as hypertension. Altogether, these observations suggest that polyphenol-rich sources of natural products have the potential to improve the function of blood vessels and, hence, to protect the vascular system.