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Abstract Glioblastoma (GBM) is one of the most aggressive types of cancer, which begins within the brain. It is the most invasive type of glioma developed from astrocytes. Until today, Temozolomide (TMZ) is the only standard chemotherapy for patients with GBM. Even though chemotherapy extends the survival of patients, there are many undesirable side effects, and most cases show resistance to TMZ. FL3 is a synthetic flavagline which displays potent anticancer activities, and is known to inhibit cell proliferation, by provoking cell cycle arrest, and leads to apoptosis in a lot of cancer cell lines. However, the effect of FL3 in glioblastoma cancer cells has not yet been examined. Hypoxia is a major problem for patients with GBM, resulting in tumor resistance and aggressiveness. In this study, we explore the effect of FL3 in glioblastoma cells under normoxia and hypoxia conditions. Our results clearly indicate that this synthetic flavagline inhibits cell proliferation and induced senescence in glioblastoma cells cultured under both conditions. In addition, FL3 treatment had no effect on human brain astrocytes. These findings support the notion that the FL3 molecule could be used in combination with other chemotherapeutic agents or other therapies in glioblastoma treatments.

The impact of cancer on lifespan is significantly increasing worldwide. Enhanced activity of drug efflux pumps and the incidences of the tumor microenvironment such as the apparition of a hypoxic gradient inside of the bulk tumor, are the major causes of chemotherapy failure. For instance, expression of Hypoxia-inducible factor (HIF-1α) has been associated with metastasis, resistance to chemotherapy and reduced survival rate. One of the current challenges to fight against cancer is therefore to find new molecules with therapeutic potential that could overcome this chemoresistance. In the present study, we focused on the bioactive plant flavonoid quercetin, which has strong antioxidant and anti-proliferative properties. We examined the efficacy of combined treatments of quercetin and the anti-cancer drugs gemcitabine and doxorubicin, known to specifically act on human pancreatic and hepatic cancer cells, respectively. Moreover, our study aimed to investigate more in-depth the implication of the multidrug transporter MDR1 and HIF-1α n chemoresistance and if quercetin could act on the activity of the drug efflux pumps and the hypoxia-associated effects. We observed that the anti-cancer drugs, were more effective when administered in combination with quercetin, as shown by an increased percentage of dead cells up to 60% in both 2D and 3D cultures. In addition, our results indicated that the combination of anti-cancer drugs and quercetin down-regulated the expression of HIF-1α and increased the expression levels of the regulator of apoptosis p53. Moreover, we observed that quercetin could inhibit the efflux activity of MDR1. Finally, our in vitro study suggests that the efficiency of the chemotherapeutic activity of known anti-cancer drugs might be significantly increased upon combination with quercetin. This flavonoid may therefore be a promising pharmacological agent for novel combination therapy since it potentializes the cytotoxic activity of gemcitabine and doxorubicin on by targeting the chemoresistance developed by the pancreatic and liver cancer cells respectively.

Polycomb group (PcG) proteins are epigenetic regulators that reduce tumor suppressor gene expression and promote cancer cell survival. The aim of the present study was to determine whether a bilberry extract (Antho 50) inhibits the expression of PcG proteins in Jurkat cells and, if so, to determine the underlying mechanism. Apoptotic rates and the formation of reactive oxygen species (ROS) were assessed by flow cytometry, and protein expression by Western blotting. Antho 50 induced apoptosis, augmented ROS formation, increased p73, p21 and cleaved caspase-3 expression levels, and decreased those of p-Akt, survivin, PcG proteins, HDACs, DNMT1 and UHRF1. The antioxidant enzyme PEG-catalase prevented the formation of ROS and apoptosis induced by Antho 50 and also by H2O2. These findings indicate that Antho 50 promotes apoptosis in Jurkat cells, in part, by decreasing the expression levels of PcG proteins, and, hence, the subsequent PcG proteins-dependent pro-survival events via a redox-dependent mechanism.

A diet rich in plant-derived products is expected to have anticancer chemopreventive effects by acting on the appearance and growth of cancer stem cells (CSCs). Thus the effects of Aronia melanocarpa juice (AMJ) on the mouse embryonal carcinoma (EC) stem cell line P19 were investigated. AMJ inhibited cell proliferation, induced cell cycle arrest in S phase and triggered apoptosis. A pronounced upregulation of tumour suppressors p53 and p73 was observed in association with caspase-3 activation and a downregulation of the anti-apoptotic protein UHRF1 and the stemness factor Oct-4. Overall the results strongly suggest that AMJ is functionally able to counteract the carcinogenesis process by targeting CSCs. Interestingly AMJ selectively kills undifferentiated EC cells, without significant effects on normal restricted pluripotent cells (i.e. NIH/3T3 fibroblasts) or even differentiated EC cells. This argues that a differentiation therapy might normalize the pathological phenotype of a CSC which becomes insensitive to further plant-derived pharmacological treatment.

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.