Transient Receptor Potential (TRP) Ion Channels Involved in Malignant Glioma Cell Death and Therapeutic Perspectives.

Among the most biologically, thus clinically, aggressive primary brain tumors are found malignant gliomas. Despite recent advances in adjuvant therapies, which include targeted and immunotherapies, after surgery and radio/chemotherapy, the tumor is recurrent and always lethal. Malignant gliomas also contain a pool of initiating stem cells that are highly invasive and resistant to conventional treatment. Ion channels and transporters are markedly involved in cancer cell biology, including glioma cell biology. Transient receptor potential (TRP) ion channels are calcium-permeable channels implicated in Ca2+ changes in multiple cellular compartments by modulating the driving force for Ca2+ entry. Recent scientific reports have shown that these channels contribute to the increase in glioblastoma aggressiveness, with glioblastoma representing the ultimate level of glioma malignancy. The current review focuses on each type of TRP ion channel potentially involved in malignant glioma cell death, with the ultimate goal of identifying new therapeutic targets to clinically combat malignant gliomas. It thus appears that cannabidiol targeting the TRPV2 type could be such a potential target.

Algae metabolites: from in vitro growth inhibitory effects to promising anticancer activity.

Covering: 1957 to 2017 Algae constitute a heterogeneous group of eukaryotic photosynthetic organisms, mainly found in the marine environment. Algae produce numerous metabolites that help them cope with the harsh conditions of the marine environment. Because of their structural diversity and uniqueness, these molecules have recently gained a lot of interest for the identification of medicinally useful agents, including those with potential anticancer activities. In the current review, which is not a catalogue-based one, we first highlight the major biological events that lead to various types of cancer, including metastatic ones, to chemoresistance, thus to any types of current anticancer treatment relating to the use of chemotherapeutics. We then review algal metabolites for which scientific literature reports anticancer activity. Lastly, we focus on algal metabolites with promising anticancer activity based on their ability to target biological characteristics of cancer cells responsible for poor treatment outcomes. Thus, we highlight compounds that have, among others, one or more of the following characteristics: selectivity in reducing the proliferation of cancer cells over normal ones, potential for killing cancer cells through non-apoptotic signaling pathways, ability to circumvent MDR-related efflux pumps, and activity in vivo in relevant pre-clinical models.

Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical development-related pharmacological tests.

This review is part of a special issue entitled "Role of dietary pattern, foods, nutrients and nutraceuticals in supporting cancer prevention and treatment" and describes a pharmacological strategy to determine the potential contribution of food-related components as anticancer agents against established cancer. Therefore, this review does not relate to chemoprevention, which is analysed in several other reviews in the current special issue, but rather focuses on the following: i) the biological events that currently represent barriers against the treatment of certain types of cancers, primarily metastatic cancers; ii) the in vitro and in vivo pharmacological pre-clinical tests that can be used to analyse the potential anticancer effects of food-related components; and iii) several examples of food-related components with anticancer effects. This review does not represent a catalogue-based listing of food-related components with more or less anticancer activity. By contrast, this review proposes an original pharmacological strategy that researchers can use to analyse the potential anticancer activity of any food-related component-e.g., by considering the crucial characteristics of cancer biological aggressiveness. This review also highlights that cancer patients undergoing chemotherapy should restrict the use of "food complements" without supervision by a medical nutritionist. By contrast, an equilibrated diet that includes the food-related components listed herein would be beneficial for cancer patients who are not undergoing chemotherapy.

5,10b-Ethanophenanthridine amaryllidaceae alkaloids inspire the discovery of novel bicyclic ring systems with activity against drug resistant cancer cells.

Plants of the Amaryllidaceae family produce a large variety of alkaloids and non-basic secondary metabolites, many of which are investigated for their promising anticancer activities. Of these, crinine-type alkaloids based on the 5,10b-ethanophenanthridine ring system were recently shown to be effective at inhibiting proliferation of cancer cells resistant to various pro-apoptotic stimuli and representing tumors with dismal prognoses refractory to current chemotherapy, such as glioma, melanoma, non-small-cell lung, esophageal, head and neck cancers, among others. Using this discovery as a starting point and taking advantage of a concise biomimetic route to the crinine skeleton, a collection of crinine analogues were synthetically prepared and evaluated against cancer cells. The compounds exhibited single-digit micromolar activities and retained this activity in a variety of drug-resistant cancer cell cultures. This investigation resulted in the discovery of new bicyclic ring systems with significant potential in the development of effective clinical cancer drugs capable of overcoming cancer chemotherapy resistance.

[Glutamate and malignant gliomas, from epilepsia to biological aggressiveness: therapeutic implications]. / Glutamate et gliomes malins, de l'épilepsie à l'agressivité biologique : implications thérapeutiques.

In this review article, we describe the unrecognized roles of glutamate and glutamate receptors in malignant glioma biology. The neurotransmitter glutamate released from malignant glioma cells in the extracellular matrix is responsible for seizure induction and at higher concentration neuronal cell death. This neuronal cell death will create vacated place for tumor growth. Glutamate also stimulates the growth and the migration of glial tumor cells by means of the activation of glutamate receptors on glioma cells in a paracrine and autocrine manner. The multitude of effects of glutamate in glioma biology supports the rationale for pharmacological targeting of glutamate receptors and transporters in the adjuvant treatment of malignant gliomas in neurology and neuro-oncology. Using the website www.clinicaltrials.gov/ as a reference - a service developed by the National Library of Medicine for the National Health Institute in USA - we have evoked the few clinical trials completed and currently ongoing with therapies targeting the glutamate receptors.

Secondary metabolites from a culture of the fungus Neosartorya pseudofischeri and their in vitro cytostatic activity in human cancer cells.

Four known (1, 2, 3, and 6) and three new compounds including a 1,4-diacetyl-2,5-dibenzylpiperazine derivative (4), a quinazolinone-containing indole derivative (5), and a new ester of 2,4-dihydroxy-6-methylbenzoic acid (7) were isolated from the fungus Neosartorya pseudofischeri S. W. Peterson. Compound 2 displayed in vitro growth inhibitory activity that ranged between the activities of etoposide and carboplatin, chosen as reference compounds, in six distinct cancer cell lines. Compound 1 displayed less activity than 2. Computer-assisted phase-contrast microscopy-related analysis revealed that 2 displayed cytostatic, not cytotoxic, effects in human U373 glioblastoma and A549 non-small cell lung cancer apoptosis-resistant cells with marked inhibition of mitotic rates. Cancer cells in the remaining phases of the cell cycle were unchanged. Flow cytometry analysis further confirmed that 2 does not induce apoptotic features in U373 or A549 cancer cells. Thus, 2 represents a novel chemical scaffold from which derivatives for anticancer cytostatic compounds can be derived.

In vitro growth inhibitory effects of cytochalasins and derivatives in cancer cells.

The in vitro anticancer activity of eight natural cytochalasins and three hemisynthetic derivatives of cytochalasin B on six cancer cell lines was evaluated. The IC (50) in vitro growth inhibitory concentrations, as determined by an MTT colorimetric assay, ranged between 3 and 90 µM and did not relate to the intrinsic sensitivity of the cancer cell lines to proapoptotic stimuli. Structure activity relationship (SAR) analyses revealed that the presence of an unmodified hydroxyl group at C-7 of the perhydroisoinsolyl-1-one residue as well as the functionalities and the conformational freedom of the macrocycle are all important features for cytochalasin-mediated anticancer activities in vitro. Computer-assisted phase-contrast microscopy revealed two groups of cytochalasins, i.e., cytotoxic versus cytostatic ones. Our data open new possibilities for tuning cytochalasin targets and developing nontoxic, cytostatic cytochalasins to combat cancers associated with poor prognoses, such as those that display intrinsic resistance to proapoptotic stimuli.

Editorial: on the road to multi-modal and pluri-disciplinary treatment of glioblastomas.

Despite major advances in the management of malignant gliomas of which glioblastomas represent the ultimate grade of malignancy, they remain incurable. Indeed, glioblastoma patients have a median survival expectancy of only 14 months on the current standard treatment of surgical resection to the extent which is feasible, followed by adjuvant radiotherapy plus temozolomide given concomitantly with and after radiotherapy (Lefranc et al., J Clin Oncol 23:2411-2422, 2005; Expert Rev Anticancer Ther 6:719-732, 2006; Stummer et al., Neurosurgery 62:564-576, 2008). Accordingly, the present editorial discusses (1) the high cell motility and resistance to apoptosis which characterise glioblastoma growth and malignancy with respect to the failure of conventional therapy, (2) ways to overcome apoptosis resistance and the real hope offered by temozolomide, (3) targeted chemotherapeutic approaches and the disappointing results obtained in monotherapy but their potential in combination therapy, (4) anti-migratory strategies that could supplement conventional therapy notably by inhibiting a new target; the alpha1 subunit of the sodium pump, (5) dendritic cell therapy, (6) cancer stem cell targeting and finally (7) topical therapies and new surgical approaches for more radical resection which could be used to complement multi-modal treatments within a multi-disciplinary approach.