scholarly journals Methylxanthines: Potential Therapeutic Agents for Glioblastoma

2019 ◽  
Vol 12 (3) ◽  
pp. 130
Author(s):  
Daniel Pérez-Pérez ◽  
Iannel Reyes-Vidal ◽  
Elda Georgina Chávez-Cortez ◽  
Julio Sotelo ◽  
Roxana Magaña-Maldonado
Keyword(s):  
Cancer Progression ◽  
Poor Prognosis ◽  
Median Overall Survival ◽  
Primary Brain Tumor ◽  
Therapeutic Agents ◽  
The Poor ◽  
Pde Inhibitors ◽  
Anti Cancer ◽  
Cell Processes ◽  
Cancer Agent

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Currently, treatment is ineffective and the median overall survival is 20.9 months. The poor prognosis of GBM is a consequence of several altered signaling pathways that favor the proliferation and survival of neoplastic cells. One of these pathways is the deregulation of phosphodiesterases (PDEs). These enzymes participate in the development of GBM and may have value as therapeutic targets to treat GBM. Methylxanthines (MXTs) such as caffeine, theophylline, and theobromine are PDE inhibitors and constitute a promising therapeutic anti-cancer agent against GBM. MTXs also regulate various cell processes such as proliferation, migration, cell death, and differentiation; these processes are related to cancer progression, making MXTs potential therapeutic agents in GBM.

scholarly journals The Interplay between Glioblastoma and Its Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2257
Author(s):  
Mark Dapash ◽  
David Hou ◽  
Brandyn Castro ◽  
Catalina Lee-Chang ◽  
Maciej S. Lesniak
Keyword(s):  
Tumor Microenvironment ◽  
Patient Outcomes ◽  
Poor Prognosis ◽  
Primary Brain Tumor ◽  
Major Contributor ◽  
Complex Interplay ◽  
Environmental Pressures ◽  
The Poor ◽  
Adaptive Nature ◽  
Poor Efficacy

GBM is the most common primary brain tumor in adults, and the aggressive nature of this tumor contributes to its extremely poor prognosis. Over the years, the heterogeneous and adaptive nature of GBM has been highlighted as a major contributor to the poor efficacy of many treatments including various immunotherapies. The major challenge lies in understanding and manipulating the complex interplay among the different components within the tumor microenvironment (TME). This interplay varies not only by the type of cells interacting but also by their spatial distribution with the TME. This review highlights the various immune and non-immune components of the tumor microenvironment and their consequences f the efficacy of immunotherapies. Understanding the independent and interdependent aspects of the various sub-populations encapsulated by the immune and non-immune components will allow for more targeted therapies. Meanwhile, understanding how the TME creates and responds to different environmental pressures such as hypoxia may allow for other multimodal approaches in the treatment of GBM. Ultimately, a better understanding of the GBM TME will aid in the development and advancement of more effective treatments and in improving patient outcomes.

scholarly journals BRAF Mutations and the Utility of RAF and MEK Inhibitors in Primary Brain Tumors

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1262 ◽  
Author(s):  
Karisa C. Schreck ◽  
Stuart A. Grossman ◽  
Christine A. Pratilas
Keyword(s):  
Brain Tumors ◽  
Poor Prognosis ◽  
Primary Brain Tumor ◽  
High Grade ◽  
Braf Mutations ◽  
Mek Inhibitors ◽  
Primary Brain Tumors ◽  
The Poor ◽  
Oncogenic Mutations ◽  
Tumor Types

BRAF mutations have been identified as targetable, oncogenic mutations in many cancers. Given the paucity of treatments for primary brain tumors and the poor prognosis associated with high-grade gliomas, BRAF mutations in glioma are of considerable interest. In this review, we present the spectrum of BRAF mutations and fusion alterations present in each class of primary brain tumor based on publicly available databases and publications. We also summarize clinical experience with RAF and MEK inhibitors in patients with primary brain tumors and describe ongoing clinical trials of RAF inhibitors in glioma. Sensitivity to RAF and MEK inhibitors varies among BRAF mutations and between tumor types as only class I BRAF V600 mutations are sensitive to clinically available RAF inhibitors. While class II and III BRAF mutations are found in primary brain tumors, further research is necessary to determine their sensitivity to third-generation RAF inhibitors and/or MEK inhibitors. We recommend that the neuro-oncologist consider using these drugs primarily in the setting of a clinical trial for patients with BRAF-altered glioma in order to advance our knowledge of their efficacy in this patient population.

scholarly journals Development of a Cationic Amphiphilic Helical Peptidomimetic (B18L) As A Novel Anti-Cancer Drug Lead

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2448 ◽  
Author(s):  
Yuan Lyu ◽  
Steven Kopcho ◽  
Folnetti A. Alvarez ◽  
Bryson C. Okeoma ◽  
Chioma M. Okeoma
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Drug ◽  
Cancer Cell Death ◽  
Drug Lead ◽  
Anti Cancer ◽  
Cancer Agent ◽  
Caspase Substrate ◽  
Dynamics Simulations

BST-2 is a novel driver of cancer progression whose expression confers oncogenic properties to breast cancer cells. As such, targeting BST-2 in tumors may be an effective therapeutic approach against breast cancer. Here, we sought to develop potent cytotoxic anti-cancer agent using the second-generation BST-2-based anti-adhesion peptide, B18, as backbone. To this end, we designed a series of five B18-derived peptidomimetics. Among these, B18L, a cationic amphiphilic α-helical peptidomimetic, was selected as the drug lead because it displayed superior anti-cancer activity against both drug-resistant and drug-sensitive cancer cells, with minimal toxicity on normal cells. Probing mechanism of action using molecular dynamics simulations, biochemical and membrane biophysics studies, we observed that B18L binds BST-2 and possesses membranolytic characteristics. Furthermore, molecular biology studies show that B18L dysregulates cancer signaling pathways resulting in decreased Src and Erk1/2 phosphorylation, increased expression of pro-apoptotic Bcl2 proteins, caspase 3 cleavage products, as well as processing of the caspase substrate, poly (ADP-ribose) polymerase-1 (PARP-1), to the characteristic apoptotic fragment. These data indicate that through the coordinated regulation of membrane, mitochondrial and signaling events, B18L executes cancer cell death and thus has the potential to be developed into a potent and selective anti-cancer compound.

scholarly journals Tumor-Associated Microglia and Macrophages in the Glioblastoma Microenvironment and their Implications for Therapy

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4255
Author(s):  
Rikke Sick Andersen ◽  
Atul Anand ◽  
Dylan Scott Lykke Harwood ◽  
Bjarne Winther Kristensen
Keyword(s):  
Poor Prognosis ◽  
Therapeutic Strategy ◽  
Treatment Strategies ◽  
Treatment Resistance ◽  
Standard Of Care ◽  
Primary Brain Tumor ◽  
Therapeutic Strategies ◽  
The Poor ◽  
Temozolomide Chemotherapy

Glioblastoma is the most frequent and malignant primary brain tumor. Standard of care includes surgery followed by radiation and temozolomide chemotherapy. Despite treatment, patients have a poor prognosis with a median survival of less than 15 months. The poor prognosis is associated with an increased abundance of tumor-associated microglia and macrophages (TAMs), which are known to play a role in creating a pro-tumorigenic environment and aiding tumor progression. Most treatment strategies are directed against glioblastoma cells; however, accumulating evidence suggests targeting of TAMs as a promising therapeutic strategy. While TAMs are typically dichotomously classified as M1 and M2 phenotypes, recent studies utilizing single cell technologies have identified expression pattern differences, which is beginning to give a deeper understanding of the heterogeneous subpopulations of TAMs in glioblastomas. In this review, we evaluate the role of TAMs in the glioblastoma microenvironment and discuss how their interactions with cancer cells have an extensive impact on glioblastoma progression and treatment resistance. Finally, we summarize the effects and challenges of therapeutic strategies, which specifically aim to target TAMs.

scholarly journals Multimodality imaging and mathematical modelling of drug delivery to glioblastomas

2016 ◽  
Vol 6 (5) ◽  
pp. 20160039 ◽  
Author(s):  
Ahmed Boujelben ◽  
Michael Watson ◽  
Steven McDougall ◽  
Yi-Fen Yen ◽  
Elizabeth R. Gerstner ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Blood Flow ◽  
Poor Prognosis ◽  
Median Overall Survival ◽  
Multimodality Imaging ◽  
Tumour Microenvironment ◽  
Therapeutic Agents ◽  
Vessel Permeability ◽  
And Diffusion ◽  
Tissue Diffusion

Patients diagnosed with glioblastoma, an aggressive brain tumour, have a poor prognosis, with a median overall survival of less than 15 months. Vasculature within these tumours is typically abnormal, with increased tortuosity, dilation and disorganization, and they typically exhibit a disrupted blood–brain barrier (BBB). Although it has been hypothesized that the ‘normalization’ of the vasculature resulting from anti-angiogenic therapies could improve drug delivery through improved blood flow, there is also evidence that suggests that the restoration of BBB integrity might limit the delivery of therapeutic agents and hence their effectiveness. In this paper, we apply mathematical models of blood flow, vascular permeability and diffusion within the tumour microenvironment to investigate the effect of these competing factors on drug delivery. Preliminary results from the modelling indicate that all three physiological parameters investigated—flow rate, vessel permeability and tissue diffusion coefficient—interact nonlinearly to produce the observed average drug concentration in the microenvironment.

Benzoxazinoids in human diet: an anti-cancer agent?

2019 ◽  
Author(s):  
B Bhattarai ◽  
SK Steffensen ◽  
PL Gregersen ◽  
JH Jensen ◽  
KD Sørensen ◽  
...  
Keyword(s):  
Human Diet ◽  
Anti Cancer ◽  
Cancer Agent

Future Oncotargets: Targeting Overexpressed Conserved Protein Targets in Androgen Independent Prostate Cancer Cell Lines

2020 ◽  
Vol 20 (8) ◽  
pp. 1017-1027
Author(s):  
Abdul M. Baig ◽  
Zohaib Rana ◽  
Mohammad M. Mannan ◽  
Areeba Khaleeq ◽  
Fizza Nazim ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cell Lines ◽  
Drug Efflux ◽  
Adapter Proteins ◽  
Cancer Drugs ◽  
Protein Targets ◽  
Anti Cancer ◽  
Drug Efflux Pumps ◽  
Cancer Agent ◽  
Androgen Independent

Background: Targeting evolutionarily conserved proteins in malignant cells and the adapter proteins involved in signalling that generates from such proteins may play a cardinal role in the selection of anti-cancer drugs. Drugs targeting these proteins could be of importance in developing anti-cancer drugs. Objectives: We inferred that drugs like loperamide and promethazine that act as antagonists of proteins conserved in cancer cells like voltage-gated Calcium channels (Cav), Calmodulin (CaM) and drug efflux (ABCB1) pump may have the potential to be re-purposed as an anti-cancer agent in Prostate Cancer (PCa). Methods: Growth and cytotoxic assays were performed by selecting loperamide and promethazine to target Cav, CaM and drug efflux (ABCB1) pumps to elucidate their effects on androgen-independent PC3 and DU145 PCa cell lines. Results: We show that loperamide and promethazine in doses of 80-100μg/ml exert oncocidal effects when tested in DU145 and PC3 cell lines. Diphenhydramine, which shares its targets with promethazine, except the CaM, failed to exhibit oncocidal effects. Conclusion: Anti-cancer effects can be of significance if structural analogues of loperamide and promethazine that specifically target Cav, CaM and ABCB1 drug efflux pumps can be synthesized, or these two drugs could be re-purposed after human trials in PCa.

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