scholarly journals The Role of Bcl-2 Family Proteins in Therapy Responses of Malignant Astrocytic Gliomas: Bcl2L12 and Beyond

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Fotini M. Kouri ◽  
Samuel A. Jensen ◽  
Alexander H. Stegh
Keyword(s):  
Radiation Therapy ◽  
Clinical Studies ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapy Resistance ◽  
Brain Parenchyma ◽  
Normal Brain ◽  
Future Drug ◽  
Induced Apoptosis ◽  
Proliferative Indices

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer with a median survival of less than two years after diagnosis. Hallmarks of GBM tumors include soaring proliferative indices, high levels of angiogenesis, diffuse invasion into normal brain parenchyma, resistance toward therapy-induced apoptosis, and pseudopallisading necrosis. Despite the recent advances in neurosurgery, radiation therapy, and the development of targeted chemotherapeutic regimes, GBM remains one of the deadliest types of cancer. Particularly, the alkylating agent temozolomide (TMZ) in combination with radiation therapy prolonged patient survival only marginally, and clinical studies assessing efficacies of targeted therapies, foremost ATP mimetics inhibiting the activity of receptor tyrosine kinases (RTKs), revealed only few initial responders; tumor recurrence is nearly universal, and salvage therapies to combat such progression remain ineffective. Consequently, myriad preclinical and clinical studies began to define the molecular mechanisms underlying therapy resistance of GBM tumors, and pointed to the Bcl-2 protein family, in particular the atypical member Bcl2-Like 12 (Bcl2L12), as important regulators of therapy-induced cell death. This review will discuss the multi-facetedmodi operandiof Bcl-2 family proteins, describe their roles in therapy resistance of malignant glioma, and outline current and future drug development efforts to therapeutically target Bcl-2 proteins.

scholarly journals The Molecular Pathogenesis of Haemangioma

2021 ◽  
Author(s):  
◽  
Anasuya Vishvanath
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Treatment Options ◽  
Janus Kinase ◽  
Stem Cell Population ◽  
Induced Apoptosis

<p>Haemangioma is a primary tumour of the microvasculature characterised by active angiogenesis and endothelial cell (EC)  proliferation followed by slow regression or involution whereby the newly formed blood vessels are gradually replaced by fibrofatty tissue. These developmental changes have been arbitrarily divided into the proliferative, involuting and involuted phases. The cellular and molecular events that initiate and regulate the proliferation and spontaneous involution of haemangioma remain poorly understood. This study examined the expression of a number of genes known to be associated with angiogenesis. These include members of the signal transducers and activators of transcription (STAT) protein family of transcription factors, STAT-3 and STAT-1, and the endothelial receptor tyrosine kinases, VEGFR-1 and VEGFR-2. While STAT-3, STAT-1 and VEGFR-1 expression was detected in all phases of haemangioma, VEGFR-2 expression was found to be abundant only during the proliferative phase and decreased with ongoing involution. In this study the cellular structures that form capillary-like outgrowths in an in vitro haemangioma explant model were characterised as haemangioma-derived mesenchymal stem cells (HaemDMSCs) while the cells obtained directly from dissociated proliferative haemangioma tissue were defined as haemangioma-derived endothelial progenitor cells (HaemDEPCs). This investigation showed that although the vascular endothelial growth factor (VEGF), a key growth factor for ECs, was able to maintain HaemDEPCs morphology and immunophenotype for a limited period, these cells eventually differentiated into HaemDMSCs, which subsequently differentiated into adipocytes. Furthermore, while VEGF induced significant capillary-like sprouting from tissue explants, both capillary-like sprouting and HaemDMSCs proliferation was inhibited by the addition of AG490, a Janus kinase (JAK) inhibitor which has also been shown to inhibit the STAT protein pathway. These findings indicate that the development and differentiation of a progenitor cell and a stem cell population underlies the aethiopathogenesis of haemangioma and that VEGF and STAT signalling is involved in the programmed life-cycle of haemangioma. The in vitro explant model for haemangioma offers an opportunity to study and identify novel treatment options for haemangioma. Interferon-alpha (IFN ) has been used to treat steroid-resistant haemangioma but is associated with serious side-affects. The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically induce apoptosis of cancer cells while sparing normal cells. As IFN has previously been shown to sensitise cells to TRAIL-induced apoptosis, this study examined the efficacy of low dose IFN in combination with TRAIL in the in vitro explant model and also in the purified HaemDMSCs. Results showed that combining IFN with TRAIL led to synergistic inhibition of capillary-like outgrowth. These results indicate that IFN in combination with TRAIL serves as a potential treatment option for haemangioma. In contrast, HaemDMSCs were protected from TRAIL-induced killing. These cells were found to express high levels of the decoy receptors, osteoprotegerin (OPG) and decoy receptor 2 (DcR2). Increased OPG expression was also detected in the extracellular matrix and in the conditioned medium of HaemDMSCs. From these findings, we postulate that the increased level of extracellular OPG by HaemDMSCs is a stress response induced by their in vitro expansion and that secreted OPG functions as a protective shield preventing TRAIL action. The empirical and unsatisfactory nature of the current therapies for haemangioma underscores the importance of a scientific approach to this common tumour. A better understanding of the molecular mechanisms that govern haemangioma is of both clinical and biological interest as it may provide vital information with therapeutic potential for haemangioma and also for other angiogenesis-dependent conditions.</p>

scholarly journals The Molecular Pathogenesis of Haemangioma

2021 ◽  
Author(s):  
◽  
Anasuya Vishvanath
Keyword(s):  
Growth Factor ◽  
Tyrosine Kinases ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Primary Tumour ◽  
Treatment Options ◽  
Janus Kinase ◽  
Stem Cell Population ◽  
Induced Apoptosis

<p>Haemangioma is a primary tumour of the microvasculature characterised by active angiogenesis and endothelial cell (EC)  proliferation followed by slow regression or involution whereby the newly formed blood vessels are gradually replaced by fibrofatty tissue. These developmental changes have been arbitrarily divided into the proliferative, involuting and involuted phases. The cellular and molecular events that initiate and regulate the proliferation and spontaneous involution of haemangioma remain poorly understood. This study examined the expression of a number of genes known to be associated with angiogenesis. These include members of the signal transducers and activators of transcription (STAT) protein family of transcription factors, STAT-3 and STAT-1, and the endothelial receptor tyrosine kinases, VEGFR-1 and VEGFR-2. While STAT-3, STAT-1 and VEGFR-1 expression was detected in all phases of haemangioma, VEGFR-2 expression was found to be abundant only during the proliferative phase and decreased with ongoing involution. In this study the cellular structures that form capillary-like outgrowths in an in vitro haemangioma explant model were characterised as haemangioma-derived mesenchymal stem cells (HaemDMSCs) while the cells obtained directly from dissociated proliferative haemangioma tissue were defined as haemangioma-derived endothelial progenitor cells (HaemDEPCs). This investigation showed that although the vascular endothelial growth factor (VEGF), a key growth factor for ECs, was able to maintain HaemDEPCs morphology and immunophenotype for a limited period, these cells eventually differentiated into HaemDMSCs, which subsequently differentiated into adipocytes. Furthermore, while VEGF induced significant capillary-like sprouting from tissue explants, both capillary-like sprouting and HaemDMSCs proliferation was inhibited by the addition of AG490, a Janus kinase (JAK) inhibitor which has also been shown to inhibit the STAT protein pathway. These findings indicate that the development and differentiation of a progenitor cell and a stem cell population underlies the aethiopathogenesis of haemangioma and that VEGF and STAT signalling is involved in the programmed life-cycle of haemangioma. The in vitro explant model for haemangioma offers an opportunity to study and identify novel treatment options for haemangioma. Interferon-alpha (IFN ) has been used to treat steroid-resistant haemangioma but is associated with serious side-affects. The tumour necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) has been shown to specifically induce apoptosis of cancer cells while sparing normal cells. As IFN has previously been shown to sensitise cells to TRAIL-induced apoptosis, this study examined the efficacy of low dose IFN in combination with TRAIL in the in vitro explant model and also in the purified HaemDMSCs. Results showed that combining IFN with TRAIL led to synergistic inhibition of capillary-like outgrowth. These results indicate that IFN in combination with TRAIL serves as a potential treatment option for haemangioma. In contrast, HaemDMSCs were protected from TRAIL-induced killing. These cells were found to express high levels of the decoy receptors, osteoprotegerin (OPG) and decoy receptor 2 (DcR2). Increased OPG expression was also detected in the extracellular matrix and in the conditioned medium of HaemDMSCs. From these findings, we postulate that the increased level of extracellular OPG by HaemDMSCs is a stress response induced by their in vitro expansion and that secreted OPG functions as a protective shield preventing TRAIL action. The empirical and unsatisfactory nature of the current therapies for haemangioma underscores the importance of a scientific approach to this common tumour. A better understanding of the molecular mechanisms that govern haemangioma is of both clinical and biological interest as it may provide vital information with therapeutic potential for haemangioma and also for other angiogenesis-dependent conditions.</p>

Radiotherapy for Brain Tumors: Current Practice and Future Directions

2020 ◽  
Vol 16 (3) ◽  
pp. 182-195
Author(s):  
Sarah Baker ◽  
Natalie Logie ◽  
Kim Paulson ◽  
Adele Duimering ◽  
Albert Murtha
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Benign Tumors ◽  
Tumor Control ◽  
Normal Brain ◽  
Neurocognitive Deficits ◽  
Close Proximity ◽  
Recent Developments ◽  
High Level

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

Potential Therapeutic Targets of Curcumin, Most Abundant Active Compound of Turmeric Spice: Role in the Management of Various Types of Cancer

2020 ◽  
Vol 15 ◽  
Author(s):  
Saleh A. Almatroodi ◽  
Mansoor Ali Syed ◽  
Arshad Husain Rahmani
Keyword(s):  
Clinical Trials ◽  
Cancer Cells ◽  
Active Compound ◽  
Molecular Mechanisms ◽  
Human Subjects ◽  
Cell Signalling ◽  
Chemopreventive Agents ◽  
Signalling Molecules ◽  
Cancer Management ◽  
Induced Apoptosis

Background:: Curcumin, an active compound of turmeric spice is one of the most-studies natural compounds and have been widely recognized as chemopreventive agents. Several molecular mechanisms have been proven, curcumin and its analogs play a role in cancer prevention through modulating various cell signaling pathways as well as inhibition of carcinogenesis process. Objective:: To study the potential role of curcumin in the management of various types of cancer through modulating cell signalling molecules based on available literature and recent patents. Methods:: A wide-ranging literature survey was performed based on Scopus, PubMed, PubMed central and Google scholar for the implication of curcumin in cancer management along with special emphasis on human clinical trials. Moreover, patents were searched through www.google.com/patents, www.freepatentsonline.com and www.freshpatents.com. Result:: Recent studies based on cancer cells have proven that curcumin have potential effects against cancer cells, prevent the growth of cancer and act as cancer therapeutic agents. Besides, curcumin exerted anticancer effects through inducing apoptosis, activating tumor suppressor genes, cell cycle arrest, inhibiting tumor angiogenesis, initiation, promotion and progression stages of tumor. It was established that co-treatment of curcumin and anti-cancer drugs could induce apoptosis and also play a significant role in the suppression of the invasion and metastasis of cancer cells. Conclusion:: Accumulating evidences suggest that curcumin has potentiality to inhibit cancer growth, induced apoptosis and modulate various cell signalling pathways molecules. Well-designed clinical trials of curcumin based on human subjects are still needed to establish the bioavailability, mechanism of action, efficacy and safe dose in the management of various cancers.

VDAC1 Mediated Anticancer Activity of Gallic Acid in Human Lung Adenocarcinoma A549 Cells

2018 ◽  
Vol 18 (2) ◽  
pp. 255-262 ◽  
Author(s):  
Aikebaier Maimaiti ◽  
Amier Aili ◽  
Hureshitanmu Kuerban ◽  
Xuejun Li
Keyword(s):  
Western Blot ◽  
Cell Viability ◽  
Gallic Acid ◽  
Molecular Mechanisms ◽  
A549 Cells ◽  
Dependent Manner ◽  
Lung Carcinoma Cells ◽  
Induced Apoptosis ◽  
The Impact

Aims: Gallic acid (GA) is generally distributed in a variety of plants and foods, and possesses cell growth-inhibiting activities in cancer cell lines. In the present study, the impact of GA on cell viability, apoptosis induction and possible molecular mechanisms in cultured A549 lung carcinoma cells was investigated. Methods: In vitro experiments showed that treating A549 cells with various concentrations of GA inhibited cell viability and induced apoptosis in a dose-dependent manner. In order to understand the mechanism by which GA inhibits cell viability, comparative proteomic analysis was applied. The changed proteins were identified by Western blot and siRNA methods. Results: Two-dimensional electrophoresis revealed changes that occurred to the cells when treated with or without GA. Four up-regulated protein spots were clearly identified as malate dehydrogenase (MDH), voltagedependent, anion-selective channel protein 1(VDAC1), calreticulin (CRT) and brain acid soluble protein 1(BASP1). VDAC1 in A549 cells was reconfirmed by western blot. Transfection with VDAC1 siRNA significantly increased cell viability after the treatment of GA. Further investigation showed that GA down regulated PI3K/Akt signaling pathways. These data strongly suggest that up-regulation of VDAC1 by GA may play an important role in GA-induced, inhibitory effects on A549 cell viability.

Galectin-3: A factotum in carcinogenesis bestowing an archery for prevention

Tumor Biology ◽  
2021 ◽  
Vol 43 (1) ◽  
pp. 77-96
Author(s):  
T. Jeethy Ram ◽  
Asha Lekshmi ◽  
Thara Somanathan ◽  
K. Sujathan
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Therapy Resistance ◽  
Cellular Level ◽  
Clinical Samples ◽  
Innovative Strategy ◽  
Mesenchymal Transition ◽  
Galectin 3

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

Molecular mechanisms involved in the adaptive response to cadmium-induced apoptosis in human myelomonocytic lymphoma U937 cells

2011 ◽  
Vol 25 (8) ◽  
pp. 1687-1693 ◽  
Author(s):  
Zheng-Guo Cui ◽  
Ryohei Ogawa ◽  
Jin-Lan Piao ◽  
Kei Hamazaki ◽  
Loreto B. Feril ◽  
...  
Keyword(s):  
Adaptive Response ◽  
Molecular Mechanisms ◽  
U937 Cells ◽  
Induced Apoptosis

scholarly journals Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

2021 ◽  
Vol 14 (7) ◽  
pp. 626
Author(s):  
Julie Bolcaen ◽  
Shankari Nair ◽  
Cathryn H. S. Driver ◽  
Tebatso M. G. Boshomane ◽  
Thomas Ebenhan ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Receptor Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Radionuclide Therapy ◽  
Kinase Inhibitors ◽  
Nuclear Imaging ◽  
Therapy Resistance ◽  
Targeted Radionuclide Therapy ◽  
Therapy Strategy ◽  
Dismal Prognosis

Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

scholarly journals Loss of histone methyltransferase ASH1L in the developing mouse brain causes autistic-like behaviors

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Yuen Gao ◽  
Natalia Duque-Wilckens ◽  
Mohammad B. Aljazi ◽  
Yan Wu ◽  
Adam J. Moeser ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mouse Brain ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Autism Spectrum ◽  
Normal Brain ◽  
Critical Function ◽  
Developmental Defects ◽  
Neurodevelopmental Disease ◽  
Developing Mouse Brain

AbstractAutism spectrum disorder (ASD) is a neurodevelopmental disease associated with various gene mutations. Recent genetic and clinical studies report that mutations of the epigenetic gene ASH1L are highly associated with human ASD and intellectual disability (ID). However, the causality and underlying molecular mechanisms linking ASH1L mutations to genesis of ASD/ID remain undetermined. Here we show loss of ASH1L in the developing mouse brain is sufficient to cause multiple developmental defects, core autistic-like behaviors, and impaired cognitive memory. Gene expression analyses uncover critical roles of ASH1L in regulating gene expression during neural cell development. Thus, our study establishes an ASD/ID mouse model revealing the critical function of an epigenetic factor ASH1L in normal brain development, a causality between Ash1L mutations and ASD/ID-like behaviors in mice, and potential molecular mechanisms linking Ash1L mutations to brain functional abnormalities.

scholarly journals Splicing Genomics Events in Cervical Cancer: Insights for Phenotypic Stratification and Biomarker Potency

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 130
Author(s):  
Flavia Zita Francies ◽  
Sheynaz Bassa ◽  
Aristotelis Chatziioannou ◽  
Andreas Martin Kaufmann ◽  
Zodwa Dlamini
Keyword(s):  
Cervical Cancer ◽  
Alternative Splicing ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Therapy Resistance ◽  
Splicing Factors ◽  
Aberrant Splicing ◽  
Molecular Alteration ◽  
Common Cancer ◽  
Potential Biomarkers

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

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