Targeting Mcl-1 and Other Bcl-2 Family Member Proteins in Cancer Therapy

Publication date: Available online 19 October 2018Source: Pharmacology &TherapeuticsAuthor(s): Ryuji Yamaguchi, Lydia Lartigue, Guy PerkinsAbstractRegulation of both the extrinsic and the mitochondria-dependent intrinsic apoptotic pathways plays a key role in the development of the hematopoietic system, for sustaining cell survival during generation of various cell types, in eliminating cells with dual identities such as CD4/CD8 double-positive cells1,2, for sustaining cells during the rapid clonal expansion phase3, as well as eliminating cells during the contraction phase4. The anti-apoptotic protein Mcl-1 is necessary for sustaining hematopoietic stem cells (HPS)5,6. The anti-apoptotic factors Mcl-1, Bcl-2, and Bcl-xL were also found to be over-expressed in acute myeloid leukemia (AML)7 and acute lymphocytic leukemia (ALL)8, suggesting that dis-regulated apoptotic processes could be a factor in the instigation of leukemia and/or its relapse. Molecules targeting these proteins were used as single agents to treat leukemia. However, by using a set of recently developed specific molecule inhibitors targeting anti-apoptotic proteins, distinct roles are being discovered for these anti-apoptotic proteins during hematopoietic and tumor development. Furthermore, using these inhibitors in proper combinations can effectively induce apoptosis in various solid tumors, even though each agent on its own cannot induce apoptosis in them. These new findings suggest that inhibiting anti-a...
Source: Pharmacology and Therapeutics - Category: Drugs & Pharmacology Source Type: research

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Conclusions Several model systems are now available to characterize the MSC-tumour interplay in the TME. These offer early promise in establishing robust preclinical platforms for the identification of crucial molecular pathways and for the assessment of clinical efficacy of novel drugs to inhibit cancer development and progression. However, selection of the right model for a given study should be shaped on the purpose, and should also consider fixed biological, biochemical, and biophysical parameters according to the specific tumour type. Finally, in order to get reliable and useful results to be translated to the clinic...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, e-As4S4 holds great potential for an alternative therapeutics in the treatment of breast cancer, due to its unique function of correcting the aggressive microenvironment. Introduction Metastasis is the leading cause of breast cancer mortality, which has been one major challenge in clinical treatment (1). In particular, triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptors (ER), progesterone receptors (PR) and HER2 receptors, which is one of the most aggressive types of breast cancers, marked by high rates of relapse, visceral metastases and early death (2, 3). The...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Conclusion Several TISC-based immunotherapeutic approaches are under development in various stages of preclinical studies. As outlined in this review article, a careful and more exhaustive genetic and metabolic understanding of TISC-associated phenotypes is critical to develop novel TISC based immunotherapies. Various components within the tumor microenvironment such as tumor cells, infiltrating immune cells, and supporting stromal cells impact the TISC metabolism. This unique metabolic profile leads to upregulation of certain enzymes and proteins such as ALDH1, CEP55, IDO COA1 etc., which can be utilized for development ...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
In conclusion, we showed hypermethylation of CpGs as a novel mechanism of action for DNMTi agents and identified 638 hypermethylated molecular targets (CpGs) common to decitabine and azacytidine therapy. These novel results suggest that hypermethylation of CpGs should be considered when predicting the DNMTi responses and side effects in cancer patients. Introduction DNA methyltransferase inhibitors (DNMTi) are widely used as chemical tools for hypomethylating the genome, with an aim to understand the role of DNA methylation in multiple processes (e.g., X-chromosome inactivation and DNA imprinting) and as an anti-ca...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
Markus Hartl* and Rainer Schneider Center of Molecular Biosciences (CMBI), Institute of Biochemistry, University of Innsbruck, Innsbruck, Austria The neuronal proteins GAP43 (neuromodulin), MARCKS, and BASP1 are highly expressed in the growth cones of nerve cells where they are involved in signal transmission and cytoskeleton organization. Although their primary structures are unrelated, these signaling proteins share several structural properties like fatty acid modification, and the presence of cationic effector domains. GAP43, MARCKS, and BASP1 bind to cell membrane phospholipids, a process reversibly regulate...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Discussion Suppressor of cytokine signaling 1 is an essential molecule for maintaining immune homeostasis and subverting inflammation. Disorders arising from excess inflammation or SOCS1 deficiency can be potentially treated with SOCS1 mimetics (Ahmed et al., 2015). While SOCS1 has promising potential in many disorders, it should be noted that new targets and actions of SOCS1 are still being discovered and not all the effects of this protein are beneficial in autoimmune diseases and cancer. For instance, SOCS1 degrades IRS1 and IRS2, required for insulin signaling, via the SOCS Box domain, thus, limiting its potential in ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research
In conclusion, MPT0G413 and BTZ synergistically inhibit MM viability, providing a framework for the clinical evaluation of combined therapies for MM. Introduction Multiple myeloma (MM) is a B cell malignancy characterized by the proliferation of bone marrow (BM) plasma cells and the production of large amounts of abnormal immunoglobulins (1) In the United States, it was estimated that 30,770 new MM cases would be diagnosed in 2018, accounting for 1.8% of newly diagnosed cancer cases (2). Furthermore, 12,770 MM-related deaths in 2018 accounted for an estimated 2.1% of all cancer deaths (2). In the past decade, MM t...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research
Adults diagnosed with acute myeloid leukemia have a poor prognosis, with only 30% surviving at five years. Despite advances in our understanding of the molecular underpinnings of AML, the chemotherapy backbone used to treat most patients (combination cytarabine and anthracycline) remains unchanged since 1973.With the goal of identifying a new differentiation therapy, we previously performed a small molecule phenotypic screen to find compounds that triggered myeloid maturation. Unexpectedly, our most active hits were inhibitors of the enzyme dihydroorotate dehydrogenase (DHODH). The DHODH-inhibitor brequinar demonstrated dr...
Source: Blood - Category: Hematology Authors: Tags: 616. Acute Myeloid Leukemia: Novel Therapy, excluding Transplantation: Poster II Source Type: research
The hematopoietic system is one of the most well-studied and well-characterized differentiation hierarchies in the mammalian body, and hematopoiesis has for decades served as a paradigm for how stem cells generate complex, self-renewing tissues and maintain them under homeostatic, physiological stress and regenerative conditions. The hematopoietic stem cell (HSC) plays a central role in all of these scenarios: HSCs provide the developmental origin of definitive hematopoiesis, sustain baseline blood cell production and are activated in response to physiological stress. In addition, HSC are capable of regenerating the hemato...
Source: Blood - Category: Hematology Authors: Tags: Thrombopoiesis Revised: From Lung to Hematopoietic Stem Cell Platelet Bias Source Type: research
(UCLA Samueli School of Engineering) A cancer therapy based on fusing two types of cells into a single unit shows promise in strengthening existing treatments for acute myeloid leukemia. The approach joins blood platelets that carry cancer drugs with stem cells that guide the platelets into bone marrow where leukemia begins.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
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