The Therapeutic Potential of Targeting Autophagy in The Treatment of Cancer

: Autophagy is a mechanism by which unwanted cellular components are degraded through a pathway that involves the lysosomes and contributes to several pathological conditions such as cancer. Gastrointestinal cancers affect the digestive organs from the esophagus to the anus and are among the most commonly diagnosed cancers globally. The modulation of autophagy using pharmacologic agents potentially offers a great potential for cancer therapy. In this review, some commonly used compounds, together with their molecular target and the mechanism through which they stimulate or block the autophagy pathway as well as their therapeutic benefit in treating patients with gastrointestinal cancers, are summarized.

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Modulation of Autophagy for Controlling Immunity

Cells ◽

10.3390/cells8020138 ◽

2019 ◽

Vol 8 (2) ◽

pp. 138 ◽

Cited By ~ 18

Author(s):

Young Jin Jang ◽

Jae Hwan Kim ◽

Sanguine Byun

Keyword(s):

Immune Responses ◽

Therapeutic Potential ◽

Inflammatory Diseases ◽

Mechanisms Of Action ◽

Innate And Adaptive Immunity ◽

Pathological Conditions ◽

Physiological Homeostasis ◽

Autophagy Pathway ◽

Key Steps ◽

Additional Role

Autophagy is an essential process that maintains physiological homeostasis by promoting the transfer of cytoplasmic constituents to autophagolysosomes for degradation. In immune cells, the autophagy pathway plays an additional role in facilitating proper immunological functions. Specifically, the autophagy pathway can participate in controlling key steps in innate and adaptive immunity. Accordingly, alterations in autophagy have been linked to inflammatory diseases and defective immune responses against pathogens. In this review, we discuss the various roles of autophagy signaling in coordinating immune responses and how these activities are connected to pathological conditions. We highlight the therapeutic potential of autophagy modulators that can impact immune responses and the mechanisms of action responsible.

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Transferrin-Conjugated Nanocarriers as Active-Targeted Drug Delivery Platforms for Cancer Therapy

Current Pharmaceutical Design ◽

10.2174/1381612822666161026162347 ◽

2017 ◽

Vol 23 (3) ◽

pp. 454-466 ◽

Cited By ~ 16

Author(s):

Daniele R. Nogueira-Librelotto ◽

Cristiane F. Codevilla ◽

Ammad Farooqi ◽

Clarice M. B. Rolim

Keyword(s):

Drug Delivery ◽

Cancer Therapy ◽

Tumor Cells ◽

Therapeutic Benefit ◽

Active Targeting ◽

Future Research ◽

Passive Targeting ◽

The Right ◽

Review Current ◽

Target Effects

A lot of effort has been devoted to achieving active targeting for cancer therapy in order to reach the right cells. Hence, increasingly it is being realized that active-targeted nanocarriers notably reduce off-target effects, mainly because of targeted localization in tumors and active cellular uptake. In this context, by taking advantage of the overexpression of transferrin receptors on the surface of tumor cells, transferrin-conjugated nanodevices have been designed, in hope that the biomarker grafting would help to maximize the therapeutic benefit and to minimize the side effects. Notably, active targeting nanoparticles have shown improved therapeutic performances in different tumor models as compared to their passive targeting counterparts. In this review, current development of nano-based devices conjugated with transferrin for active tumor-targeting drug delivery are highlighted and discussed. The main objective of this review is to provide a summary of the vast types of nanomaterials that have been used to deliver different chemotherapeutics into tumor cells, and to ultimately evaluate the progression on the strategies for cancer therapy in view of the future research.

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Classic and Novel Signaling Pathways Involved in Cancer: Targeting the NF-κB and Syk Signaling Pathways

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180723104340 ◽

2019 ◽

Vol 14 (3) ◽

pp. 219-225 ◽

Cited By ~ 6

Author(s):

Cong Tang ◽

Guodong Zhu

Keyword(s):

Cancer Therapy ◽

Tyrosine Kinase ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Cell Receptor ◽

Transmembrane Receptors ◽

Biological Responses ◽

Different Types

The nuclear factor kappa B (NF-κB) consists of a family of transcription factors involved in the regulation of a wide variety of biological responses. Growing evidence support that NF-κB plays a major role in oncogenesis as well as its well-known function in the regulation of immune responses and inflammation. Therefore, we made a review of the diverse molecular mechanisms by which the NF-κB pathway is constitutively activated in different types of human cancers and the potential role of various oncogenic genes regulated by this transcription factor in cancer development and progression. We also discussed various pharmacological approaches employed to target the deregulated NF-κB signaling pathway and their possible therapeutic potential in cancer therapy. Moreover, Syk (Spleen tyrosine kinase), non-receptor tyrosine kinase which mediates signal transduction downstream of a variety of transmembrane receptors including classical immune-receptors like the B-cell receptor (BCR), which can also activate the inflammasome and NF-κB-mediated transcription of chemokines and cytokines in the presence of pathogens would be discussed as well. The highlight of this review article is to summarize the classic and novel signaling pathways involved in NF-κB and Syk signaling and then raise some possibilities for cancer therapy.

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Structural-Based Optimizations of the Marine-Originated Meridianin C as Glucose Uptake Agents by Inhibiting GSK-3β

Marine Drugs ◽

10.3390/md19030149 ◽

2021 ◽

Vol 19 (3) ◽

pp. 149

Author(s):

Shuwen Han ◽

Chunlin Zhuang ◽

Wei Zhou ◽

Fener Chen

Keyword(s):

Glucose Uptake ◽

Therapeutic Potential ◽

Glycogen Synthase ◽

Molecular Target ◽

Optimization Strategy ◽

Lead Compounds ◽

Significant Toxicity ◽

Treatment Of Diabetes ◽

Gsk 3Β ◽

Positive Compound

Glycogen synthase kinase 3β (GSK-3β) is a widely investigated molecular target for numerous diseases, and inhibition of GSK-3β activity has become an attractive approach for the treatment of diabetes. Meridianin C, an indole-based natural product isolated from marine Aplidium meridianum, has been reported as a potent GSK-3β inhibitor. In the present study, applying the structural-based optimization strategy, the pyrimidine group of meridianin C was modified by introducing different substituents based on the 2-aminopyrimidines-substituted pyrazolo pyridazine scaffold. Among them, compounds B29 and B30 showed a much higher glucose uptake than meridianin C (<5%) and the positive compound 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8, 16%), with no significant toxicity against HepG2 cells at the same time. Furthermore, they displayed good GSK-3β inhibitory activities (IC50 = 5.85; 24.4 μM). These results suggest that these meridianin C analogues represent novel lead compounds with therapeutic potential for diabetes.

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Guanylyl Cyclase 2C (GUCY2C) in Gastrointestinal Cancers: Recent Innovations and Therapeutic Potential

Expert Opinion on Therapeutic Targets ◽

10.1080/14728222.2021.1937124 ◽

2021 ◽

Author(s):

Ariana A. Entezari ◽

Adam E. Snook ◽

Scott A. Waldman

Keyword(s):

Guanylyl Cyclase ◽

Therapeutic Potential ◽

Gastrointestinal Cancers

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Targeting the Ubiquitin Signaling Cascade in Tumor Microenvironment for Cancer Therapy

International Journal of Molecular Sciences ◽

10.3390/ijms22020791 ◽

2021 ◽

Vol 22 (2) ◽

pp. 791

Author(s):

Qi Liu ◽

Bayonle Aminu ◽

Olivia Roscow ◽

Wei Zhang

Keyword(s):

Tumor Microenvironment ◽

Cancer Therapy ◽

Therapeutic Agents ◽

Biological Processes ◽

Post Translational Modification ◽

E3 Ligases ◽

Tumor Microenvironments ◽

Cellular Immune ◽

Ubiquitin Conjugating Enzymes ◽

Cellular Components

Tumor microenvironments are composed of a myriad of elements, both cellular (immune cells, cancer-associated fibroblasts, mesenchymal stem cells, etc.) and non-cellular (extracellular matrix, cytokines, growth factors, etc.), which collectively provide a permissive environment enabling tumor progression. In this review, we focused on the regulation of tumor microenvironment through ubiquitination. Ubiquitination is a reversible protein post-translational modification that regulates various key biological processes, whereby ubiquitin is attached to substrates through a catalytic cascade coordinated by multiple enzymes, including E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes and E3 ubiquitin ligases. In contrast, ubiquitin can be removed by deubiquitinases in the process of deubiquitination. Here, we discuss the roles of E3 ligases and deubiquitinases as modulators of both cellular and non-cellular components in tumor microenvironment, providing potential therapeutic targets for cancer therapy. Finally, we introduced several emerging technologies that can be utilized to develop effective therapeutic agents for targeting tumor microenvironment.

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Friend or Foe: Paradoxical Roles of Autophagy in Gliomagenesis

Cells ◽

10.3390/cells10061411 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1411

Author(s):

Don Carlo Ramos Batara ◽

Moon-Chang Choi ◽

Hyeon-Uk Shin ◽

Hyunggee Kim ◽

Sung-Hak Kim

Keyword(s):

Brain Tumor ◽

Glioblastoma Multiforme ◽

Cancer Biology ◽

Molecular Mechanisms ◽

Primary Brain Tumor ◽

Molecular Target ◽

Therapeutic Strategies ◽

Homeostatic Mechanism ◽

Cellular Context ◽

Cellular Components

Glioblastoma multiforme (GBM) is the most common and aggressive type of primary brain tumor in adults, with a poor median survival of approximately 15 months after diagnosis. Despite several decades of intensive research on its cancer biology, treatment for GBM remains a challenge. Autophagy, a fundamental homeostatic mechanism, is responsible for degrading and recycling damaged or defective cellular components. It plays a paradoxical role in GBM by either promoting or suppressing tumor growth depending on the cellular context. A thorough understanding of autophagy’s pleiotropic roles is needed to develop potential therapeutic strategies for GBM. In this paper, we discussed molecular mechanisms and biphasic functions of autophagy in gliomagenesis. We also provided a summary of treatments for GBM, emphasizing the importance of autophagy as a promising molecular target for treating GBM.

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COVID-19—The Potential Beneficial Therapeutic Effects of Spironolactone during SARS-CoV-2 Infection

Pharmaceuticals ◽

10.3390/ph14010071 ◽

2021 ◽

Vol 14 (1) ◽

pp. 71

Author(s):

Katarzyna Kotfis ◽

Kacper Lechowicz ◽

Sylwester Drożdżal ◽

Paulina Niedźwiedzka-Rystwej ◽

Tomasz K. Wojdacz ◽

...

Keyword(s):

Pulmonary Fibrosis ◽

Therapeutic Potential ◽

Severe Pneumonia ◽

Therapeutic Benefit ◽

World Health ◽

Therapeutic Effects ◽

Severe Acute Respiratory Infection ◽

Dual Action ◽

Health Organization ◽

Transmembrane Serine Protease

In March 2020, coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 was declared a global pandemic by the World Health Organization (WHO). The clinical course of the disease is unpredictable but may lead to severe acute respiratory infection (SARI) and pneumonia leading to acute respiratory distress syndrome (ARDS). It has been shown that pulmonary fibrosis may be one of the major long-term complications of COVID-19. In animal models, the use of spironolactone was proven to be an important drug in the prevention of pulmonary fibrosis. Through its dual action as a mineralocorticoid receptor (MR) antagonist and an androgenic inhibitor, spironolactone can provide significant benefits concerning COVID-19 infection. The primary effect of spironolactone in reducing pulmonary edema may also be beneficial in COVID-19 ARDS. Spironolactone is a well-known, widely used and safe anti-hypertensive and antiandrogenic medication. It has potassium-sparing diuretic action by antagonizing mineralocorticoid receptors (MRs). Spironolactone and potassium canrenoate, exerting combined pleiotropic action, may provide a therapeutic benefit to patients with COVID-19 pneumonia through antiandrogen, MR blocking, antifibrotic and anti-hyperinflammatory action. It has been proposed that spironolactone may prevent acute lung injury in COVID-19 infection due to its pleiotropic effects with favorable renin–angiotensin–aldosterone system (RAAS) and ACE2 expression, reduction in transmembrane serine protease 2 (TMPRSS2) activity and antiandrogenic action, and therefore it may prove to act as additional protection for patients at highest risk of severe pneumonia. Future prospective clinical trials are warranted to evaluate its therapeutic potential.

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Macrophage-Derived Inflammation Induces a Transcriptome Makeover in Mesenchymal Stromal Cells Enhancing Their Potential for Tissue Repair

International Journal of Molecular Sciences ◽

10.3390/ijms22020781 ◽

2021 ◽

Vol 22 (2) ◽

pp. 781

Author(s):

Inés Maldonado-Lasunción ◽

Nick O’Neill ◽

Oliver Umland ◽

Joost Verhaagen ◽

Martin Oudega

Keyword(s):

Growth Factor ◽

Tissue Repair ◽

Therapeutic Potential ◽

Vascular Endothelial ◽

Glial Derived Neurotrophic Factor ◽

Transcriptomic Changes ◽

Endothelial Growth Factor ◽

Cellular Components ◽

Hepatocyte Growth ◽

Go Terms

Pre-clinical and clinical studies revealed that mesenchymal stromal cell (MSC) transplants elicit tissue repair. Conditioning MSC prior to transplantation may boost their ability to support repair. We investigated macrophage-derived inflammation as a means to condition MSC by comprehensively analyzing their transcriptome and secretome. Conditioning MSC with macrophage-derived inflammation resulted in 3208 differentially expressed genes, which were annotated with significantly enriched GO terms for 1085 biological processes, 85 cellular components, and 79 molecular functions. Inflammation-mediated conditioning increased the secretion of growth factors that are key for tissue repair, including vascular endothelial growth factor, hepatocyte growth factor, nerve growth factor and glial-derived neurotrophic factor. Furthermore, we found that inflammation-mediated conditioning induces transcriptomic changes that challenge the viability and mobility of MSC. Our data support the notion that macrophage-derived inflammation stimulates MSC to augment their paracrine repair-supporting activity. The results suggest that inflammatory pre-conditioning enhances the therapeutic potential of MSC transplants.

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