scholarly journals Cell Death Pathways as Therapeutic Targets in Rhabdomyosarcoma

Sarcoma ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Acquired Resistance ◽  
Aberrant Expression ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Rational Development ◽  
Current Therapies ◽  
Key Issues ◽  
Cytotoxic Therapies

Resistance of rhabdomyosarcoma to current therapies remains one of the key issues in pediatric oncology. Since the success of most cytotoxic therapies in the treatment of cancer, for example, chemotherapy, depends on intact signaling pathways that mediate programmed cell death (apoptosis), defects in apoptosis programs in cancer cells may result in resistance. Evasion of apoptosis in rhabdomyosarcoma may be caused by defects in the expression or function of critical mediators of apoptosis or in aberrant expression of antiapoptotic proteins. Therefore, the identification of the molecular mechanisms that confer primary or acquired resistance to apoptosis in rhabdomyosarcoma presents a critical step for the rational development of molecular targeted drugs. This approach will likely open novel perspectives for the treatment of rhabdomyosarcoma.

scholarly journals Mechanisms of Deregulation of Apoptosis in Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. SCI-10-SCI-10
Author(s):  
Simone Fulda
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Binding Motif ◽  
Apoptosis Resistance ◽  
Aberrant Expression ◽  
Antiapoptotic Proteins ◽  
Human Cancers

Programmed cell death is a fundamental cellular program that is inherent in every cell of the human body. Apoptosis represents one of the most extensively studied forms of programmed cell death that plays a critical role during various physiological processes as well as in a variety of pathological conditions. Against the background that tissue homeostasis is maintained by a subtle balance between cell death on one side and cell proliferation on the other side, any changes in one of these parameters can form the basis for human diseases. The fact that under normal conditions apoptosis represents a safeguard mechanism to prevent tumorigenesis implies that evasion of apoptosis constitutes a characteristic feature of human cancers. Too little cell death contributes not only to cancer formation, but also to cancer progression and treatment resistance. A better understanding of the mechanisms that are involved in the regulation of apoptosis in human cancers over the last decades has led to the development of novel approaches for exploiting this cellular program for cancer therapy. Also, the elucidation of the molecular mechanisms that underlie the intrinsic apoptosis resistance of human cancers resulted in the identification of target structures that can be exploited for therapeutic purposes. For example, cell death is frequently impaired in cancers by aberrant expression of antiapoptotic proteins, for example "Inhibitor of Apoptosis" (IAP) proteins, which are expressed at high levels in many human cancers. Among the therapeutic approaches that have been developed to target IAP proteins, the most widely used strategy is based on mimicking the IAP-binding motif of second mitochondria-derived activator of caspases (Smac), which functions as an endogenous IAP antagonist. Current and future perspectives on targeting cell death pathways, for example by using Smac mimetics, for therapeutic intervention in human cancers will be discussed. Since antiapoptotic proteins of the BCL-2 family, including BCL-2, BCL-xL and MCL-1, play a critical role in disabling the mitochondrial pathway of apoptosis, these antiapoptotic BCL-2 family proteins have gained a lot of attention for the development of mitochondria-targeted cancer therapeutics. To this end, structure-based, rational drug design has resulted in the development of small-molecule inhibitors of antiapoptotic proteins of the BCL-2 family. The concept to rationally target apoptosis signal transduction pathways has important implications for cancer therapy, since intact apoptosis programs are critical for the therapeutic efficacy of most anticancer therapies. Reactivation of apoptosis not only directly triggers cell death in cancer cells, but also lowers the threshold for apoptosis in response to other apoptotic stimuli, thus sensitizing tumor cells for apoptosis. In principle, the idea to target apoptosis pathways has been translated into first clinical applications. The challenge in future years will be to further exploit this concept for cancer therapy to the best possible extent. Disclosures No relevant conflicts of interest to declare.

scholarly journals Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2009 ◽  
Author(s):  
Dominique Delmas ◽  
Jianbo Xiao ◽  
Anne Vejux ◽  
Virginie Aires
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Organic Anion ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Anion Transporters ◽  
Atp Binding Cassettes

Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing enzymes (phase I and phase II) to protect normal cells against various toxic molecules or to protect against deleterious effects of chemotherapeutic agents on normal cells. Furthermore, silymarin and its main bioactive compounds inhibit organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters, thus contributing to counteracting potential chemoresistance. Silymarin and its derivatives play a double role, namely, limiting the progression of cancer cells through different phases of the cycle—thus forcing them to evolve towards a process of cell death—and accumulating cancer cells in a phase of the cell cycle—thus making it possible to target a greater number of tumor cells with a specific anticancer agent. Silymarin exerts a chemopreventive effect by inducing intrinsic and extrinsic pathways and reactivating cell death pathways by modulation of the ratio of proapoptotic/antiapoptotic proteins and synergizing with agonists of death domains receptors. In summary, we highlight how silymarin may act as a chemopreventive agent and a chemosensitizer through multiple pathways.

scholarly journals Targeting the Interplay between Cancer Metabolic Reprogramming and Cell Death Pathways as a Viable Therapeutic Path

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1942
Author(s):  
Elisabetta Iessi ◽  
Rosa Vona ◽  
Camilla Cittadini ◽  
Paola Matarrese
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Anticancer Agents ◽  
Acquired Resistance ◽  
Metabolic Reprogramming ◽  
Metabolic Characteristics ◽  
Cell Death Pathways ◽  
Therapeutic Drugs ◽  
Metabolic Adaptations ◽  
Close Relationship

In cancer cells, metabolic adaptations are often observed in terms of nutrient absorption, biosynthesis of macromolecules, and production of energy necessary to meet the needs of the tumor cell such as uncontrolled proliferation, dissemination, and acquisition of resistance to death processes induced by both unfavorable environmental conditions and therapeutic drugs. Many oncogenes and tumor suppressor genes have a significant effect on cellular metabolism, as there is a close relationship between the pathways activated by these genes and the various metabolic options. The metabolic adaptations observed in cancer cells not only promote their proliferation and invasion, but also their survival by inducing intrinsic and acquired resistance to various anticancer agents and to various forms of cell death, such as apoptosis, necroptosis, autophagy, and ferroptosis. In this review we analyze the main metabolic differences between cancer and non-cancer cells and how these can affect the various cell death pathways, effectively determining the susceptibility of cancer cells to therapy-induced death. Targeting the metabolic peculiarities of cancer could represent in the near future an innovative therapeutic strategy for the treatment of those tumors whose metabolic characteristics are known.

scholarly journals Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

Biomedicines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 169
Author(s):  
Marianna Carinci ◽  
Bianca Vezzani ◽  
Simone Patergnani ◽  
Peter Ludewig ◽  
Katrin Lessmann ◽  
...  
Keyword(s):  
Cell Death ◽  
Ischemic Stroke ◽  
Molecular Mechanisms ◽  
Mitochondrial Permeability Transition ◽  
Permeability Transition Pore ◽  
Permeability Transition ◽  
Brain Diseases ◽  
Cell Death Pathways ◽  
Molecular Pattern ◽  
Neuroprotective Strategies

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis.

scholarly journals Insights into the Role of Defective Apoptosis in Cancer Pathogenesis and Therapy

2021 ◽  
Author(s):  
Sonia Thapa ◽  
Rafiq A. Rather ◽  
Shashank K. Singh ◽  
Madhulika Bhagat
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Causative Factor ◽  
Specific Cell ◽  
Apoptotic Signaling ◽  
Antiapoptotic Proteins ◽  
Therapeutic Modalities ◽  
Oncogenic Mutations ◽  
Apoptotic Proteins

One form of programmed cell death (PCD) is apoptosis. Defective apoptosis is an indispensable causative factor in the development of cancer that allows cancer cells to survive longer and favors the accumulation of oncogenic mutations. Further, upregulation of antiapoptotic proteins (e.g., Bcl-2, Mcl-1) and loss of pro-apoptotic proteins (e.g., Bid, Bad, Bax, Bak) strongly favors apoptosis evasion. The ability of cancer cells to evade apoptosis is critical for the progression and clonal expansion of malignantly transformed cells. Defective apoptosis imparts proliferative advantage to cancer cells or cells with the potential to become cancerous. The mechanisms employed by cancer cells to evade apoptosis can be used in the strategic design of therapeutic regimens aimed at exploiting apoptotic signaling networks to ensure tumor-specific cell death. Therefore, to ensure tumor-specific cell death, we may need to exploit the expression and/or function of different components of apoptotic signaling that are critical for maintaining cell survival and are regulated differently in tumor cells than normal cells. Both inhibitors of anti-apoptotic proteins and activators of pro-apoptotic proteins can be used for cancer therapy. In this chapter, we attempted to summarize the knowledge about the molecular mechanisms of defective apoptosis that could be translated into the development of novel therapeutic agents and therapeutic modalities for cancer treatment.

scholarly journals Induction of hyperandrogenism and insulin resistance differentially modulates ferroptosis in uterine and placental tissues of pregnant rats

2020 ◽  
Author(s):  
Yuehui Zhang ◽  
Min Hu ◽  
Wenyan Jia ◽  
Guoqi Liu ◽  
Jiao Zhang ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Cell Death ◽  
Polycystic Ovary ◽  
Fetal Loss ◽  
Gravid Uterus ◽  
Mitochondrial Morphology ◽  
Pregnant Rats ◽  
Aberrant Expression ◽  
Cell Death Pathways ◽  
Increased Risk

Ferroptosis, a form of regulated necrotic cell death, plays roles in diverse physiological processes and diseases. Women with polycystic ovary syndrome (PCOS) have hyperandrogenism and insulin resistance (HAIR) and an increased risk of miscarriage and placental dysfunction during pregnancy. However, whether maternal HAIR alters mechanisms leading to ferroptosis in the gravid uterus and placenta remains unknown. Previous studies in rats showed that maternal exposure to 5α-dihydrotestosterone (DHT) and insulin (INS) from gestational day 7.5 to 13.5 induces HAIR and subsequently leads to placental insufficiency and fetal loss. We therefore hypothesized that maternal HAIR triggers ferroptosis in the uterus and placenta in association with fetal loss in pregnant rats. Compared with controls, we found that co-exposure to DHT and INS led to decreased levels of Gpx4 and glutathione (GSH), increased GSH+glutathione disulfide (GSSG) and malondialdehyde (MDA), aberrant expression of ferroptosis-associated genes (Acsl4, Tfrc, Slc7a11, and Gclc), increased iron deposition, and activated ERK/p38/JNK phosphorylation in the gravid uterus. However, in the placenta, DHT and INS exposure only partially altered the expression of ferroptosis-related markers (e.g., region-dependent Gpx4, GSH+GSSG, MDA, Gls2 and Slc7a11 mRNAs, and phosphorylated p38 levels). In the uteri co-exposed to DHT and INS, we also observed shrunken mitochondria with electron-dense cristae, which are key features of ferroptosis-related mitochondrial morphology, as well as increased expression of Dpp4, a mitochondria-encoded gene responsible for ferroptosis induction. In contrast, in placentas co-exposed to DHT and INS we found decreased expression of Dpp4 mRNA and increased expression of Cisd1 mRNA (a mitochondria-encoded iron-export factor). Further, DHT+INS-exposed pregnant rats exhibited decreased apoptosis in the uterus and increased necroptosis in the placenta. Our findings suggest that maternal HAIR causes the activation of ferroptosis in the gravid uterus and placenta, although this is mediated via different mechanisms operating at the molecular and cellular levels. Furthermore, our data suggest other cell death pathways may play a role in coordinating or compensating for HAIR-induced ferroptosis when the gravid uterus and placenta are dysfunctional.

scholarly journals The role of death domain proteins in host response upon SARS-CoV-2 infection: modulation of programmed cell death and translational applications

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Nikita V. Ivanisenko ◽  
Kamil Seyrek ◽  
Nikolay A. Kolchanov ◽  
Vladimir A. Ivanisenko ◽  
Inna N. Lavrik
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Molecular Mechanisms ◽  
Control Cell ◽  
Death Domain ◽  
Global Public Health ◽  
Cell Death Pathways ◽  
Rapid Spread ◽  
Cell Signaling Networks

Abstract The current pandemic of novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) poses a significant global public health threat. While urgent regulatory measures in control of the rapid spread of this virus are essential, scientists around the world have quickly engaged in this battle by studying the molecular mechanisms and searching for effective therapeutic strategies against this deadly disease. At present, the exact mechanisms of programmed cell death upon SARS-CoV-2 infection remain to be elucidated, though there is increasing evidence suggesting that cell death pathways play a key role in SARS-CoV-2 infection. There are several types of programmed cell death, including apoptosis, pyroptosis, and necroptosis. These distinct programs are largely controlled by the proteins of the death domain (DD) superfamily, which play an important role in viral pathogenesis and host antiviral response. Many viruses have acquired the capability to subvert the program of cell death and evade the host immune response, mainly by virally encoded gene products that control cell signaling networks. In this mini-review, we will focus on SARS-CoV-2, and discuss the implication of restraining the DD-mediated signaling network to potentially suppress viral replication and reduce tissue damage.

scholarly journals Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Antioxidants ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 309 ◽  
Author(s):  
Moran Benhar
Keyword(s):  
Cell Death ◽  
Mammalian Cells ◽  
Molecular Mechanisms ◽  
Nitrosative Stress ◽  
Neurological Diseases ◽  
Antioxidant Systems ◽  
Cell Death Pathways ◽  
Regulated Cell Death ◽  
Thiol Redox ◽  
Redox Switches

It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, nitrosative stress and dysregulated cell death are implicated in a wide variety of pathological conditions, including cancer, cardiovascular and neurological diseases. Therefore, much effort is devoted to elucidate the molecular mechanisms linking oxidant/antioxidant systems and cell death pathways. This review is focused on thiol redox modifications as a major mechanism by which oxidants and antioxidants influence specific regulated cell death pathways in mammalian cells. Growing evidence indicates that redox modifications of cysteine residues in proteins are involved in the regulation of multiple cell death modalities, including apoptosis, necroptosis and pyroptosis. In addition, recent research suggests that thiol redox switches play a role in the crosstalk between apoptotic and necrotic forms of regulated cell death. Thus, thiol-based redox circuits provide an additional layer of control that determines when and how cells die.

Vascular Stress Signaling in Hypertension

2021 ◽  
Vol 128 (7) ◽  
pp. 969-992
Author(s):  
Stephanie M. Cicalese ◽  
Josiane Fernandes da Silva ◽  
Fernanda Priviero ◽  
R. Clinton Webb ◽  
Satoru Eguchi ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Survival ◽  
Molecular Mechanisms ◽  
Mitochondrial Fission ◽  
Antioxidant Response ◽  
Intracellular Accumulation ◽  
Unfolded Protein ◽  
Cell Death Pathways ◽  
Signaling Mechanisms ◽  
Survival Signaling

Cells respond to stress by activating a variety of defense signaling pathways, including cell survival and cell death pathways. Although cell survival signaling helps the cell to recover from acute insults, cell death or senescence pathways induced by chronic insults can lead to unresolved pathologies. Arterial hypertension results from chronic physiological maladaptation against various stressors represented by abnormal circulating or local neurohormonal factors, mechanical stress, intracellular accumulation of toxic molecules, and dysfunctional organelles. Hypertension and aging share common mechanisms that mediate or prolong chronic cell stress, such as endoplasmic reticulum stress and accumulation of protein aggregates, oxidative stress, metabolic mitochondrial stress, DNA damage, stress-induced senescence, and proinflammatory processes. This review discusses common adaptive signaling mechanisms against these stresses including unfolded protein responses, antioxidant response element signaling, autophagy, mitophagy, and mitochondrial fission/fusion, STING (signaling effector stimulator of interferon genes)-mediated responses, and activation of pattern recognition receptors. The main molecular mechanisms by which the vasculature copes with hypertensive and aging stressors are presented and recent advancements in stress-adaptive signaling mechanisms as well as potential therapeutic targets are discussed.

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