scholarly journals Cancer Treatment Goes Viral: Using Viral Proteins to Induce Tumour-Specific Cell Death

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1975 ◽  
Author(s):  
Jasmine Wyatt ◽  
Manuel M. Müller ◽  
Mahvash Tavassoli
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Current Knowledge ◽  
Cancer Therapeutics ◽  
Viral Proteins ◽  
Chemotherapeutic Agents ◽  
Tumour Cells ◽  
Specific Cell ◽  
Cancer Therapies ◽  
The Past

Cell death is a tightly regulated process which can be exploited in cancer treatment to drive the killing of the tumour. Several conventional cancer therapies including chemotherapeutic agents target pathways involved in cell death, yet they often fail due to the lack of selectivity they have for tumour cells over healthy cells. Over the past decade, research has demonstrated the existence of numerous proteins which have an intrinsic tumour-specific toxicity, several of which originate from viruses. These tumour-selective viral proteins, although from distinct backgrounds, have several similar and interesting properties. Though the mechanism(s) of action of these proteins are not fully understood, it is possible that they can manipulate several cell death modes in cancer exemplifying the intricate interplay between these pathways. This review will discuss our current knowledge on the topic and outstanding questions, as well as deliberate the potential for viral proteins to progress into the clinic as successful cancer therapeutics.

scholarly journals The Role of Cancer Stem Cells in Drug Resistance in Gastroesophageal Junction Adenocarcinoma

2021 ◽  
Vol 8 ◽  
Author(s):  
Kate Dinneen ◽  
Anne-Marie Baird ◽  
Ciara Ryan ◽  
Orla Sheils
Keyword(s):  
Stem Cells ◽  
Drug Resistance ◽  
Cancer Stem Cells ◽  
Current Knowledge ◽  
Gastroesophageal Junction ◽  
Western World ◽  
Specific Cell ◽  
Cancer Therapies ◽  
Mesenchymal Transition ◽  
Anti Cancer

Gastroesophageal junction adenocarcinomas (GEJA) have dramatically increased in incidence in the western world since the mid-20th century. Their prognosis is poor, and conventional anti-cancer therapies do not significantly improve survival outcomes. These tumours are comprised of a heterogenous population of both cancer stem cells (CSC) and non-CSCs, with the former playing a crucial role in tumorigenesis, metastasis and importantly drug resistance. Due to the ability of CSCs to self-replicate indefinitely, their resistance to anti-cancer therapies poses a significant barrier to effective treatment of GEJA. Ongoing drug development programmes aim to target and eradicate CSCs, however their characterisation and thus identification is difficult. CSC regulation is complex, involving an array of signalling pathways, which are in turn influenced by a number of entities including epithelial mesenchymal transition (EMT), microRNAs (miRNAs), the tumour microenvironment and epigenetic modifications. Identification of CSCs commonly relies on the expression of specific cell surface markers, yet these markers vary between different malignancies and indeed are often co-expressed in non-neoplastic tissues. Development of targeted drug therapies against CSCs thus requires an understanding of disease-specific CSC markers and regulatory mechanisms. This review details the current knowledge regarding CSCs in GEJA, with particular emphasis on their role in drug resistance.

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.

Principles of Cancer Treatment

2010 ◽  
Author(s):  
Eric H. Rubin ◽  
William N Hait
Keyword(s):  
Drug Resistance ◽  
Nucleic Acid ◽  
Cancer Treatment ◽  
Cancer Biology ◽  
Performance Status ◽  
Cancer Therapeutics ◽  
Acid Synthesis ◽  
Chemotherapeutic Agents ◽  
Nucleic Acid Synthesis ◽  
World Health

This review is divided into three primary sections dealing with management of cancer patients, the specific basis of cancer treatment, and specific chemotherapeutic agents. The first section outlines the diagnosis, staging, performance status, and treatment of cancer. The discussion of the specific basis of cancer treatment describes cancer biology (including its transformation and proliferation, cell viability and cell death, and invasion and metastases) and the principles of cancer pharmacology. The discussion on pharmacology details dose response and schedule, drug resistance, combination chemotherapy, common toxicities, and pharmacokinetics and pharmacogenetics. Among the specific chemotherapeutic agents discussed are drugs that alter nucleic acid synthesis or function (including DNA alkylating and cross-linking agents, inhibitors of nucleic acid synthesis, and DNA topoisomerase inhibitors); antimicrotubule drugs (eg, vinca alkaloids, taxanes, and estramustine); drugs that affect growth factors, receptors, and signal transduction pathways; drugs that inhibit metastases or angiogenesis; gene-based therapies; and immunotherapies. Tables describe the World Health Organization Performance Scale and chemotherapeutic agents, and figures illustrate targets for new cancer therapeutics and mechanisms of chemotherapeutic drug resistance. This review contains 4 highly rendered figures, 2 tables, and 90 references.

Reactive Oxygen Species (ROS): Key components in Cancer Therapies

2021 ◽  
Vol 21 ◽  
Author(s):  
Biswa Mohan Sahoo ◽  
Bimal Krishna Banik ◽  
Preetismita Borah ◽  
Adya Jain
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
Hypochlorous Acid ◽  
Molecular Form ◽  
Experimental Studies ◽  
Reactive Oxygen ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
Oxygen Species ◽  
Cell Organelles

: Reactive oxygen species (ROS) refer to the highly reactive substances, which contain oxygen radicals. Hypochlorous acid, peroxides, superoxide, singlet oxygen, alpha-oxygen and hydroxyl radicals are the major examples of ROS. Generally, the reduction of oxygen (O2) in molecular form produces superoxide (•O2−) anion. ROS are produced during a variety of biochemical reactions within the cell organelles, such as endoplasmic reticulum, mitochondria and peroxisome. Naturally, ROS are also formed as a byproduct of the normal metabolism of oxygen. The production of ROS can be induced by various factors such as heavy metals, tobacco, smoke, drugs, xenobiotics, pollutants and radiation. From various experimental studies, it is reported that ROS act as either tumor suppressing or tumor promoting agent. The elevated levels of ROS can arrest the growth of tumor through the persistent increase in cell cycle inhibition. The increased level of ROS can induce apoptosis by both intrinsic and extrinsic pathways. ROS are considered to be tumor suppressing agent as the production of ROS is due to the use of most of the chemotherapeutic agents in order to activate the cell death. The cytotoxic effect of ROS provides impetus towards apoptosis, but in higher levels, ROS can cause initiation of malignancy that leads to uncontrolled cell death in cancer cells. Whereas, some species of ROS can influence various activities at the cellular level that include cell proliferation. This review highlights the genesis of ROS within cells by various routes and their role in cancer therapies.

scholarly journals At a Crossroads to Cancer: How p53-induced Cell Fate Decisions Secure Genome Integrity

2021 ◽  
Author(s):  
Dario Rizzotto ◽  
Lukas Englmaier ◽  
Andreas Villunger
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Specific Cell ◽  
Cell Type ◽  
Cell Fate Decisions

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may well be cell type and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered as critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview on multiple ways how p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems is critical to understand cell type specific cell fate induced by p53 upon its activation, in order to resolve the remaining mystery of its tumor suppressive function.

scholarly journals Nerve Growth Factor in Cancer Cell Death and Survival

Cancers ◽  
2011 ◽  
Vol 3 (1) ◽  
pp. 510-530 ◽  
Author(s):  
Niamh Molloy ◽  
Danielle Read ◽  
Adrienne Gorman
Keyword(s):  
Cell Death ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Current Knowledge ◽  
Death Receptor ◽  
Cancer Therapeutics ◽  
Aberrant Expression ◽  
Nerve Growth ◽  
Cancer Cell Death ◽  
Survival Signaling

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.

scholarly journals At a Crossroads to Cancer: How p53-Induced Cell Fate Decisions Secure Genome Integrity

2021 ◽  
Vol 22 (19) ◽  
pp. 10883
Author(s):  
Dario Rizzotto ◽  
Lukas Englmaier ◽  
Andreas Villunger
Keyword(s):  
Cell Death ◽  
Cell Fate ◽  
Target Genes ◽  
Nuclear Translocation ◽  
Current Knowledge ◽  
Cellular Transformation ◽  
Model Systems ◽  
Specific Cell ◽  
Cell Type ◽  
Cell Fate Decisions

P53 is known as the most critical tumor suppressor and is often referred to as the guardian of our genome. More than 40 years after its discovery, we are still struggling to understand all molecular details on how this transcription factor prevents oncogenesis or how to leverage current knowledge about its function to improve cancer treatment. Multiple cues, including DNA-damage or mitotic errors, can lead to the stabilization and nuclear translocation of p53, initiating the expression of multiple target genes. These transcriptional programs may be cell-type- and stimulus-specific, as is their outcome that ultimately imposes a barrier to cellular transformation. Cell cycle arrest and cell death are two well-studied consequences of p53 activation, but, while being considered critical, they do not fully explain the consequences of p53 loss-of-function phenotypes in cancer. Here, we discuss how mitotic errors alert the p53 network and give an overview of multiple ways that p53 can trigger cell death. We argue that a comparative analysis of different types of p53 responses, elicited by different triggers in a time-resolved manner in well-defined model systems, is critical to understand the cell-type-specific cell fate induced by p53 upon its activation in order to resolve the remaining mystery of its tumor-suppressive function.

scholarly journals Exploration of nilotinib enhancing the anti-leukaemic effects of Gas6 deletion in Ph+ B-ALL by inducing immunogenic cell death

2021 ◽  
Author(s):  
◽  
Carolin Wachtel
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Fusion Gene ◽  
Philadelphia Chromosome ◽  
Chemotherapeutic Agents ◽  
Tumour Cells ◽  
Immunogenic Cell Death ◽  
Tumour Immunity

Cancer is the major cause of death besides cardiovascular disease. Leukaemia represents the most prevalent malignancy in children with a frequency of 30 % and is one of the ten leading types of cancer in adults. Philadelphia Chromosome-positive B-ALL (Ph+ B-ALL) is driven by the cytogenetic aberration of the reciprocal chromosomal translocation t(9;22)(q34;q11) leading to the formation of the Philadelphia chromosome with a BCR-ABL1 fusion gene. This fusion gene encodes a BCR-ABL1 oncoprotein which is characterized by a constitutively enhanced tyrosine kinase activity promoting amplified proliferation, differentiation arrest and resistance to cell death. Ph+ B-ALL is considered the most aggressive ALL subtype with a long-term survival rate in the range of only 30 % despite intensive standard of care including chemotherapy in combination with a tyrosine kinase inhibitor (TKI) followed by allogeneic stem cell transplantation after remission for clinically fit patients. The efficacy of chemotherapy has long been mainly attributed to tumour cell toxicity while immune modulating effects have been overlooked, especially in light of known immunosuppressive properties. Accumulative evidence, however, emphasizes the ability of chemotherapeutic agents, including TKIs, to normalise or re-educate a dysfunctional tumour microenvironment (TME) resulting in enhanced anti-tumour immunity. One of the underlying mechanisms of immune modulation is the induction of immunogenic cell death (ICD). ICD is an anti-tumour agent-induced cell death modality determined by the capacity to convert cancer cells into anti-cancer vaccines. The induction of ICD relies on the release of damage-associated molecular patterns (DAMPs) from dying tumour cells succumbing to ICD. Translocation of CALR to the cell surface, extracellular secretion of ATP and release of HMGB1 from the nucleus are key hallmarks of ICD that mediate anti-tumour immunity upon binding to antigen presenting cells resulting in a tumour antigen-specific immune response. Besides these molecular determinants, ICD is functionally defined by the inhibition of tumour growth in a vaccination assay in which mice are injected with tumour cells exposed to the potential ICD inducer in-vitro and then re-challenged with live tumour cells of the same cancer type. Both molecular and functional criteria determine the gold standard approach to assess ICD. By increasing the immunogenicity of cancer cells, ICD contributes to the restoration of immunosurveillance as an essential feature of tumour rejection, which is clinically reflected by improved therapeutic efficacy and disease outcome in patients. Therefore, identifying novel ICD inducers is an objective of interest in the context of cancer therapy. In respect of these considerations, the aim addressed in the present work is the examination of the second-generation TKI Nilotinib for the ability to induce ICD. The thesis is set in the context of the group's research on the role of Gas6/TAM signalling within the TME regarding the pathogenesis of acute leukaemia. In in-vivo experiments of our research group it has been consistently observed that the use of Nilotinib enhances the anti-leukaemic immunity mediated by a deletion of Gas6. Against the background of increasing importance of chemotherapeutic agents as potent modulators of a dysregulated TME, it was hypothesized that Nilotinib may synergize with a Gas6-deficient environment by inducing ICD in Ph+ B-ALL cells. In growth inhibition and Annexin V/Propidium iodide cell death assays Nilotinib was shown to induce cell death in concentration-dependent manner that occurs bimodally in terms of cell death modality ranging between apoptosis and necrosis. By ICD marker analysis, comprising flow-cytometric detection of CALR exposure, chemoluminescence-based ATP measurement and immunoblotting for HMGB1, it was found that Nilotinib-induced cell death is not accompanied by CALR exposure and ATP secretion, but is associated with the release of HMGB1. In macrophages co-culture experiments with Nilotinib-treated leukaemic cells, no relevant shift in terms of macrophages activation and polarisation was observed in either a juxtacrine or paracrine setup. In consistency with the results obtained in the in-vitro experiments, Nilotinib was not potent to elicit a protective immune response in mice within a vaccination assay. Conclusively, Nilotinib was identified to not qualify as bona fide ICD inducer. The role of Nilotinib-induced cell death and HMGB1 release are proposed as objective for further investigation concerning the synergistic interplay between Nilotinib and a Gas6-deficient environment. Efforts addressing exploration and optimisation of the immunological potential of chemotherapeutic agents are a promising approach aimed at providing cancer patients with the best possible treatment in future.

The Link between Conventional and Novel Anti-Cancer Therapeutics with Thrombotic Microangiopathy

2021 ◽  
Vol 14 ◽  
Author(s):  
Carmen Elena Cervantes ◽  
Sam Kant ◽  
Mohamed Atta
Keyword(s):  
Kidney Disease ◽  
Thrombotic Microangiopathy ◽  
Cancer Therapeutics ◽  
Chemotherapeutic Agents ◽  
Cancer Therapies ◽  
Drug Induced ◽  
Anti Cancer ◽  
Poor Nutritional Status ◽  
Dose Dependent ◽  
Pathophysiologic Mechanisms

Background: Kidney disease associated with cancer and anti-cancer therapies has been increasingly recognized in the field of Onco-nephrology. In particular, drug-induced nephrotoxicity has necessary implications since most chemotherapeutic agents have nephrotoxic potential. Also, standard creatinine clearance methods used to measure kidney function have been questioned in cancer patients due to factors like low muscle mass and poor nutritional status. Overestimations of the glomerular filtration rate not only increase the nephrotoxic potential of different agents but also can further limit the use of first-line therapies. Objective: This review covers drug-induced thrombotic microangiopathy explicitly. It has two pathophysiologic mechanisms, including immune or idiosyncratic reactions and non-immune or dose-dependent ones. Conclusion: As novel cancer therapies are developed, it is paramount to understand better conventional and novel chemotherapeutic agents and their role in kidney disease.

Pharmacological Targeting of Ferroptosis in Cancer Treatment

2021 ◽  
Vol 21 ◽  
Author(s):  
Mehdi Rabiee Valashedi ◽  
Amirsadegh Nikoo ◽  
Nima Najafi-Ghalehlou ◽  
Kazuo Tomita ◽  
Yoshikazu Kuwahara ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Antioxidant Defense ◽  
Lipid Peroxides ◽  
Antioxidant Defense System ◽  
The Past ◽  
Regulated Cell Death ◽  
Underlying Mechanisms ◽  
Excessive Accumulation ◽  
Tumor Cell Resistance

: Ferroptosis is a non-apoptotic mode of Regulated Cell Death (RCD) driven by excessive accumulation of toxic lipid peroxides and iron overload. Ferroptosis could be triggered by inhibiting the antioxidant defense system and accumulating iron-dependent Reactive Oxygen Species (ROS) that react with polyunsaturated fatty acids in abundance. Emerging evidence over the past few years has revealed that ferroptosis is of great potential in inhibiting growth and metastasis and overcoming tumor cell resistance. Thus, targeting this form of cell death could be perceived as a potentially burgeoning approach in cancer treatment. This review briefly presents the underlying mechanisms of ferroptosis and further aims to discuss various types of existing drugs and natural compounds that could be potentially repurposed for targeting ferroptosis in tumor cells. This, in turn, will provide critical perspectives on future studies concerning ferroptosis-based cancer therapy.

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