Accumulating evidence shows that the anti-cancer potential of the immune response that can be activated by modulation of the immunogenicity of dying cancer cells. This regulated cell death process is ...called immunogenic cell death (ICD) and constitutes a new innovating anti-cancer strategy with immune-modulatory potential thanks to the release of damage-associated molecular patterns (DAMPs). Some conventional clinically-used chemotherapeutic drugs, as well as preclinically-investigated compounds of natural origins such as anthracyclines, microtubule-destabilizing agents, cardiac glycosides or hypericin derivatives, possess such an immune-stimulatory function by triggering ICD. Here, we discuss the effects of ICD inducers on the release of DAMPs and the activation of corresponding signaling pathways triggering immune recognition. We will discuss potential strategies allowing to overcome resistance mechanisms associated with this treatment approach as well as co-treatment strategies to overcome the immunosuppressive microenvironment. We will highlight the potential role of metronomic immune modulation as well as targeted delivery of ICD-inducing compounds with nanoparticles or liposomal formulations to improving the immunogenicity of ICD inducers aiming at long-term clinical benefits.
Redox changes and generation of reactive oxygen species (ROS) are part of normal cell metabolism. While low ROS levels are implicated in cellular signaling pathways necessary for survival, higher ...levels play major roles in cancer development as well as cell death signaling and execution. A role for redox changes in apoptosis has been long established; however, several new modalities of regulated cell death have been brought to light, for which the importance of ROS production as well as ROS source and targets are being actively investigated. In this review, we summarize recent findings on the role of ROS and redox changes in the activation and execution of two major forms of regulated cell death, necroptosis and ferroptosis. We also discuss the potential of using modulators of these two forms of cell death to exacerbate ROS as a promising anticancer therapy.
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•Reactive oxygen species (ROS) play dichotomous roles in the cell.•ROS involvement in cell death other than apoptosis is less clearly defined.•Necroptosis and ferroptosis are two forms of regulated cell death.•There is a potential for necroptosis and ferroptosis inducers as anticancer agents.
Cell death plays an essential role in the development of organs, homeostasis, and cancer. Apoptosis and programmed necrosis are two major types of cell death, characterized by different cell ...morphology and pathways. Accumulating evidence shows autophagy as a new alternative target to treat tumor resistance. Besides its well-known pro-survival role, autophagy can be a physiological cell death process linking apoptosis and programmed necrosis cell death pathways, by various molecular mediators.
Here, we summarize the effects of pharmacologically active compounds as modulators of different types of cancer cell death depending on the cellular context. Indeed, current findings show that both natural and synthetic compounds regulate the interplay between apoptosis, autophagy and necroptosis stimulating common molecular mediators and sharing common organelles. In response to specific stimuli, the same death signal can cause cells to switch from one cell death modality to another depending on the cellular setting.
The discovery of important interconnections between the different cell death mediators and signaling pathways, regulated by pharmacologically active compounds, presents novel opportunities for the targeted treatment of cancer. The aim of this review is to highlight the potential role of these compounds for context-specific anticancer therapy.
The immune system represents the major primary defense line against carcinogenesis and acts by identifying and eradicating nascent transformed cells. A growing body of evidence is indicating that ...aberrant epigenetic reprogramming plays a key role in tumor immune escape through: 1) impaired efficient recognition of neoplastic cells by the immune system, resulting from a downregulation or loss of the expression of tumor‐associated antigens, human leukocyte antigens, antigen processing and presenting machinery, and costimulatory molecule genes; 2) aberrant expression of immune checkpoint proteins and their ligands; and 3) modification of cytokine profiles and tumor‐associated immune cell populations toward an immunosuppressive state in the tumor microenvironment. Consistent with the inherent reversibility of epigenetic alterations, epigenetic drugs, including DNA methyltransferase and histone deacetylase inhibitors, have the unique potential to favorably modify the tumor microenvironment, restore tumor recognition and stimulate an antitumor immune response. The objective of this review is to highlight selected, naturally occurring epigenetic modulators, namely, butyrate, curcumin, (−)‐epigallocatechin‐3‐gallate, resveratrol, romidepsin, and trichostatin A, with a special focus on their antitumor immune properties.
Epigenetic‐mediated aberrant immunomodulation plays a critical role in tumor immune escape. Natural epigenetic modulators can stimulate or prime antitumor immune responses in addition to immunotherapeutic approaches.
Natural products like coumarins, chalcones, and resveratrol have inherent biological activity in several models of diseases; therefore, their natural dimeric forms are highlighted in this review and ...their key structural similarities, isolation and pharmacological significance is discussed. These natural products may be dimerized during their biosynthesis, which proceeds through atom- and energy-sufficient methods involving dimeric enzymes, to provide complex structures from simple compounds. Coumarin-derived dimers features the C–C or C–O–C biaryl, terpene sidechain linkages or by cyclobutane ring and acts as inhibitors of α-glucosidase, and cytochrome p450 while some show anti-inflammatory and anti-viral activities, while chalcone-derived dimers have the 1,3-dihydroxy phenyl (resorcinol) substitution on the periphery of cyclobutane or cyclohexane ring and inhibit topoisomerase, protein tyrosine phosphatase 1B (PTP1B), and cathepsins and others possess anti-cancer, anti-inflammatory, and anti-plasmodial activities. Resveratrol-derived dimers have the resorcinol structure and are formed by oxidative coupling showing antioxidant, neuroprotective, anti-HIV, anti-tyrosinase, and cytotoxic activity. Bioavailability evidence of closely related structural monomers could be applicable to their dimeric forms. Application of bioisosteric principles to such dimeric compounds is also discussed. Overall, these dimeric natural products can provide potent templates for the natural product-based drug discovery against several diseases.
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•Monomeric coumarins, chalcones and resveratrol have inherent biological effect on chronic diseases.•Coumarin derived dimers-inhibition of α-glucosidase, cytochrome 450 enzyme CYP3A4; can function as anti-inflammatory and anti-viral agents.•Chalcone derived dimers- inhibit topoisomerase, protein tyrosine phosphatase 1B (PTP1B), and cathepsins; function as anti-cancer, anti-inflammatory, and anti-plasmodial agents.•Anti-oxidant resveratrol derived dimeric forms- have neuroprotection, anti-HIV, anti-tyrosinase, and cytotoxic activity.•Complexity arising from simple molecules and their biological activity is discussed.
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Natural compounds act as immunoadjuvants as their therapeutic effects trigger cancer stress response and release of damage-associated molecular patterns (DAMPs). These reactions occur ...through an increase in the immunogenicity of cancer cells that undergo stress followed by immunogenic cell death (ICD). These processes result in a chemotherapeutic response with a potent immune-mediating reaction. Natural compounds that induce ICD may function as an interesting approach in converting cancer into its own vaccine. However, multiple parameters determine whether a compound can act as an ICD inducer, including the nature of the inducer, the premortem stress pathways, the cell death pathways, the intrinsic antigenicity of the cell, and the potency and availability of an immune cell response. Thus, the identification of hallmarks of ICD is important in determining the prognostic biomarkers for new therapeutic approaches and combination treatments.
Abstract
The recent search for new anti-cancer drugs focuses more on natural compounds from the regular human diet because these compounds rarely exhibit severe side-effects yet efficiently act on a ...wide range of molecular targets involved in carcinogenesis. One promising compound, which is now being tested in clinical studies, is the tomato-derived carotenoid lycopene. This review summarizes the current knowledge about the cellular action of lycopene and presents the molecular targets responsible for its remarkable chemopreventive and anti-proliferative activity. Its antioxidant effects include a considerable reactive oxygen species (ROS) scavenging activity, which allows lycopene to prevent lipid peroxidation and DNA damage. Simultaneously, lycopene induces enzymes of the cellular antioxidant defense systems by activating the antioxidant response element transcription system. As another chemopreventive strategy, lycopene increases gap junctional communication, which is suppressed during carcinogenesis. This review focuses also on the synergistic effects of lycopene with other natural antioxidants that might be important for its future application in anti-cancer treatment. Lastly, this review provides evidence for the biological activity of some oxidized lycopene metabolites, which seem to be partially responsible for the strong and manifold anti-cancer potential of lycopene.
Immune checkpoint inhibitors (ICIs) are an expanding class of immunotherapeutic agents with the potential to cure cancer. Despite the outstanding clinical response in patient subsets, most ...individuals become refractory or develop resistance. Patient stratification and personalized immunotherapies are limited by the absence of predictive response markers. Recent findings show that dominant patterns of immune cell composition, T-cell status and heterogeneity, and spatiotemporal distribution of immune cells within the tumor microenvironment (TME) are becoming essential determinants of prognosis and therapeutic response. In this context, ICIs also function as investigational tools and proof of concept, allowing the validation of the identified mechanisms. After reviewing the current state of ICIs, this article will explore new comprehensive predictive markers for ICIs based on recent discoveries. We will discuss the recent establishment of a classification of TMEs into immune archetypes as a tool for personalized immune profiling, allowing patient stratification before ICI treatment. We will discuss the developing comprehension of T-cell diversity and its role in shaping the immune profile of patients. We describe the potential of strategies that score the mutual spatiotemporal modulation between T-cells and other cellular components of the TME. Additionally, we will provide an overview of a range of synthetic and naturally occurring or derived small molecules. We will compare compounds that were recently identified by in silico prediction to wet lab-validated drug candidates with the potential to function as ICIs and/or modulators of the cellular components of the TME.
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•Immune checkpoints can lead to resistance and inability to respond to ICIs.•Diversified TME immune profiles determine ICI response.•Cellular heterogeneity shapes patients’ immune landscape.•Intratumoral spatiotemporal distribution of T-cells is a valuable prognostic indicator.•ICIs can be replaced by small molecules as an alternative to monoclonal antibodies.
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