For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism t Show more
For decades, great strides have been made in the field of immunometabolism. A plethora of evidence ranging from basic mechanisms to clinical transformation has gradually embarked on immunometabolism to the center stage of innate and adaptive immunomodulation. Given this, we focus on changes in immunometabolism, a converging series of biochemical events that alters immune cell function, propose the immune roles played by diversified metabolic derivatives and enzymes, emphasize the key metabolism-related checkpoints in distinct immune cell types, and discuss the ongoing and upcoming realities of clinical treatment. It is expected that future research will reduce the current limitations of immunotherapy and provide a positive hand in immune responses to exert a broader therapeutic role. Show less
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical inv Show more
Mitochondria are central actors in diverse physiological phenomena ranging from energy metabolism to stress signaling and immune modulation. Accumulating scientific evidence points to the critical involvement of specific mitochondrial-associated events, including mitochondrial quality control, intercellular mitochondrial transfer, and mitochondrial genetics, in potentiating the metastatic cascade of neoplastic cells. Furthermore, numerous recent studies have consistently emphasized the highly significant role mitochondria play in coordinating the regulation of tumor-infiltrating immune cells and immunotherapeutic interventions. This review provides a comprehensive and rigorous scholarly investigation of this subject matter, exploring the intricate mechanisms by which mitochondria contribute to tumor metastasis and examining the progress of mitochondria-targeted cancer therapies. Show less
Background Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a the Show more
Background Hypoxia is a common feature of many solid tumors and causes radiotherapy and immunotherapy resistance. Pharmacological inhibition of oxidative phosphorylation (OXPHOS) has emerged as a therapeutic strategy to reduce hypoxia. However, the OXPHOS inhibitors tested in clinical trials caused only moderate responses in hypoxia alleviation or trials were terminated due to dose-limiting toxicities. To improve the therapeutic benefit, FDA approved OXPHOS inhibitors (e.g. atovaquone) were conjugated to triphenylphosphonium (TPP + ) to preferentially target cancer cellâs mitochondria. In this study, we evaluated the hypoxia reducing effects of several mitochondria-targeted OXPHOS inhibitors and compared them to non-mitochondria-targeted OXPHOS inhibitors using newly developed spheroid models for diffusion-limited hypoxia. Methods B16OVA murine melanoma cells and MC38 murine colon cancer cells expressing a HIF-Responsive Element (HRE)-induced Green Fluorescent Protein (GFP) with an oxygen-dependent degradation domain (HRE-eGFP-ODD) were generated to assess diffusion-limited hypoxia dynamics in spheroids. Spheroids were treated with IACS-010759, atovaquone, metformin, tamoxifen or with mitochondria-targeted atovaquone (Mito-ATO), PEGylated mitochondria-targeted atovaquone (Mito-PEG-ATO) or mitochondria-targeted tamoxifen (MitoTam). Hypoxia dynamics were followed and quantified over time using the IncuCyte Zoom Live Cell-Imaging system. Results Hypoxic cores developed in B16OVA.HRE and MC38.HRE spheroids within 24Â h hours after seeding. Treatment with IACS-010759, metformin, atovaquone, Mito-PEG-ATO and MitoTam showed a dose-dependent reduction of hypoxia in both B16OVA.HRE and MC38.HRE spheroids. Mito-ATO only alleviated hypoxia in MC38.HRE spheroids while tamoxifen was not able to reduce hypoxia in any of the spheroid models. The mitochondria-targeted OXPHOS inhibitors demonstrated stronger anti-hypoxic effects compared to the non-mito-targeted OXPHOS inhibitors. Conclusions We successfully developed a high-throughput spheroid model in which hypoxia dynamics can be quantified over time. Using this model, we showed that the mitochondria-targeted OXPHOS inhibitors Mito-ATO, Mito-PEG-ATO and MitoTam reduce hypoxia in tumor cells in a dose-dependent manner, potentially sensitizing hypoxic tumor cells for radiotherapy. Supplementary Information The online version contains supplementary material available at 10.1186/s40170-024-00342-6. Show less
Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most im Show more
Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its presence to the patientâs prognosis in order to analyse which of the two opposing functions of mitochondria dominates during the malignant progression of ovarian cancer. Monoclonal antibodies directed against different mitochondrial specific proteins, namely heat shock proteins 60 (HSP60), fumarase and succinic dehydrogenase, were used in immunohistochemistry in preliminary experiments to identify the antibody most suited to detect mitochondria in ovarian cancer cells in clinical tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the anti-HSP60 antibody, which was used for the subsequent clinical study staining primary ovarian cancers ( n â=â155), borderline tumours ( n â=â24) and recurrent ovarian cancers ( n â=â26). The staining results were semi-quantitatively scored into three groups according to their mitochondrial content: low ( n â=â26), intermediate ( n â=â50) and high ( n â=â84). Survival analysis showed that high mitochondrial content correlated with a statistically significant overall reduced survival rate In addition to the clinical tissue samples, mitochondrial content was analysed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and COV644) and in vivo in severe combined immunodeficiency (SCID) mice. In in vivo grown SKOV3 and OVCAR8 cells, the number of mitochondria positive cells was markedly down-regulated compared to the in vitro grown cells indicating that mitochondrial number is subject to regulatory processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitochondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitochondrial content is highly adaptable to the growth condition of the cancer cells. Show less
We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not nor Show more
We have designed cell-penetrating peptides that target the leucine zipper transcription factors ATF5, CEBPB and CEBPD and that promote apoptotic death of a wide range of cancer cell types, but not normal cells, in vitro and in vivo. Though such peptides have the potential for clinical application, their mechanisms of action are not fully understood. Here, we show that one such peptide, Dpep, compromises glucose uptake and glycolysis in a cell context-dependent manner (in about two-thirds of cancer lines assessed). These actions are dependent on induction of tumor suppressor TXNIP (thioredoxin-interacting protein) mRNA and protein. Knockdown studies show that TXNIP significantly contributes to apoptotic death in those cancer cells in which it is induced by Dpep. The metabolic actions of Dpep on glycolysis led us to explore combinations of Dpep with clinically approved drugs metformin and atovaquone that inhibit oxidative phosphorylation and that are in trials for cancer treatment. Dpep showed additive to synergistic activities in all lines tested. In summary, we find that Dpep induces TXNIP in a cell context-dependent manner that in turn suppresses glucose uptake and glycolysis and contributes to apoptotic death of a range of cancer cells. Show less
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the i Show more
Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases. Show less
Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to th Show more
Cancer, the world's second leading cause of death after cardiovascular diseases, is characterized by hallmarks such as uncontrolled cell growth, metastasis, angiogenesis, hypoxia, and resistance to therapy. Autophagy, a cellular process that can both support and inhibit cancer progression, plays a critical role in cancer development and progression. This process involves the formation of autophagosomes that ultimately fuse with lysosomes to degrade cellular components. A key regulator of this process is Sirtuin 1 (SIRT1), which significantly influences autophagy. This review delves into the role of SIRT1 in modulating autophagy and its broader impacts on carcinogenesis. SIRT1 regulates crucial autophagy mediators, such as AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR), effectively promoting or suppressing autophagy. Beyond its direct effects on autophagy, SIRT1's regulatory actions extend to other cell death processes, including apoptosis and ferroptosis, thereby influencing tumor cell proliferation, metastasis, and chemotherapy responses. These insights underscore the complex interplay between SIRT1 and autophagy, with significant implications for cancer therapy. Targeting SIRT1 and its associated pathways presents a promising strategy to manipulate autophagy in cancer treatment. This review underscores the potential of SIRT1 as a therapeutic target, opening new avenues for enhancing cancer treatment efficacy. Show less
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000 Show more
Colorectal cancer (CRC) is the third most common cancer worldwide, and the second most common cause of cancer-related death. In 2020, the estimated number of deaths due to CRC was approximately 930000, accounting for 10% of all cancer deaths worldwide. Accordingly, there is a vast amount of ongoing research aiming to find new and improved treatment modalities for CRC that can potentially increase survival and decrease overall morbidity and mortality. Current management strategies for CRC include surgical procedures for resectable cases, and radiotherapy, chemotherapy, and immunotherapy, in addition to their combination, for non-resectable tumors. Despite these options, CRC remains incurable in 50% of cases. Nonetheless, significant improvements in research techniques have allowed for treatment approaches for CRC to be frequently updated, leading to the availability of new drugs and therapeutic strategies. This review summarizes the most recent therapeutic approaches for CRC, with special emphasis on new strategies that are currently being studied and have great potential to improve the prognosis and lifespan of patients with CRC. Show less
Abstract Ferroptosis is a new form of regulated cell death featuring ironâdependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosisâ Show more
Abstract Ferroptosis is a new form of regulated cell death featuring ironâdependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosisâbased cancer therapy in eradicating refractory malignancies that are resistant to apoptosisâbased conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosisârelated signaling pathways. Encouraged by the rapid development of ferroptosisâdriven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosisâinduced tumor therapy, including metal complexes, metalâbased nanoparticles, and metalâfree nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted. Show less
DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its Show more
DNA structure has many potential places where endogenous compounds and xenobiotics can bind. Therefore, xenobiotics bind along the sites of the nucleic acid with the aim of changing its structure, its genetic message, and, implicitly, its functions. Currently, there are several mechanisms known to be involved in DNA binding. These mechanisms are covalent and non-covalent interactions. The covalent interaction or metal base coordination is an irreversible binding and it is represented by an intra-/interstrand cross-link. The non-covalent interaction is generally a reversible binding and it is represented by intercalation between DNA base pairs, insertion, major and/or minor groove binding, and electrostatic interactions with the sugar phosphate DNA backbone. In the present review, we focus on the types of DNAâmetal complex interactions (including some representative examples) and on presenting the methods currently used to study them. Show less
Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for Show more
Drug resistance remains a major challenge in cancer treatment, necessitating the development of novel strategies to overcome it. Protein arginine methyltransferases (PRMTs) are enzymes responsible for epigenetic arginine methylation, which regulates various biological and pathological processes, as a result, they are attractive therapeutic targets for overcoming anti-cancer drug resistance. The ongoing development of small molecules targeting PRMTs has resulted in the generation of chemical probes for modulating most PRMTs and facilitated clinical treatment for the most advanced oncology targets, including PRMT1 and PRMT5. In this review, we summarize various mechanisms underlying protein arginine methylation and the roles of specific PRMTs in driving cancer drug resistance. Furthermore, we highlight the potential clinical implications of PRMT inhibitors in decreasing cancer drug resistance. PRMTs promote the formation and maintenance of drug-tolerant cells via several mechanisms, including altered drug efflux transporters, autophagy, DNA damage repair, cancer stem cell-related function, epithelial-mesenchymal transition, and disordered tumor microenvironment. Multiple preclinical and ongoing clinical trials have demonstrated that PRMT inhibitors, particularly PRMT5 inhibitors, can sensitize cancer cells to various anti-cancer drugs, including chemotherapeutic, targeted therapeutic, and immunotherapeutic agents. Combining PRMT inhibitors with existing anti-cancer strategies will be a promising approach for overcoming anti-cancer drug resistance. Furthermore, enhanced knowledge of the complex functions of arginine methylation and PRMTs in drug resistance will guide the future development of PRMT inhibitors and may help identify new clinical indications. Show less
In this study, a new ligand, 5-(4-pyrimidinecarboxamido)-1H-tetrazol (4-H2pat), was synthesized by connecting the pyrimidine group and tetrazole group through an amide bond for the first time, Show more
In this study, a new ligand, 5-(4-pyrimidinecarboxamido)-1H-tetrazol (4-H2pat), was synthesized by connecting the pyrimidine group and tetrazole group through an amide bond for the first time, aiming to construct new POM-based metalâorganic complexes (POMOCs). By using the ligand 4-H2pat, two new POMOCs, [Cu4(4-pat)2(ÎŒ2-OH)(CrMo6(OH)6O18)(H2O)3]·2H2O (1) and [Cu2(4-pat)(ÎČ-Mo8O26)0.5(H2O)3] (2), were successfully synthesized under solvothermal and hydrothermal conditions, respectively. The structures were characterized by single crystal X-ray diffraction analysis, IR spectroscopy and powder X-ray diffraction (PXRD). In complex 1, the 1D [Cu4(ÎŒ2-OH)(4-pat)2]n3n+ metalâorganic chains were connected by ÎŒ2-bridging [CrMo6(OH)6O18]3â (CrMo6) anions to construct a 2D layered structure. In complex 2, the 2D [Cu2(4-pat)]n2n+ metalâorganic grid framework was consolidated by the ÎŒ4-bridging [ÎČ-Mo8O26]4â (Mo8) anions. The use of two different POM anion clusters results in the formation of two diverse 2D framework structures. Complexes 1 and 2 can effectively catalyze the oxidation of methyl phenyl sulfide as non-homogeneous catalysts with 97% and 95% conversions, respectively. They can also be used as electrocatalysts to prepare bulk-modified electrodes for detecting Cr(VI) and Fe(III) ions with low detection limits. In addition, the effects of different POMs on the structures and catalytic/electrocatalytic performances of the title complexes were discussed.
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The application of artificial intelligence (AI) has been considered a revolutionary change in drug discovery and development. In 2020, the AlphaFold computer program predicted protein structur Show more
The application of artificial intelligence (AI) has been considered a revolutionary change in drug discovery and development. In 2020, the AlphaFold computer program predicted protein structures for the whole human genome, which has been considered a remarkable breakthrough in both AI applications and structural biology. Despite the varying confidence levels, these predicted structures could still significantly contribute to structure-based drug design of novel targets, especially the ones with no or limited structural information. In this work, we successfully applied AlphaFold to our end-to-end AI-powered drug discovery engines, including a biocomputational platform PandaOmics and a generative chemistry platform Chemistry42. A novel hit molecule against a novel target without an experimental structure was identified, starting from target selection towards hit identification, in a cost- and time-efficient manner. PandaOmics provided the protein of interest for the treatment of hepatocellular carcinoma (HCC) and Chemistry42 generated the molecules based on the structure predicted by AlphaFold, and the selected molecules were synthesized and tested in biological assays. Through this approach, we identified a small molecule hit compound for cyclin-dependent kinase 20 (CDK20) with a binding constant Kd value of 9.2 ± 0.5 ΌM (n = 3) within 30 days from target selection and after only synthesizing 7 compounds. Based on the available data, a second round of AI-powered compound generation was conducted and through this, a more potent hit molecule, ISM042-2-048, was discovered with an average Kd value of 566.7 ± 256.2 nM (n = 3). Compound ISM042-2-048 also showed good CDK20 inhibitory activity with an IC50 value of 33.4 ± 22.6 nM (n = 3). In addition, ISM042-2-048 demonstrated selective anti-proliferation activity in an HCC cell line with CDK20 overexpression, Huh7, with an IC50 of 208.7 ± 3.3 nM, compared to a counter screen cell line HEK293 (IC50 = 1706.7 ± 670.0 nM). This work is the first demonstration of applying AlphaFold to the hit identification process in drug discovery.
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Platinum-based drugs have revolutionized cancer chemotherapy; however, their therapeutic efficacy has been limited by severe side effects and drug resistance. Recently, approaches that target Show more
Platinum-based drugs have revolutionized cancer chemotherapy; however, their therapeutic efficacy has been limited by severe side effects and drug resistance. Recently, approaches that target specific organelles in cancer cells have emerged as attractive alternatives to overcome these challenges. Many studies have validated these strategies and highlighted that organelle-targeted platinum complexes demonstrate increased anticancer activity, the ability to overcome drug resistance, novel molecular mechanisms, or even lower toxicity. This review provides a brief summary of various organelle-targeting strategies that promote the accumulation of platinum complexes in certain intracellular areas, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. Moreover, the mechanisms through which these strategies improve anticancer performance, overcome drug resistance, and alter the action mode of conventional platinum drugs are discussed. By providing an extensive account of platinum complexes targeting different organelles, this review aims to assist researchers in understanding the design principles, identifying potential targets, and fostering innovative ideas for the development of platinum complexes.
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Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, Show more
Lung cancer is a common malignant tumor that occurs in the human body and poses a serious threat to human health and quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, and radiotherapy. However, due to the strong metastatic characteristics of lung cancer and the emergence of related drug resistance and radiation resistance, the overall survival rate of lung cancer patients is not ideal. There is an urgent need to develop new treatment strategies or new effective drugs to treat lung cancer. Ferroptosis, a novel type of programmed cell death, is different from the traditional cell death pathways such as apoptosis, necrosis, pyroptosis and so on. It is caused by the increase of iron-dependent reactive oxygen species due to intracellular iron overload, which leads to the accumulation of lipid peroxides, thus inducing cell membrane oxidative damage, affecting the normal life process of cells, and finally promoting the process of ferroptosis. The regulation of ferroptosis is closely related to the normal physiological process of cells, and it involves iron metabolism, lipid metabolism, and the balance between oxygen-free radical reaction and lipid peroxidation. A large number of studies have confirmed that ferroptosis is a result of the combined action of the cellular oxidation/antioxidant system and cell membrane damage/repair, which has great potential application in tumor therapy. Therefore, this review aims to explore potential therapeutic targets for ferroptosis in lung cancer by clarifying the regulatory pathway of ferroptosis. Based on the study of ferroptosis, the regulation mechanism of ferroptosis in lung cancer was understood and the existing chemical drugs and natural compounds targeting ferroptosis in lung cancer were summarized, with the aim of providing new ideas for the treatment of lung cancer. In addition, it also provides the basis for the discovery and clinical application of chemical drugs and natural compounds targeting ferroptosis to effectively treat lung cancer. Show less
NRF2 (nuclear factor erythroid 2-related factor 2) is a master regulator of protective responses in healthy tissues. However, when it is active in tumor cells, it can result in drug resistance. KEAP1, Show more
NRF2 (nuclear factor erythroid 2-related factor 2) is a master regulator of protective responses in healthy tissues. However, when it is active in tumor cells, it can result in drug resistance. KEAP1, the endogenous NRF2 inhibitor, binds NRF2 and redirects it to proteasomal degradation, so the KEAP1/NRF2 interaction is critical for maintaining NRF2 at a basal level. A number of clinically relevant KEAP1 mutations were shown to disrupt this critical KEAP1/NRF2 interaction, leading to elevated NRF2 levels and drug resistance. Here, we describe a small-molecule NRF2 inhibitor, R16, that selectively binds KEAP1 mutants and restores their NRF2-inhibitory function by repairing the disrupted KEAP1/NRF2 interactions. R16 substantially sensitizes KEAP1-mutated tumor cells to cisplatin and gefitinib, but does not do so for wild-type KEAP1 cells, and sensitizes KEAP1 G333C-mutated xenograft to cisplatin. We developed a BRET2-based biosensor system to detect the KEAP1/NRF2 interaction and classify KEAP1 mutations. This strategy would identify drug-resistant KEAP1 somatic mutations in clinical molecular profiling of tumors. Show less
p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by Show more
p97 is a ubiquitin-targeted ATP-dependent segregase that regulates proteostasis, in addition to a variety of other cellular functions. Previously, we demonstrated that p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex, facilitating proteasomal destruction. In the current study, we identified p97 as an NRF2-target gene that contains a functional ARE, indicating the presence of an NRF2-p97-NRF2 negative feedback loop that maintains redox homeostasis. Using CRISPR/Cas9 genome editing, we generated endogenous p97 ARE-mutated BEAS-2B cell lines. These p97 ARE-mutated cell lines exhibit altered expression of p97 and NRF2, as well as a compromised response to NRF2 inducers. Importantly, we also found a positive correlation between NRF2 activation and p97 expression in human cancer patients. Finally, using chronic arsenic-transformed cell lines, we demonstrated a synergistic effect of NRF2 and p97 inhibition in killing cancer cells with high NRF2 and p97 expression. Our study suggests dual upregulation of NRF2 and p97 occurs in certain types of cancers, suggesting that inhibition of both NRF2 and p97 could be a promising treatment strategy for stratified cancer patients. Show less
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly i Show more
Abstract Imaging contrast agents are widely investigated in preclinical and clinical studies, among which biogenic imaging contrast agents (BICAs) are developing rapidly and playing an increasingly important role in biomedical research ranging from subcellular level to individual level. The unique properties of BICAs, including expression by cells as reporters and specific genetic modification, facilitate various in vitro and in vivo studies, such as quantification of gene expression, observation of protein interactions, visualization of cellular proliferation, monitoring of metabolism, and detection of dysfunctions. Furthermore, in human body, BICAs are remarkably helpful for disease diagnosis when the dysregulation of these agents occurs and can be detected through imaging techniques. There are various BICAs matched with a set of imaging techniques, including fluorescent proteins for fluorescence imaging, gas vesicles for ultrasound imaging, and ferritin for magnetic resonance imaging. In addition, bimodal and multimodal imaging can be realized through combining the functions of different BICAs, which helps overcome the limitations of monomodal imaging. In this review, the focus is on the properties, mechanisms, applications, and future directions of BICAs. Show less
Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria- Show more
Introduction: Drugs targeting mitochondria are emerging as promising antitumor therapeutics in preclinical models. However, a few of these drugs have shown clinical toxicity. Developing mitochondria-targeted modified natural compounds and US FDA-approved drugs with increased therapeutic index in cancer is discussed as an alternative strategy. Areas Covered: Triphenylphosphonium cation (TPP + )-based drugs selectively accumulate in the mitochondria of cancer cells due to their increased negative membrane potential, target the oxidative phosphorylation proteins, inhibit mitochondrial respiration, and inhibit tumor proliferation. TPP + -based drugs exert minimal toxic side effects in rodents and humans. These drugs can sensitize radiation and immunotherapies. Expert Opinion: TPP + -based drugs targeting the tumor mitochondrial electron transport chain are a new class of oxidative phosphorylation inhibitors with varying antiproliferative and antimetastatic potencies. Some of these TPP + -based agents, which are synthesized from naturally occurring molecules and FDA-approved drugs, have been tested in mice and did not show notable toxicity, including neurotoxicity, when used at doses under the maximally tolerated dose. Thus, more effort should be directed toward the clinical translation of TPP + -based OXPHOS-inhibiting drugs in cancer prevention and treatment. Show less
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we re Show more
Developing novel therapeutics often follows three steps: target identification, design of strategies to suppress target activity and drug development to implement the strategies. In this review, we recount the evidence identifying the basic leucine zipper transcription factors ATF5, CEBPB, and CEBPD as targets for brain and other malignancies. We describe strategies that exploit the structures of the three factors to create inhibitory dominant-negative (DN) mutant forms that selectively suppress growth and survival of cancer cells. We then discuss and compare four peptides (CP-DN-ATF5, Dpep, Bpep and ST101) in which DN sequences are joined with cell-penetrating domains to create drugs that pass through tissue barriers and into cells. The peptide drugs show both efficacy and safety in suppressing growth and in the survival of brain and other cancers in vivo, and ST101 is currently in clinical trials for solid tumors, including GBM. We further consider known mechanisms by which the peptides act and how these have been exploited in rationally designed combination therapies. We additionally discuss lacunae in our knowledge about the peptides that merit further research. Finally, we suggest both short- and long-term directions for creating new generations of drugs targeting ATF5, CEBPB, CEBPD, and other transcription factors for treating brain and other malignancies. Show less
The Zα domain has a compact α/ÎČ architecture containing a three-helix bundle flanked on one side by a twisted antiparallel ÎČ sheet. This domain displays a specific affinity for double-stranded nucleic Show more
The Zα domain has a compact α/ÎČ architecture containing a three-helix bundle flanked on one side by a twisted antiparallel ÎČ sheet. This domain displays a specific affinity for double-stranded nucleic acids that adopt a left-handed helical conformation. Currently, only three Zα-domain proteins have been identified in eukaryotes, specifically ADAR1, ZBP1, and PKZ. ADAR1 is a double-stranded RNA (dsRNA) binding protein that catalyzes the conversion of adenosine residues to inosine, resulting in changes in RNA structure, function, and expression. In addition to its editing function, ADAR1 has been shown to play a role in antiviral defense, gene regulation, and cellular differentiation. Dysregulation of ADAR1 expression and activity has been associated with various disease states, including cancer, autoimmune disorders, and neurological disorders. As a sensing molecule, ZBP1 exhibits the ability to recognize nucleic acids with a left-handed conformation. ZBP1 harbors a RIP homotypic interaction motif (RHIM), composed of a highly charged surface region and a leucine-rich hydrophobic core, enabling the formation of homotypic interactions between proteins with similar structure. Upon activation, ZBP1 initiates a downstream signaling cascade leading to programmed cell death, a process mediated by RIPK3 via the RHIM motif. PKZ was identified in fish, and contains two Zα domains at the N-terminus. PKZ is essential for normal growth and development and may contribute to the regulation of immune system function in fish. Interestingly, some pathogenic microorganisms also encode Zα domain proteins, such as, Vaccinia virus and Cyprinid Herpesvirus. Zα domain proteins derived from pathogenic microorganisms have been demonstrated to be pivotal contributors in impeding the host immune response and promoting virus replication and spread. This review focuses on the mammalian Zα domain proteins: ADAR1 and ZBP1, and thoroughly elucidates their functions in the immune response. Show less
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntingtonâs di Show more
Parthanatos is a form of regulated cell death involved in the pathogenesis of many diseases, particularly neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntingtonâs disease, and amyotrophic lateral sclerosis. Parthanatos is a multistep cell death pathway cascade that involves poly (ADP-ribose) polymerase 1 (PARP-1) overactivation, PAR accumulation, PAR binding to apoptosis-inducing factor (AIF), AIF release from the mitochondria, nuclear translocation of the AIF/macrophage migration inhibitory factor (MIF) complex, and MIF-mediated large-scale DNA fragmentation. All the key players in the parthanatos pathway are pleiotropic proteins with diverse functions. An in-depth understanding of the structure-based activity of the key factors, and the biochemical mechanisms of parthanatos, is crucial for the development of drugs and therapeutic strategies. In this review, we delve into the key players of the parthanatos pathway and reveal the multiple levels of therapeutic opportunities for treating parthanatos-based pathogenesis. Show less
Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based t Show more
Metal complexes have demonstrated significant antitumor activities and platinum complexes are well established in the clinical application of cancer chemotherapy. However, the platinum-based treatment of different types of cancers is massively hampered by severe side effects and resistance development. Consequently, the development of novel metal-based drugs with different mechanism of action and pharmaceutical profile attracts modern medicinal chemists to design and synthesize novel metal-based agents. Among non-platinum anticancer drugs, gold complexes have gained considerable attention due to their significant antiproliferative potency and efficacy. In most situations, the gold complexes exhibit anticancer activities by targeting thioredoxin reductase (TrxR) or other thiol-rich proteins and enzymes and trigger cell death via reactive oxygen species (ROS). Interestingly, gold complexes were recently reported to elicit biochemical hallmarks of immunogenic cell death (ICD) as an ICD inducer. In this review, the recent progress of gold(I) and gold(III) complexes is comprehensively summarized, and their activities and mechanism of action are documented.
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Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary coordination sphere must play an import Show more
Metalloenzymes catalyze a variety of reactions using a limited number of natural amino acids and metallocofactors. Therefore, the environment beyond the primary coordination sphere must play an important role in both conferring and tuning their phenomenal catalytic properties, enabling active sites with otherwise similar primary coordination environments to perform a diverse array of biological functions. However, since the interactions beyond the primary coordination sphere are numerous and weak, it has been difficult to pinpoint structural features responsible for the tuning of activities of native enzymes. Designing artificial metalloenzymes (ArMs) offers an excellent basis to elucidate the roles of these interactions and to further develop practical biological catalysts. In this review, we highlight how the secondary coordination spheres of ArMs influence metal binding and catalysis, with particular focus on the use of native protein scaffolds as templates for the design of ArMs by either rational design aided by computational modeling, directed evolution, or a combination of both approaches. In describing successes in designing heme, nonheme Fe, and Cu metalloenzymes, heteronuclear metalloenzymes containing heme, and those ArMs containing other metal centers (including those with non-native metal ions and metallocofactors), we have summarized insights gained on how careful controls of the interactions in the secondary coordination sphere, including hydrophobic and hydrogen bonding interactions, allow the generation and tuning of these respective systems to approach, rival, and, in a few cases, exceed those of native enzymes. We have also provided an outlook on the remaining challenges in the field and future directions that will allow for a deeper understanding of the secondary coordination sphere a deeper understanding of the secondary coordintion sphere to be gained, and in turn to guide the design of a broader and more efficient variety of ArMs. Show less
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potenti Show more
The elucidation of a compound's Mechanism of Action (MoA) is a challenging task in the drug discovery process, but it is important in order to rationalise phenotypic findings and to anticipate potential side-effects. Bioinformatic approaches, advances in machine learning techniques and the increasing deposition of high-throughput data in public databases have significantly contributed to recent advances in the field, but it is not straightforward to decide which data and methods are most suitable to use in a given case. In this review, we focus on these methods and data and their applications in generating MoA hypotheses for subsequent experimental validation. We discuss compound-specific data such as -omics, cell morphology and bioactivity data, as well as commonly used supplementary prior knowledge such as network and pathway data, and provide information on databases where this data can be accessed. In terms of methodologies, we discuss both well-established methods (connectivity mapping, pathway enrichment) as well as more developing methods (neural networks and multi-omics integration). Finally, we review case studies where the MoA of a compound was successfully suggested from computational analysis by incorporating multiple data modalities and/or methodologies. Our aim for this review is to provide researchers with insights into the benefits and drawbacks of both the data and methods in terms of level of understanding, biases and interpretation â and to highlight future avenues of investigation which we foresee will improve the field of MoA elucidation, including greater public access to -omics data and methodologies which are capable of data integration. Show less