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In recent decades, cancer has posed a challenging obstacle that humans strive to overcome. While phototherapy and immunotherapy are two emerging therapies compared to traditional methods, they each have their advantages and limitations. These limitations include easy metastasis and recurrence, low response rates, and strong side effects. To address these issues, researchers have increasingly focused on combining these two therapies by utilizing a nano-drug delivery system due to its superior targeting effect and high drug loading rate, yielding remarkable results. The combination therapy demonstrates enhanced response efficiency and effectiveness, leading to a preparation that is highly targeted, responsive, and with low recurrence rates. This paper reviews several main mechanisms of anti-tumor effects observed in combination therapy based on the nano-drug delivery system over the last five years. Furthermore, the challenges and future prospects of this combination therapy are also discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic disease is the leading cause of cancer-related morbidity and mortality, accounting for over 80% of cancer deaths. Recent studies have introduced and refined several theories on cancer metastasis, including ghost mitochondria (GM), vasculogenic mimicry (VM), and the formation of polyploid giant cancer cells (PGCCs). Understanding the complex processes of cancer metastasis is crucial for developing effective treatment options. The capacity of cancer cells to migrate from a primary tumor, disseminate throughout the body, and eventually establish secondary tumors is a fundamental aspect of metastasis. A detailed understanding of the cellular and molecular mechanisms underpinning this multifaceted process would facilitate the rational development of therapies aimed at treating metastatic disease. Although various hypotheses and models have been proposed, no single concept fully explains the mechanism of metastasis or integrates all observations and experimental findings. Recent advancements in metastasis research have refined existing theories and introduced new ones. This review evaluates several novel/emerging theories, focusing on ghost mitochondria (GM), vasculogenic mimicry (VM), and polyploid giant cancer cells (PGCCs). [ABSTRACT FROM AUTHOR]

Deubiquitinating enzymes (DUBs) prevent ubiquitination by eliminating ubiquitin from their substrates. Deubiquitinating enzymes have important roles in a number of cell biology subfields that are highly relevant to diseases like neurodegeneration, cancer, autoimmune disorders, and long-term inflammation. Deubiquitinating enzymes feature a well-defined active site and, for the most part, catalytic cysteine, which makes them appealing targets for small-molecule drug development. Ubiquitin-specific protease 46 (USP46) is a member of the ubiquitin-specific protease family, the largest subfamily of DUBs. Over the past 10 years, some studies have steadily demonstrated the significance of USP46 in several biological processes, although it was identified later and early research progress was modest. Specifically, in the last few years, the carcinogenic properties of USP46 have become more apparent. In the current review, we provide a comprehensive overview of the current knowledge about USP46 including its characteristics, structure, inhibitors, function in diseases, especially in the nervous system, and the correlation of USP46 with cancers. [ABSTRACT FROM AUTHOR]

T-cell acute lymphoblastic leukemia (T-ALL) is a challenging childhood cancer to treat, with limited therapeutic options and high relapse rates. This study explores deamidated triosephosphate isomerase (dTPI) as a novel therapeutic target. We hypothesized that selectively inhibiting dTPI could reduce T-ALL cell viability without affecting normal T lymphocytes. Computational modeling and recombinant enzyme assays revealed that disulfiram (DS) and curcumin (CU) selectively bind and inhibit dTPI activity without affecting the non-deamidated enzyme. At the cellular level, treatment with DS and CU significantly reduced Jurkat T-ALL cell viability and endogenous TPI enzymatic activity, with no effect on normal T lymphocytes, whereas the combination of sodium dichloroacetate (DCA) with DS or CU showed synergistic effects. Furthermore, we demonstrated that dTPI was present and accumulated only in Jurkat cells, confirming our hypothesis. Finally, flow cytometry confirmed apoptosis in Jurkat cells after treatment with DS and CU or their combination with DCA. These findings strongly suggest that targeting dTPI represents a promising and selective target for T-ALL therapy. [ABSTRACT FROM AUTHOR]

Background: Despite advancements in cancer treatment, chemotherapy side effects significantly impact patients both physically and emotionally. While pharmacological treatments can mitigate these side effects, they may trigger additional side effects, exacerbating the overall discomfort experienced by patients; moreover, psychological factors influencing physical symptoms are beyond the reach of pharmacological interventions. Nonpharmacological interventions, however, offer the potential for complementary or alternative solutions. Objectives: This review aims to offer a comprehensive analysis of the literature on the effectiveness of nonpharmacological interventions in managing the physical side effects of chemotherapy. Methods: This review, based on a search of PubMed, PsycINFO, and Web of Science databases, identified 46 relevant studies. It categorizes interventions and evaluates their effectiveness in managing common chemotherapy side effects (fatigue, nausea, pain, diarrhea, and constipation). Results: Guided imagery, tailored exercises, and Qigong show promise in reducing fatigue, while interventions like yoga and cognitive-behavioral approaches address nausea and vomiting. Pain benefits result from guided imagery and educational interventions. Limited evidence exists for diarrhea and constipation interventions, necessitating further research. Conclusions: This review offers provisional conclusions, emphasizing the potential of integrating evidence-based nonpharmacological approaches alongside pharmacological interventions to enhance patient outcomes and reduce chemotherapy-induced side effects, considering factors such as accessibility, safety, customization, and adaptability in clinical settings. [ABSTRACT FROM AUTHOR]

Simple Summary: TGF-β is an important cytokine shown to drive oncogenesis in head and neck squamous cell carcinoma (HNSCC) through its diverse influences on the tumor microenvironment. While this cytokine is vital in maintaining tissue homeostasis in normal head and neck epithelia, in cancer, it paradoxically drives metastasis, angiogenesis, immune evasion, and therapy resistance. Despite promising preclinical data, the outcome of clinical trials of TGF-β inhibitors for HNSCC has been suboptimal. Patient stratification is warranted to improve this targeted therapy. Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cause of cancer worldwide according to GLOBOCAN estimates from 2022. Current therapy options for recurrent or metastatic disease are limited to conventional cytotoxic chemotherapy and immunotherapy, with few targeted therapy options readily available. Recent single-cell transcriptomic analyses identified TGF-β signaling as an important mediator of functional interplays between cancer-associated fibroblasts and a subset of mesenchymal cancer cells. This signaling was shown to drive invasiveness, treatment resistance, and immune evasion. These data provide renewed interest in the TGF-β pathway as an alternative therapeutic target, prompting a critical review of previous clinical data which suggest a lack of benefit from TGF-β inhibitors. While preclinical data have demonstrated the great anti-tumorigenic potential of TGF-β inhibitors, the underwhelming results of ongoing and completed clinical trials highlight the difficulty actualizing these benefits into clinical practice. This topical review will discuss the relevant preclinical and clinical findings for TGF-β inhibitors in HNSCC and will explore the potential role of patient stratification in the development of this therapeutic strategy. [ABSTRACT FROM AUTHOR]

Cellular metabolism is crucial for various physiological processes, with folate-dependent one-carbon (1C) metabolism playing a pivotal role. Folate, a B vitamin, is a key cofactor in this pathway, supporting DNA synthesis, methylation processes, and antioxidant defenses. In dividing cells, folate facilitates nucleotide biosynthesis, ensuring genomic stability and preventing carcinogenesis. Additionally, in neurodevelopment, folate is essential for neural tube closure and central nervous system formation. Thus, dysregulation of folate metabolism can contribute to pathologies such as cancer, severe birth defects, and neurodegenerative diseases. Epidemiological evidence highlights folate's impact on disease risk and its potential as a therapeutic target. In cancer, antifolate drugs that inhibit key enzymes of folate-dependent 1C metabolism and strategies targeting folate receptors are current therapeutic options. However, folate's impact on cancer risk is complex, varying among cancer types and dietary contexts. In neurodegenerative conditions, including Alzheimer's and Parkinson's diseases, folate deficiency exacerbates cognitive decline through elevated homocysteine levels, contributing to neuronal damage. Clinical trials of folic acid supplementation show mixed outcomes, underscoring the complexities of its neuroprotective effects. This review integrates current knowledge on folate metabolism in cancer and neurodegeneration, exploring molecular mechanisms, clinical implications, and therapeutic strategies, which can provide crucial information for advancing treatments. [ABSTRACT FROM AUTHOR]

Telomeres play a crucial role in maintaining chromosomal integrity and regulating the number of cell divisions and have been associated with cellular aging. Telomere length (TL) has been widely studied in manifold cancer types; however, the results have been inconsistent. This systematic review and meta-analysis aims to analyze the evidence on the association between TL and head and neck cancer (HNC) risk. We comprehensively searched the literature in PubMed, Cochrane Library, and Scopus and identified nine eligible studies, which yielded 11 datasets. The odds ratios (ORs) and 95% confidence intervals (CIs) were used to ascertain the strength of the association. On the basis of the median TL, we defined two groups, short TL and long TL, with the latter being the reference group. Our analysis found a significant relationship between short TL and increased HNC risk (OR 1.38, 95% CI: 1.10–1.73, p = 0.005), while significant heterogeneity among the studies was noted. The subgroup analysis on HNC subtypes revealed a significant association between short TL and oral cancers (OR 2.08, 95% CI: 1.23–3.53, p = 0.007). Additionally, subgroup analysis indicates that adjustments for age, sex, and smoking did not affect the significance of our findings. In conclusion, our meta-analysis found evidence for an association between short TL and HNC risk, which could indicate that TL might act as a potential biomarker for HNC risk, but high-quality prospective studies are imperative to validate our findings. [ABSTRACT FROM AUTHOR]

The emergence of digitalization and artificial intelligence has had a profound impact on society, especially in the field of medicine. Digital health is now a reality, with an increasing number of people using chatbots for prognostic or diagnostic purposes, therapeutic planning, and monitoring, as well as for nutritional and mental health support. Initially designed for various purposes, chatbots have demonstrated significant advantages in the medical field, as indicated by multiple sources. However, there are conflicting views in the current literature, with some sources highlighting their drawbacks and limitations, particularly in their use in oncology. This state-of-the-art review article seeks to present both the benefits and the drawbacks of chatbots in the context of medicine and cancer, while also addressing the challenges in their implementation, offering expert insights on the subject. [ABSTRACT FROM AUTHOR]

Background: The increasing burden of cancer has economic implications for the healthcare system in England. However, there is limited evidence on the cost of cancer treatment. We calculated the costs of initial cancer treatment (resection, radiotherapy, systemic anti-cancer therapy [SACT]) based on stage at diagnosis. Methods: Data from England's National Cancer Registration Dataset were matched to English Hospital, Radiotherapy and SACT data for breast, lung, prostate, colon and rectal cancers diagnosed between 2016 and 2018. Treatment data were matched to National Schedule of Reference Costs data to calculate the cost of each treatment event. Results: Breast, colon and rectal cancers treated with resection, radiotherapy or SACT had increasing costs with later stage at diagnosis; costs for lung and prostate cancers were lower at stages 1 and 4 compared to stages 2 and 3. In general, surgery and SACT were the most expensive treatments. Radiotherapy and SACT costs showed little change across stages 1–3; radiotherapy costs decreased in stage 4, while SACT costs increased. Conclusions: This analysis estimates initial treatment costs by stage based on observed data. Future research can build on this to provide more comprehensive costings associated with cancer; this is important for future planning of cancer services. [ABSTRACT FROM AUTHOR]

Cancer is one of the leading causes of morbidity and death worldwide, making it a serious global health concern. Chemotherapy, radiotherapy, and surgical treatment are the most used conventional therapeutic approaches, although they show several side effects that limit their effectiveness. For these reasons, the discovery of new effective alternative therapies still represents an enormous challenge for the treatment of tumour diseases. Recently, anticancer peptides (ACPs) have gained attention for cancer diagnosis and treatment. ACPs are small bioactive molecules which selectively induce cancer cell death through a variety of mechanisms such as apoptosis, membrane disruption, DNA damage, immunomodulation, as well as inhibition of angiogenesis, cell survival, and proliferation pathways. ACPs can also be employed for the targeted delivery of drugs into cancer cells. With over 1000 clinical trials using ACPs, their potential for application in cancer therapy seems promising. Peptides can also be utilized in conjunction with imaging agents and molecular imaging methods, such as MRI, PET, CT, and NIR, improving the detection and the classification of cancer, and monitoring the treatment response. In this review we will provide an overview of the biological activity of some natural and synthetic peptides for the treatment of the most common and malignant tumours affecting people around the world. [ABSTRACT FROM AUTHOR]

Background and Aim: It is reported that miRNAs play an important role in hepatocellular carcinogenesis and may serve as non-invasive biomarkers for hepatocellular carcinoma (HCC). MiR-4510 and miR-146b-5p expression levels have been found to be associated with HCC. However, their associations with hepatitis B virus (HBV)-related HCC (HBV-HCC) are yet to be explored. We aimed to assess the predictive value of expression levels of serum miR-4510 and miR-146b-5p in patients with HBV-HCC and performed bioinformatics analyses based on the miRNA expression profile. Materials and Methods: This cross-sectional study used the serum of 16 patients with Chronic Hepatitis B (CHB), 15 hepatitis B virus-related cirrhosis (HBV-cirrhosis), 15 HBV-HCC, and 16 healthy subjects. The total RNA was isolated from serum, and the expression of miRNAs was measured by qRT-PCR, calculated using the 2-ΔΔCt methods. MIENTURNET was used to predict miRNA-target gene interactions. The Network Analyst was used to build protein-protein interactions. Results: There was a significant difference in miR-146b-5p between study groups (p=0.009). MiR-146b-5p expression was found to be significantly reduced in HBV-HCC compared to the HBV-cirrhosis group and healthy controls (p=0.005 and p=0.006, respectively). Conclusion: The serum miR-146b-5p levels might be a promising tool to be used as a non-invasive diagnostic biomarker for HCC. Our findings shed light on potential biomarkers for the diagnosis of HBV-HCC in terms of selected miRNAs. The target pathways of miR-146b-5p identified by our in-silico analysis to reveal the functional mechanism are “MAPK signaling pathways” and “Pathways in cancer.” [ABSTRACT FROM AUTHOR]

Disulfidptosis is a recently identified mode of regulated cell death. Regulating disulfidptosis in carcinoma is a promising therapeutic approach. Long non-coding RNAs (lncRNAs) have been reported to be related to the occurrence and development of many cancers. Disulfidptosis-related lncRNAs (DRLs) in HPV-negative oral squamous cell carcinoma (OSCC) have not been studied. Based on The Cancer Genome Atlas (TCGA) database, least absolute shrinkage selection operator (LASSO) analysis and Cox regression analysis were used to identify overall survival related DRLs and construct the signature. Kaplan–Meier, time-dependent receiver operating characteristics (ROC) and principal component analyses (PCA) were explored to demonstrate the prediction potential of the signature. Subgroup analysis stratified by different clinicopathological characteristics were conducted. Nomogram was established by DRLs signature and independent clinicopathological characteristics. The calibration plots were performed to reveal the accuracy of nomogram. Immune cell subset infiltration, immunotherapy response, drug sensitivity analysis, and tumor mutation burden (TMB) were conducted. Underlying functions and pathways were explored by Gene Set Enrichment Analysis (GSEA) analysis. Previous lncRNA signatures of OSCC were retrieved from PubMed for further validation. Gene expression omnibus (GEO) datasets (GSE41613 and GSE85446) were merged as an external validation for DRLs signature. Consensus clustering analysis of DRLs signature and experimental validation of DRLs were also explored. This research sheds light on the robust performance of DRLs signature in survival prediction, immune cell infiltration, immune escape, and immunotherapy of HPV-negative OSCC. [ABSTRACT FROM AUTHOR]

Physical changes in the tumor microenvironment, such as increased stiffness, regulate cancer hallmarks and play an essential role in gene expression, cell morphology, migration, and malignancy. However, the response of cancer cells to stiffness is not homogeneous and varies depending on the cell type and its mechanosensitivity. In this study, we investigated the differential responses of cervical (HeLa) and prostate (PC-3) cancer cell lines, as well as non-tumoral cell lines (HEK293 and HPrEC), to stiffness using polyacrylamide hydrogels mimicking normal and tumoral tissues. We analyzed cell morphology, migration, and the expression of neuropilin 1 (NRP1), a receptor involved in angiogenesis, cell migration, and extracellular matrix remodeling, known to be associated with cancer progression and poor prognosis. Our findings reveal that NRP1 expression increases on substrates mimicking the high stiffness characteristic of tumoral tissue in the non-tumoral cell lines HPrEC and HEK293. Conversely, in tumoral PC-3 cells, stiffness resembling normal prostate tissue induces an earlier and more sustained expression of NRP1. Furthermore, we observed that stiffness influences cell spreading, pseudopodia formation, and the mode of cell protrusion during migration. Soft substrates predominantly trigger bleb cell protrusion, while pseudopodia protrusions increase on substrates mimicking normal and tumor-like stiffnesses in HPrEC cells compared to PC-3 cells. Stiffer substrates also enhance the percentage of migratory cells, as well as their velocity and total displacement, in both non-tumoral and tumoral prostate cells. However, they only improve the persistence of migration in tumoral PC-3 cells. Moreover, we found that NRP1 co-localizes with actin, and its suppression impairs tumoral PC-3 spreading while decreasing pseudopodia protrusion mode. Our results suggest that the modulation of NRP1 expression by the stiffness can be a feedback loop to promote malignancy in non-tumoral and cancer cells, contingent upon the mechanosensitivity of the cells. [ABSTRACT FROM AUTHOR]

Cancer is a disease characterized by uncontrolled cellular growth where cancer cells take advantage of surrounding cellular populations to obtain resources and promote invasion. Carcinomas are the most common type of cancer accounting for almost 90% of cancer cases. One of the major subtypes of carcinomas are adenocarcinomas, which originate from glandular cells that line certain internal organs. Cancers such as breast, prostate, lung, pancreas, colon, esophageal, kidney are often adenocarcinomas. Current treatment strategies include surgery, chemotherapy, radiation, targeted therapy, and more recently immunotherapy. However, patients with adenocarcinomas often develop resistance or recur after the first line of treatment. Understanding how networks of tumor cells interact with each other and the tumor microenvironment is crucial to avoid recurrence, resistance, and high-dose therapy toxicities. In this review, we explore how mathematical modeling tools from different disciplines can aid in the development of effective and personalized cancer treatment strategies. Here, we describe how concepts from the disciplines of ecology and evolution, economics, and control engineering have been applied to mathematically model cancer dynamics and enhance treatment strategies. [ABSTRACT FROM AUTHOR]

Mesotrione, as a widely used herbicide, is present in the environment in detectable amounts, causing serious damage. Here, we aimed to investigate the effect of mesotrione on Caco-2 cells and the possibility of its toxicity mitigation by cichoric acid. Therefore, we analyzed the cytotoxicity of both these compounds and the selected oxidative stress parameters, apoptosis and interaction of both the tested compounds with the cell membrane and their accumulation within the cells. In cytotoxicity studies, the stimulating activity of mesotrione was observed, and simultaneously, the inhibitory effect of cichoric acid was noticed. This effect was related to the results of oxidative stress analysis and apoptosis measurements. The activity level of key enzymes (glutathione peroxidase, catalase and superoxide dismutase) in Caco-2 cells exposed to cichoric acid was higher as compared to that of the control. The treatment with mesotrione did not induce apoptosis in the Caco-2 cells. The penetration of the studied compounds into the Caco-2 cells was measured by using an HPLC methodology, and the results indicate mesotrione's high penetration capacity. The distribution of charge on the surface of the cell membranes changed under the influence of both compounds. Considering the mutual interactions of beneficial and potentially toxic food ingredients, it should be noted that, despite the observed favorable trend, cichoric acid is not able to overcome the toxic and cancer-stimulating effects of this pesticide. [ABSTRACT FROM AUTHOR]

Simple Summary: This retrospective study focused on 23 patients diagnosed with Hepatocellular Carcinoma (HCC), utilizing the Liver Imaging Reporting and Data System (LI-RADS) for classification. This system aids in the non-invasive diagnosis of HCC, potentially eliminating the need for a diagnostic biopsy. Patients were selected based on their diagnosis, confirmed either via imaging methods that identified advanced liver nodules or via histopathological findings consistent with HCC, including specific protein markers. The study aimed to assess the histopathological changes resulting from prior local interventions, such as trans-arterial chemoembolization or radiofrequency ablation, and their impact on the tumor's response to subsequent immune therapies. Key findings indicated variations in alpha-fetoprotein levels and increased expression of the immune marker PD-L1 in untreated patients, suggesting a more aggressive cancer progression in these individuals. The study's conclusions support the use of liver biopsy in refining therapeutic approaches for HCC, particularly in recurrent cases post-intervention, to enhance personalized immune therapy strategies. Background: The Liver Imaging Reporting and Data System (LI-RADS) combines standardized terminology with a classification system for imaging findings in patients with HCC, therefore rendering diagnostic biopsy unnecessary in many cases. This retrospective study included 23 patients with a biopsy diagnosis of HCC, performed either before or after local interventional procedures, in order to evaluate the histopathologic changes induced by previous procedures and their potential influence on the response to immune therapy. Material and Methods: The study encompassed a cohort of patients diagnosed with Hepatocellular Carcinoma (HCC). Diagnosis was established via contrast-enhanced computer tomography or magnetic resonance imaging that identified LI-RADS-5 nodules in conjunction with historical liver disease and elevated alpha-fetoprotein (AFP) levels or via histological examination confirming positivity for glypican3, heat shock protein 70, and glutamine synthetase. The study detailed the liver disease etiology, LI-RADS scores, characteristics and dimensions of HCC nodules, serum AFP concentrations, Edmondson–Steiner grading, and the expression of programmed cell death ligand 1 (PD-L1) in the tumor cells. Results: Among the study's cohort of Hepatocellular Carcinoma (HCC) patients, a portion had not received any prior treatments, while the remainder experienced local HCC recurrence following trans-arterial chemoembolization or radiofrequency ablation. Observations indicated elevated alpha-fetoprotein (AFP) levels in those who had not undergone any previous interventions, showing statistical significance. The Edmondson–Steiner classification predominantly identified grade III differentiation across patients, irrespective of their treatment history. Furthermore, an increase in intra-tumoral programmed cell death ligand 1 (PD-L1) expression was noted in patients who had not been subjected to previous therapies. Conclusion: Liver biopsy offers valuable insights for patients with Hepatocellular Carcinoma (HCC), assisting in the tailoring of immune therapy strategies, particularly in cases of recurrence following prior local interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is the second leading cause of death worldwide, accounting for nearly one in six deaths. One of the key underlying factors distinguishing a cancer cell from a normal cell is the pattern of expression of genes. Proteins that regulate gene expression, called transcription factors, are abnormally regulated in cancer cells, particularly a group of proteins called STATs. This causes cancer cells to survive, proliferate excessively, and escape killing by the immune system. Since normal cells can survive adequately without full STAT function, targeting these proteins is an attractive approach for a new generation of more effective and less toxic cancer therapies. In this review, we summarize the current knowledge of STAT function in cancer and the advances and challenges in developing drugs to target them. Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics. [ABSTRACT FROM AUTHOR]

Cancer continues to pose a significant global health challenge, as evidenced by the increasing incidence rates and high mortality rates, despite the advancements made in chemotherapy. The emergence of chemoresistance further complicates the effectiveness of treatment. However, there is growing interest in the potential of metformin, a commonly prescribed drug for type 2 diabetes mellitus (T2DM), as an adjuvant chemotherapy agent in cancer treatment. Although the precise mechanism of action of metformin in cancer therapy is not fully understood, it has been found to have pleiotropic effects, including the modulation of metabolic pathways, reduction in inflammation, and the regulation of cellular proliferation. This comprehensive review examines the anticancer properties of metformin, drawing insights from various studies conducted in vitro and in vivo, as well as from clinical trials and observational research. This review discusses the mechanisms of action involving both insulin-dependent and independent pathways, shedding light on the potential of metformin as a therapeutic agent for different types of cancer. Despite promising findings, there are challenges that need to be addressed, such as conflicting outcomes in clinical trials, considerations regarding dosing, and the development of resistance. These challenges highlight the importance of further research to fully harness the therapeutic potential of metformin in cancer treatment. The aims of this review are to provide a contemporary understanding of the role of metformin in cancer therapy and identify areas for future exploration in the pursuit of effective anticancer strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: We have recently witnessed several milestones in the treatment of various cancers with immunotherapy through modulating the activity of the immune system to suppress and destroy cancer cells. One main factor involved in the anti-cancer immune system is cytotoxic immune cells known as T cells. T cells can recognize pathogenic cancer cells and launch targeted destruction attacks. However, these T cells may become non-functional due to their close association with cancer cells within the tumor microenvironment. Cancer cell activity can ultimately suppress T-cell function. New approaches that prevent the inactivation of T cells by cancer cells would result in recovery of the T-cell functions, cancer regression, and overall survival. Targeting cancer cells specifically to prevent T-cell inactivation would result in tumor disappearance, inhibition of metastasis, and the reversal of resistance to therapy. Therefore, this proposed alternative approach is promising as it is applicable to numerous cancers, including those that are resistant to treatment. During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host's immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8+ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8+ T cells. One mechanism by which the anti-tumor CD8+ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8+ T cells' functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8+ T cells' anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response. [ABSTRACT FROM AUTHOR]

The fact that the Mediterranean diet could represent a source of natural compounds with cancer-preventive and therapeutic activity has been the object of great interest, especially with regard to the mechanisms of action of polyphenols found in olive oil and olive leaves. Secoiridoid oleuropein (OLE) and its derivative hydroxytyrosol (3,4-dihydroxyphenylethanol, HT) have demonstrated anti-proliferative properties against a variety of tumors and hematological malignancies both in vivo and in vitro, with measurable effects on cellular redox status, metabolism, and transcriptional activity. With this review, we aim to summarize the most up-to-date information on the potential use of OLE and HT for cancer treatment, making important considerations about OLE and HT bioavailability, OLE- and HT-mediated effects on drug metabolism, and OLE and HT dual activity as both pro- and antioxidants, likely hampering their use in clinical routine. Also, we focus on the details available on the effects of nutritionally relevant concentrations of OLE and HT on cell viability, redox homeostasis, and inflammation in order to evaluate if both compounds could be considered cancer-preventive agents or new potential chemotherapy drugs whenever their only source is represented by diet. [ABSTRACT FROM AUTHOR]

JNK is named after c-Jun N-terminal kinase, as it is responsible for phosphorylating c-Jun. As a member of the mitogen-activated protein kinase (MAPK) family, JNK is also known as stress-activated kinase (SAPK) because it can be activated by extracellular stresses including growth factor, UV irradiation, and virus infection. Functionally, JNK regulates various cell behaviors such as cell differentiation, proliferation, survival, and metabolic reprogramming. Dysregulated JNK signaling contributes to several types of human diseases. Although the role of the JNK pathway in a single disease has been summarized in several previous publications, a comprehensive review of its role in multiple kinds of human diseases is missing. In this review, we begin by introducing the landmark discoveries, structures, tissue expression, and activation mechanisms of the JNK pathway. Next, we come to the focus of this work: a comprehensive summary of the role of the deregulated JNK pathway in multiple kinds of diseases. Beyond that, we also discuss the current strategies for targeting the JNK pathway for therapeutic intervention and summarize the application of JNK inhibitors as well as several challenges now faced. We expect that this review can provide a more comprehensive insight into the critical role of the JNK pathway in the pathogenesis of human diseases and hope that it also provides important clues for ameliorating disease conditions. [ABSTRACT FROM AUTHOR]

Adenosine-to-inosine (A-to-I) editing of RNA, catalyzed by adenosine deaminase acting on RNA (ADAR) enzymes, is a prevalent RNA modification in mammals. It has been shown that A-to-I editing plays a critical role in multiple diseases, such as cardiovascular disease, neurological disorder, and particularly cancer. ADARs are the family of enzymes, including ADAR1, ADAR2, and ADAR3, that catalyze the occurrence of A-to-I editing. Notably, A-to-I editing is mainly catalyzed by ADAR1. Given the significance of A-to-I editing in disease development, it is important to unravel the complex roles of ADAR1 in cancer for the development of novel therapeutic interventions. In this review, we briefly describe the progress of research on A-to-I editing and ADARs in cancer, mainly focusing on the role of ADAR1 in cancer from both editing-dependent and independent perspectives. In addition, we also summarized the factors affecting the expression and editing activity of ADAR1 in cancer. [ABSTRACT FROM AUTHOR]

APR3 (Apoptosis-related protein 3) is a gene that has recently been identified to be associated with apoptosis. The gene is located on human chromosome 2p22.3 and contains both transmembrane and EGF (epidermal growth factor)-like domains. Additionally, it has structural sites, including AP1, SP1, and MEF2D, that indicate NFAT (nuclear factor of activated T cells) and NF-κB (nuclear factor kappa-B) may be transcription factors for this gene. Functionally, APR3 participates in apoptosis due to the induction of mitochondrial damage to release mitochondrial cytochrome C. Concurrently, APR3 affects the cell cycle by altering the expression of Cyclin D1, which, in turn, affects the incidence and growth of malignancies and promotes cell differentiation. Previous reports indicate that APR3 is located in lysosomal membranes, where it contributes to lysosomal activity and participates in autophagy. While further research is required to determine the precise role and molecular mechanisms of APR3, earlier studies have laid the groundwork for APR3 research. There is growing evidence supporting the significance of APR3 in oncology. Therefore, this review aims to examine the current state of knowledge on the role of the newly discovered APR3 in tumorigenesis and to generate fresh insights and suggestions for future research. Highlight: 1. APR3-mediated mitochondrial damage plays a vital function in oxidative stress and apoptosis. 2. APR3 is discovered as an apoptosis-related gene and participated in cell cycle and cellular homeostasis. 3. The rivalry between NFAT and NF-κB for the binding domains of APR3 can have an impact on its transcription. 4. The expression of APR3 is increased in tumor tissues, which is expected to be an emerging disease biomarker and therapeutic target. 5. APR3 may have an integral role in nonapoptotic programmed cell death, such as autophagy, ferroptosis, cuproptosis, and pyroptosis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a major global health concern, with the Mitogen-activated protein kinase (MAPK) pathway playing a crucial role in cancerous diseases. Indole alkaloids, such as vincristine and evodiamine, have been extensively studied for their potential in cancer treatment. These naturally occurring indole alkaloids have strong anticancer properties, and research is ongoing to develop new anticancer small molecules. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment and focus on advancements in the role of indole alkaloids. The review also highlights clinical trials with indole alkaloids in cancer treatment. Cancer is the leading cause of morbidity and mortality in people throughout the world. There are many signaling pathways associated with cancerous diseases, from which the Mitogen-activated protein kinase (MAPK) pathway performs a significant role in this regard. Apoptosis and proliferation are correlated with MAPK signaling pathways. Plenty of experimental investigations were carried out to assess the role of indole alkaloids in MAPK-mediated cancerous diseases. Previous reports established that indole alkaloids, such as vincristine and evodiamine are useful small molecules in cancer treatment via the MAPK signaling system. Indole alkaloids have the anticancer potential through different pathways. Vincristine and evodiamine are naturally occurring indole alkaloids that have strong anticancer properties. Additionally, much research is ongoing or completed with molecules belonging to this group. The current review aims to evaluate how indole alkaloids affect the MAPK signaling pathway in cancer treatment. Additionally, we focused on the advancement in the role of indole alkaloids, with the intention of modifying the MAPK signaling pathways to investigate potential new anticancer small molecules. Furthermore, clinical trials with indole alkaloids in cancer treatment are also highlighted. [ABSTRACT FROM AUTHOR]

Histone deacetylases (HDACs) are the major regulators of the balance of acetylation of histone and non-histone proteins. In contrast to other HDAC isoforms, HDAC6 is mainly involved in maintaining the acetylation balance of many non-histone proteins. Therefore, the overexpression of HDAC6 is associated with tumorigenesis, invasion, migration, survival, apoptosis and growth of various malignancies. As a result, HDAC6 is considered a promising target for cancer treatment. However, none of selective HDAC6 inhibitors are in clinical use, mainly because of the low efficacy and high concentrations used to show anticancer properties, which may lead to off-target effects. Therefore, HDAC6 inhibitors with dual-target capabilities represent a new trend in cancer treatment, aiming to overcome the above problems. In this review, we summarize the advances in tumor treatment with dual-target HDAC6 inhibitors. [ABSTRACT FROM AUTHOR]

Protein S-palmitoylation, a type of post-translational modification, refers to the reversible process of attachment of a fatty acyl chain—a 16-carbon palmitate acid—to the specific cysteine residues on target proteins. By adding the lipid chain to proteins, it increases the hydrophobicity of proteins and modulates protein stability, interaction with effector proteins, subcellular localization, and membrane trafficking. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), whereas depalmitoylation is catalyzed by a family of acyl-protein thioesterases. Increasing numbers of oncoproteins and tumor suppressors have been identified to be palmitoylated, and palmitoylation is essential for their functions. Understanding how palmitoylation influences the function of individual proteins, the physiological roles of palmitoylation, and how dysregulated palmitoylation leads to pathological consequences are important drivers of current research in this research field. Further, due to the critical roles in modifying functions of oncoproteins and tumor suppressors, targeting palmitoylation has been used as a candidate therapeutic strategy for cancer treatment. Here, based on recent literatures, we discuss the progress of investigating roles of palmitoylation in regulating cancer progression, immune responses against cancer, and cancer stem cell properties. [ABSTRACT FROM AUTHOR]

Every year, cancer kills millions of people around the world. Finding more selective anticancer agents is essential to improve the low survival rates of patients with metastatic cancers. Since the research of natural products is a valuable approach to the discovery of new compounds and the Iberian flora offers a rich source of unstudied plants, we have carried out a random screening of 76 plant species from 43 families collected in Andalusia (South of Spain). Using non-malignant cells (HaCaT) and lung cancer cells (A549), we found that the extract from Arum italicum Mill. subsp. italicum (Araceae), Mandragora autumnalis Bertol. (Solanaceae), Rhamnus alaternus L. (Rhamnaceae), and Lomelosia simplex (Desf.) Raf. subsp. dentata (Jord. & Fourr.) Greuter & Burdet (Dipsacaceae) showed selective cytotoxicity against lung cancer cells. Extracts of plant species belonging to the Iridaceae family showed high selective activity against cancer cells, highlighting that the Xiphion xiphium (L.) M.B. Crespo, Mart.-Azorín & Mavrodiev flower extract was more selective against lung cancer cells than the standard anticancer drugs, cisplatin and 5-fluorouracil. This extract also showed modest selective cytotoxicity against bladder carcinoma cells (T24). The number of cells in the G1 phase increased after treatment with the extract from Xiphion xiphium. Our research indicates that various plants are potential sources for the isolation and development of new anticancer drugs. [ABSTRACT FROM AUTHOR]

Simple Summary: Recent advances in anticancer drug research led to the approval of new small molecules with different mechanisms of action, therapeutic indications, and adverse reactions. In this review, small molecules recently approved for metastatic cancer therapy or in trials belonging to different pharmacological classes are described. Particularly, we focus on receptor tyrosine kinase inhibitors, which are the largest category, and on other small molecules interfering with cell cycle mechanisms. Special attention is devoted to mutated KRAS inhibitors, which probably represent the first dream come true in anti-metastatic cancer therapy of pharmacology researchers and open the way to potentially very broad therapeutic indications. A second section deals with another family of small molecules, integrin antagonists, that has gone through light and shade moments, and the molecules of still relevant interest are critically discussed. Metastasis is the main cause of anti-cancer therapy failure, leading to unfavorable prognosis for patients. The true challenge to increase cancer patient life expectancy by making cancer a chronic disease with periodic but manageable relapses relies on the development of efficient therapeutic strategies specifically directed against key targets in the metastatic process. Traditional chemotherapy with classical alkylating agents, microtubule inhibitors, and antimetabolites has demonstrated its limited efficacy against metastatic cells due to their capacity to select chemo-resistant cell populations that undergo epithelial-to-mesenchymal transition (EMT), thus promoting the colonization of distant sites that, in turn, sustain the initial metastatic process. This scenario has prompted efforts aimed at discovering a wide variety of small molecules and biologics as potential anti-metastatic drugs directed against more specific targets known to be involved in the various stages of metastasis. In this short review, we give an overview of the most recent advances related to important families of antimetastatic small molecules: intracellular tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, KRAS inhibitors, and integrin antagonists. Although the majority of these small molecules are not yet approved and not available in the drug market, any information related to their stage of development could represent a precious and valuable tool to identify new targets in the endless fight against metastasis. [ABSTRACT FROM AUTHOR]

Mechanobiology comprises how cells perceive different mechanical stimuli and integrate them into a process called mechanotransduction; therefore, the related mechanosignaling cascades are generally important for biomedical research. The ongoing discovery of key molecules and the subsequent elucidation of their roles in mechanobiology are fundamental to understanding cell responses and tissue conditions, such as homeostasis, aging, senescence, wound healing, and cancer. Regarding the available literature on these topics, it becomes abundantly clear that in vitro cell systems from different species and tissues have been and are extremely valuable tools for enabling the discovery and functional elucidation of key mechanobiological players. Therefore, this review aims to discuss the significant contributions of in vitro cell systems to the identification and characterization of three such key players using the selected examples of yes-associated protein (YAP), its paralog transcriptional co-activator with a PDZ-binding motif (TAZ), and focal adhesion kinase (FAK) and their involvement in wound healing, cancer, aging, and senescence. In addition, the reader is given suggestions as to which future prospects emerge from the in vitro studies discussed herein and which research questions still remain open. [ABSTRACT FROM AUTHOR]

Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand–residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand–protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies. [ABSTRACT FROM AUTHOR]

Opioids are one of the most potent drugs for treating moderate to severe pain. Despite irrefutable clinical application in chronic pain management, the long‐term use of opioids has been increasingly questioned due to undesired side effects that demand attention. Opioids such as morphine mediate clinically relevant effects primarily through the µ‐opioid receptor that go beyond their classical role as analgesics, causing potentially fatal side effects such as tolerance, dependence, and addiction. Furthermore, there is growing evidence that opioids affect immune system function, cancer progression, metastasis, and recurrence. Though a biological plausibility, the clinical evidence for the action of opioids on cancer is mixed, revealing a more complex picture as researchers struggle to establish a vital link between opioid receptor agonists, cancer progression, and suppression, or both. Thus, in light of the uncertainty of opioid effects on cancer, in this review, a focused overview of the role of opioid receptors in modulating cancer progression, their underlying signaling mechanisms, and the biological activity of opioid receptor agonists and antagonists is provided. [ABSTRACT FROM AUTHOR]

Metformin is a well-known anti-diabetic drug that has been repurposed for several emerging applications, including as an anti-cancer agent. It boasts the distinct advantages of an excellent safety and tolerability profile and high cost-effectiveness at less than one US dollar per daily dose. Epidemiological evidence reveals that metformin reduces the risk of cancer and decreases cancer-related mortality in patients with diabetes; however, the exact mechanisms are not well understood. Energy metabolism may be central to the mechanism of action. Based on altering whole-body energy metabolism or cellular state, metformin's modes of action can be divided into two broad, non-mutually exclusive categories: "direct effects", which induce a direct effect on cancer cells, independent of blood glucose and insulin levels, and "indirect effects" that arise from systemic metabolic changes depending on blood glucose and insulin levels. In this review, we summarize an updated account of the current knowledge on metformin antitumor action, elaborate on the underlying mechanisms in terms of the hallmarks of cancer, and propose potential applications for repurposing metformin for cancer therapeutics. [ABSTRACT FROM AUTHOR]

KRAS is a protein that is critical to cell activation, but when it becomes mutated, it can contribute to the development of cancer. There is an urgent need for reliable and effective drugs to treat cancer, and KRAS G12C has been a major focus of research in this area. In this study, we used structure-based virtual screening to search for novel inhibitors that can target KRAS G12C. Specifically, we conducted a search for inhibitors that bind to the protein's P2 pocket, which can trap the oncoprotein in an inactive GDP-bound state. Using quantitative analysis and virtual screening, we identified a set of eight potential inhibitors that have the potential to become the next generation of drugs to treat cancer. These findings offer new insights into the mechanisms underlying KRAS G12C inhibition and provide a promising avenue for future drug development efforts. [ABSTRACT FROM AUTHOR]

RNA modification plays an important role in epigenetics at the posttranscriptional level, and 5-methylcytosine (m5C) has attracted increasing attention in recent years due to the improvement in RNA m5C site detection methods. By influencing transcription, transportation and translation, m5C modification of mRNA, tRNA, rRNA, lncRNA and other RNAs has been proven to affect gene expression and metabolism and is associated with a wide range of diseases, including malignant cancers. RNA m5C modifications also substantially impact the tumor microenvironment (TME) by targeting different groups of immune cells, including B cells, T cells, macrophages, granulocytes, NK cells, dendritic cells and mast cells. Alterations in immune cell expression, infiltration and activation are highly linked to tumor malignancy and patient prognosis. This review provides a novel and holistic examination of m5C-mediated cancer development by examining the exact mechanisms underlying the oncogenicity of m5C RNA modification and summarizing the biological effects of m5C RNA modification on tumor cells as well as immune cells. Understanding methylationrelated tumorigenesis can provide useful insights for the diagnosis as well as the treatment of cancer. [ABSTRACT FROM AUTHOR]

Cancer is a top global public health concern. At present, molecular targeted therapy has emerged as one of the main therapies for cancer, with high efficacy and safety. The medical world continues to struggle with the development of efficient, extremely selective, and low-toxicity anticancer medications. Heterocyclic scaffolds based on the molecular structure of tumor therapeutic targets are widely used in anticancer drug design. In addition, a revolution in medicine has been brought on by the quick advancement of nanotechnology. Many nanomedicines have taken targeted cancer therapy to a new level. In this review, we highlight heterocyclic molecular-targeted drugs as well as heterocyclic-associated nanomedicines in cancer. [ABSTRACT FROM AUTHOR]

The mammalian formin family comprises fifteen multi-domain proteins that regulate actin dynamics and microtubules in vitro and in cells. Evolutionarily conserved formin homology (FH) 1 and 2 domains allow formins to locally modulate the cell cytoskeleton. Formins are involved in several developmental and homeostatic processes, as well as human diseases. However, functional redundancy has long hampered studies of individual formins with genetic loss-of-function approaches and prevents the rapid inhibition of formin activities in cells. The discovery of small molecule inhibitor of formin homology 2 domains (SMIFH2) in 2009 was a disruptive change that provided a powerful chemical tool to explore formins' functions across biological scales. Here, I critically discuss the characterization of SMIFH2 as a pan-formin inhibitor, as well as growing evidence of unexpected off-target effects. By collating the literature and information hidden in public repositories, outstanding controversies and fundamental open questions about the substrates and mechanism of action of SMIFH2 emerge. Whenever possible, I propose explanations for these discrepancies and roadmaps to address the paramount open questions. Furthermore, I suggest that SMIFH2 be reclassified as a multi-target inhibitor for its appealing activities on proteins involved in pathological formin-dependent processes. Notwithstanding all drawbacks and limitations, SMIFH2 will continue to prove useful in studying formins in health and disease in the years to come. [ABSTRACT FROM AUTHOR]

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments. [ABSTRACT FROM AUTHOR]

Recent studies have demonstrated that N6-methyladenosine (m6A), the most abundant, dynamic, and reversible epigenetic RNA modification in eukaryotes, is regulated by a series of enzymes, including methyltransferases (writers), demethylases (erasers), and m6A recognition proteins (readers). Aberrant regulation of m6A modification is pivotal for tumorigenesis, progression, invasion, metastasis, and apoptosis of malignant tumors. Immune checkpoint inhibitors (ICIs) has revolutionized cancer treatment, as recognized by the 2018 Nobel Prize in Medicine and Physiology. However, not all cancer patients response to ICI therapy, which is thought to be the result of intricate immune escape mechanisms. Recently, numerous studies have suggested a novel role for m6A epigenetic modification in the regulation of tumor immune evasion. Herein, we review the relevant mechanisms of m6A regulators in regulating various key signaling pathways in cancer biology and how m6A epigenetic modifications regulate the expression of immune checkpoints, opening a new window to understand the roles and mechanisms of m6A epigenetic modifications in regulating tumor immune evasion. In addition, we highlight the prospects and development directions of future combined immunotherapy strategies based on m6A modification targeting, providing directions for promoting the treatment outcomes of immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: The gold standard for detecting cancer and profiling tumors is tissue biopsies. Despite this, tissue biopsies have been associated with many limitations leading to the desire for less invasive and more accurate solutions. One very attractive candidate for the diagnosis and prognosis of cancer in patients is provided by liquid biopsies. The number of analytes circulating in the blood that may be used for liquid biopsy testing is enormous making it a promising technique for the clinical management of oncological patients. The goal of this study is to discuss in detail the clinical relevance of liquid biopsies, as well as the opportunities they might offer for cancer prognosis, diagnosis and monitoring. The isolation process and clinical use of the biological components of the liquid biopsy will also be explained, with specific focus placed on novel procedures that can be developed as well as the approach's future possibilities. Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients' outcomes. The gold standard of tumor characterization leading to tumor diagnosis and prognosis is tissue biopsy. Amongst the constraints of tissue biopsy collection is the sampling frequency and the incomplete representation of the entire tumor bulk. Liquid biopsy approaches, including the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor-derived extracellular vesicles (EVs), as well as certain protein signatures that are released in the circulation from primary tumors and their metastatic sites, present a promising and more potent candidate for patient diagnosis and follow up monitoring. The minimally invasive nature of liquid biopsies, allowing frequent collection, can be used in the monitoring of therapy response in real time, allowing the development of novel approaches in the therapeutic management of cancer patients. In this review we will describe recent advances in the field of liquid biopsy markers focusing on their advantages and disadvantages. [ABSTRACT FROM AUTHOR]

Chalcones are synthetic and naturally occurring compounds that have been widely investigated as anticancer agents. In this work, the effect of chalcones 1–18 against the metabolic viability of cervical (HeLa) and prostate (PC-3 and LNCaP) tumor cell lines was tested, to compare the activity against solid and liquid tumor cells. Their effect was also evaluated on the Jurkat cell line. Chalcone 16 showed the highest inhibitory effect on the metabolic viability of the tested tumor cells and was selected for further studies. Recent antitumor therapies include compounds with the ability to influence immune cells on the tumor microenvironment, with immunotherapy being one actual goal in cancer treatment. Therefore, the effect of chalcone 16 on the expression of mTOR, HIF-1α, IL-1β, TNF-α, IL-10, and TGF-β, after THP-1 macrophage stimulation (none, LPS or IL-4), was evaluated. Chalcone 16 significantly increased the expression of mTORC1, IL-1β, TNF-α, and IL-10 of IL-4 stimulated macrophages (that induces an M2 phenotype). HIF-1α and TGF-β were not significantly affected. Chalcone 16 also decreased nitric oxide production by the RAW 264.7 murine macrophage cell line, this effect probably being due to an inhibition of iNOS expression. These results suggest that chalcone 16 may influence macrophage polarization, inducing the pro-tumoral M2 macrophages (IL-4 stimulated) to adopt a profile closer to the antitumor M1 profile. [ABSTRACT FROM AUTHOR]

The objective of this study was to construct amodiaquine-loaded, folic acid-conjugated polymeric nanoparticles (FA-AQ NPs) to treat cancer that could be scaled to commercial production. In this study, folic acid (FA) was conjugated with a PLGA polymer followed by the formulation of drug-loaded NPs. The results of the conjugation efficiency confirmed the conjugation of FA with PLGA. The developed folic acid-conjugated nanoparticles demonstrated uniform particle size distributions and had visible spherical shapes under transmission electron microscopy. The cellular uptake results suggested that FA modification could enhance the cellular internalization of nanoparticulate systems in non-small cell lung cancer, cervical, and breast cancer cell types. Furthermore, cytotoxicity studies showed the superior efficacy of FA-AQ NPs in different cancer cells such as MDAMB-231 and HeLA. FA-AQ NPs had better anti-tumor abilities demonstrated via 3D spheroid cell culture studies. Therefore, FA-AQ NPs could be a promising drug delivery system for cancer therapy. [ABSTRACT FROM AUTHOR]

The classical low-molecular-weight drugs are designed to bind with high affinity to the biological targets endowed with receptor or enzymatic activity, and inhibit their function. However, there are many non-receptor or non-enzymatic disease proteins that seem undruggable using the traditional drug approach. This limitation has been overcome by PROTACs, bifunctional molecules that are able to bind the protein of interest and the E3 ubiquitin ligase complex. This interaction results in the ubiquitination of POI and subsequent proteolysis in the cellular proteasome. Out of hundreds of proteins serving as substrate receptors in E3 ubiquitin ligase complexes, current PROTACs recruit only a few of them, including CRBN, cIAP1, VHL or MDM-2. This review will focus on PROTACs recruiting CRBN E3 ubiquitin ligase and targeting various proteins involved in tumorigenesis, such as transcription factors, kinases, cytokines, enzymes, anti-apoptotic proteins and cellular receptors. The structure of several PROTACs, their chemical and pharmacokinetic properties, target affinity and biological activity in vitro and in vivo, will be discussed. We will also highlight cellular mechanisms that may affect the efficacy of PROTACs and pose a challenge for the future development of PROTACs. [ABSTRACT FROM AUTHOR]

Cancer is responsible for lifelong disability and decreased quality of life. Cancer-associated changes in metabolism, in particular carbohydrate, lipid, and protein, offer a new paradigm of metabolic hits. Hence, targeting the latter, as well as related cross-linked signalling pathways, can reverse the malignant phenotype of transformed cells. The systemic toxicity and pharmacokinetic limitations of existing drugs prompt the discovery of multi-targeted and safe compounds from natural products. Mushrooms possess biological activities relevant to disease-fighting and to the prevention of cancer. They have a long-standing tradition of use in ethnomedicine and have been included as an adjunct therapy during and after oncological care. Mushroom-derived compounds have also been reported to target the key signature of cancer cells in in vitro and in vivo studies. The identification of metabolic pathways whose inhibition selectively affects cancer cells appears as an interesting approach to halting cell proliferation. For instance, panepoxydone exerted protective mechanisms against breast cancer initiation and progression by suppressing lactate dehydrogenase A expression levels and reinducing lactate dehydrogenase B expression levels. This further led to the accumulation of pyruvate, the activation of the electron transport chain, and increased levels of reactive oxygen species, which eventually triggered mitochondrial apoptosis in the breast cancer cells. Furthermore, the inhibition of hexokinase 2 by neoalbaconol induced selective cytotoxicity against nasopharyngeal carcinoma cell lines, and these effects were also observed in mouse models. Finally, GL22 inhibited hepatic tumour growth by downregulating the mRNA levels of fatty acid-binding proteins and blocking fatty acid transport and impairing cardiolipin biosynthesis. The present review, therefore, will highlight how the metabolites isolated from mushrooms can target potential biomarkers in metabolic reprogramming. [ABSTRACT FROM AUTHOR]

The protein ISG15 encoded by interferon-stimulated gene (ISG) 15 is the first identified member of the ubiquitin-like protein family and exists in the form of monomers and conjugated complexes. Like ubiquitin, ISG15 can mediate an ubiquitin-like modification by covalently modifying other proteins, known as ISGylation. There is growing evidence showing that both the free and conjugated ISG15 are involved in multiple key cellular processes, including autophagy, exosome secretion, DNA repair, immune regulation, and cancer occurrence and progression. In this review, we aim to further clarify the function of ISG15 and ISGylation in cancer, demonstrate the important relationship between ISG15/ISGylation and cancer, and emphasize new insights into the different roles of ISG15/ISGylation in cancer progression. This review may contribute to therapeutic intervention in cancer. However, due to the limitations of current research, the regulation of ISG15/ISGylation on cancer progression is not completely clear, thus further comprehensive and sufficient correlation studies are still needed. [ABSTRACT FROM AUTHOR]

Evodiamine is a major alkaloid component found in the fruit of Evodia rutaecarpa. It shows the anti-proliferative potential against a wide range of cancers by suppressing cell growth, invasion, and metastasis and inducing apoptosis both in vitro and in vivo. Evodiamine shows its anticancer potential by modulating aberrant signaling pathways. Additionally, the review focuses on several therapeutic implications of evodiamine, such as epigenetic modification, cancer stem cells, and epithelial to mesenchymal transition. Moreover, combinatory drug therapeutics along with evodiamine enhances the anticancer efficacy of chemotherapeutic drugs in various cancers by overcoming the chemo resistance and radio resistance shown by cancer cells. It has been widely used in preclinical trials in animal models, exhibiting very negligible side effects against normal cells and effective against cancer cells. The pharmacokinetic and pharmacodynamics-based collaborations of evodiamine are also included. Due to its poor bioavailability, synthetic analogs of evodiamine and its nano capsule have been formulated to enhance its bioavailability and reduce toxicity. In addition, this review summarizes the ongoing research on the mechanisms behind the antitumor potential of evodiamine, which proposes an exciting future for such interests in cancer biology. [ABSTRACT FROM AUTHOR]

Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs—oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive effect of therapy with TRL agonists on the course of hemato-oncological diseases. Ligands impact activation of antigen-presenting cells which results in production of cytokines, transfer of mentioned cells to the lymphoid tissue and co-stimulatory surface molecules expression required for T-cell activation. Toll-like receptor agonists have already been used in oncology especially in the treatment of dermatological neoplastic lesions. The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines. [ABSTRACT FROM AUTHOR]

Despite the advancement in diagnostic and treatment approach, cancer still remains as the leading cause of deaths worldwide. Due to the heterogeneity of tumours, many targeted therapies and personalised medicine have become ineffective. Recently, researchers have been working on the discovery and development of "dirty drugs" which simultaneously target several key pathways and mechanisms to kill cancerous cells. The cancer hallmarks, which consist of 10 characteristics of cancer development, have become the guideline to investigate the potential of bioactive compounds to be a "dirty drug". As a locally-grown crops, Carica papaya has been explored extensively for their pharmacological activities including anti-cancer properties. This review provides an insight to the development of papaya extracts or their bioactive compounds as a potential broad-spectrum therapy for cancer by referring the mechanisms of actions against cancer hallmarks. [ABSTRACT FROM AUTHOR]

Isoflavones are secondary metabolites that represent the most abundant category of plant polyphenols. Dietary soy, kudzu, and red clover contain primarily genistein, daidzein, glycitein, puerarin, formononetin, and biochanin A. The structural similarity of these compounds to β-estradiol has demonstrated protection against age-related and hormone-dependent diseases in both genders. Demonstrative shreds of evidence confirmed the fundamental health benefits of the consumption of these isoflavones. These relevant activities are complex and largely driven by the source, active ingredients, dose, and administration period of the bioactive compounds. However, the preclinical and clinical studies of these compounds are greatly variable, controversial, and still with no consensus due to the non-standardized research protocols. In addition, absorption, distribution, metabolism, and excretion studies, and the safety profile of isoflavones have been far limited. This highlights a major gap in understanding the potentially critical role of these isoflavones as prospective replacement therapy. Our general review exclusively focuses attention on the crucial role of isoflavones derived from these plant materials and critically highlights their bioavailability, possible anticancer, antiaging potentials, and microbiome modulation. Despite their fundamental health benefits, plant isoflavones reveal prospective therapeutic effects that worth further standardized analysis. [ABSTRACT FROM AUTHOR]

Ferroptosis is a regular cell death pathway that has been proposed as a suitable therapeutic target in cancer and neurodegenerative diseases. Since its definition in 2012, a few hundred ferroptosis modulators have been reported. Based on a literature search, we collected a set of diverse ferroptosis modulators and analyzed them in terms of their structural features and physicochemical and drug-likeness properties. Ferroptosis modulators are mostly natural products or semisynthetic derivatives. In this review, we focused on the abundant subgroup of polyphenolic modulators, primarily phenylpropanoids. Many natural polyphenolic antioxidants have antiferroptotic activities acting through at least one of the following effects: ROS scavenging and/or iron chelation activities, increased GPX4 and NRF2 expression, and LOX inhibition. Some polyphenols are described as ferroptosis inducers acting through the generation of ROS, intracellular accumulation of iron (II), or the inhibition of GPX4. However, some molecules have a dual mode of action depending on the cell type (cancer versus neural cells) and the (micro)environment. The latter enables their successful use (e.g., apigenin, resveratrol, curcumin, and EGCG) in rationally designed, multifunctional nanoparticles that selectively target cancer cells through ferroptosis induction. [ABSTRACT FROM AUTHOR]