Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy.

Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.

Cannabidiol induces ERK activation and ROS production to promote autophagy and ferroptosis in glioblastoma cells.

Small molecule-driven ERK activation is known to induce autophagy and ferroptosis in cancer cells. Herein the effect of cannabidiol (CBD), a phytochemical derived from Cannabis sativa, on ERK-driven autophagy and ferroptosis has been demonstrated in glioblastoma (GBM) cells (U87 and U373 cells). CBD imparted significant cytotoxicity in GBM cells, induced activation of ERK (not JNK and p38), and increased intracellular reactive oxygen species (ROS) levels. It increased the autophagy-related proteins such as LC3 II, Atg7, and Beclin-1 and modulated the expression of ferroptosis-related proteins such as glutathione peroxidase 4 (GPX4), SLC7A11, and TFRC. CBD significantly elevated the endoplasmic reticulum stress, ROS, and iron load, and decreased GSH levels. Inhibitors of autophagy (3-MA) and ferroptosis (Fer-1) had a marginal effect on CBD-induced autophagy/ferroptosis. Treatment with N-acetyl-cysteine (antioxidant) or PD98059 (ERK inhibitor) partly reverted the CBD-induced autophagy/ferroptosis by decreasing the activation of ERK and the production of ROS. Overall, CBD induced autophagy and ferroptosis through the activation of ERK and generation of ROS in GBM cells.

Peptide-functionalized, -assembled and -loaded nanoparticles in cancer therapy.

The combination of peptides and nanoparticles in cancer therapy has shown synergistic results. Nanoparticle functionalization with peptides can increase their targeting ability towards tumor cells. In some cases, the peptides can develop self-assembled nanoparticles, in combination with drugs, for targeted cancer therapy. The peptides can be loaded into nanoparticles and can be delivered by other drugs for synergistic cancer removal. Multifunctional types of peptide-based nanoparticles, including pH- and redox-sensitive classes, have been introduced in cancer therapy. The tumor microenvironment remolds, and the acceleration of immunotherapy and vaccines can be provided by peptide nanoparticles. Moreover, the bioimaging and labeling of cancers can be mediated by peptide nanoparticles. Therefore, peptides can functionalize nanoparticles in targeted cancer therapy.

Nanoparticles in tumor microenvironment remodeling and cancer immunotherapy.

Cancer immunotherapy and vaccine development have significantly improved the fight against cancers. Despite these advancements, challenges remain, particularly in the clinical delivery of immunomodulatory compounds. The tumor microenvironment (TME), comprising macrophages, fibroblasts, and immune cells, plays a crucial role in immune response modulation. Nanoparticles, engineered to reshape the TME, have shown promising results in enhancing immunotherapy by facilitating targeted delivery and immune modulation. These nanoparticles can suppress fibroblast activation, promote M1 macrophage polarization, aid dendritic cell maturation, and encourage T cell infiltration. Biomimetic nanoparticles further enhance immunotherapy by increasing the internalization of immunomodulatory agents in immune cells such as dendritic cells. Moreover, exosomes, whether naturally secreted by cells in the body or bioengineered, have been explored to regulate the TME and immune-related cells to affect cancer immunotherapy. Stimuli-responsive nanocarriers, activated by pH, redox, and light conditions, exhibit the potential to accelerate immunotherapy. The co-application of nanoparticles with immune checkpoint inhibitors is an emerging strategy to boost anti-tumor immunity. With their ability to induce long-term immunity, nanoarchitectures are promising structures in vaccine development. This review underscores the critical role of nanoparticles in overcoming current challenges and driving the advancement of cancer immunotherapy and TME modification.

Natural product/diet-based regulation of macrophage polarization: Implications in treatment of inflammatory-related diseases and cancer.

Macrophages are phagocytic cells with important physiological functions, including the digestion of cellular debris, foreign substances, and microbes, as well as tissue development and homeostasis. The tumor microenvironment (TME) shapes the aggressiveness of cancer, and the biological and cellular interactions in this complicated space can determine carcinogenesis. The TME can determine the progression, biological behavior, and therapy resistance of human cancers. The macrophages are among the most abundant cells in the TME, and their functions and secretions can determine tumor progression. The education of macrophages to M2 polarization can accelerate cancer progression, and therefore, the re-education and reprogramming of these cells is promising. Moreover, macrophages can cause inflammation in aggravating pathological events, including cardiovascular diseases, diabetes, and neurological disorders. The natural products are pleiotropic and broad-spectrum functional compounds that have been deployed as ideal alternatives to conventional drugs in the treatment of cancer. The biological and cellular interactions in the TME can be regulated by natural products, and for this purpose, they enhance the M1 polarization of macrophages, and in addition to inhibiting proliferation and invasion, they impair the chemoresistance. Moreover, since macrophages and changes in the molecular pathways in these cells can cause inflammation, the natural products impair the pro-inflammatory function of macrophages to prevent the pathogenesis and progression of diseases. Even a reduction in macrophage-mediated inflammation can prevent organ fibrosis. Therefore, natural product-mediated macrophage targeting can alleviate both cancerous and non-cancerous diseases.

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti-PD-1/PD-L1 cancer immunotherapy.

Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), have shown clinical efficacy in clinical tumour immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses to this treatment. An emerging avenue involves triggering non-apoptotic regulated cell death (RCD), a significant mechanism driving cancer cell death in diverse cancer treatments. Recent research demonstrates that combining RCD inducers with ICIs significantly enhances their antitumor efficacy across various cancer types. The use of anti-PD-1/PD-L1 immunotherapy activates CD8+ T cells, prompting the initiation of novel RCD forms, such as ferroptosis, pyroptosis, and necroptosis. However, the functions and mechanisms of non-apoptotic RCD in anti-PD1/PD-L1 therapy remain insufficiently explored. This review summarises the emerging roles of ferroptosis, pyroptosis, and necroptosis in anti-PD1/PD-L1 immunotherapy. It emphasises the synergy between nanomaterials and PD-1/PD-L1 inhibitors to induce non-apoptotic RCD in different cancer types. Furthermore, targeting cell death signalling pathways in combination with anti-PD1/PD-L1 therapies holds promise as a prospective immunotherapy strategy for tumour treatment.

Recent advancement of autophagy in polyploid giant cancer cells and its interconnection with senescence and stemness for therapeutic opportunities.

Recurrent chemotherapy-induced senescence and resistance are attributed to the polyploidization of cancer cells that involve genomic instability and poor prognosis due to their unique form of cellular plasticity. Autophagy, a pre-dominant cell survival mechanism, is crucial during carcinogenesis and chemotherapeutic stress, favouring polyploidization. The selective autophagic degradation of essential proteins associated with cell cycle progression checkpoints deregulate mitosis fidelity and genomic integrity, imparting polyploidization of cancer cells. In connection with cytokinesis failure and endoreduplication, autophagy promotes the formation, maintenance, and generation of the progeny of polyploid giant cancer cells. The polyploid cancer cells embark on autophagy-guarded elevation in the expression of stem cell markers, along with triggered epithelial and mesenchymal transition and senescence. The senescent polyploid escapers represent a high autophagic index than the polyploid progeny, suggesting regaining autophagy induction and subsequent autophagic degradation, which is essential for escaping from senescence/polyploidy, leading to a higher proliferative phenotypic progeny. This review documents the various causes of polyploidy and its consequences in cancer with relevance to autophagy modulation and its targeting for therapeutic intervention as a novel therapeutic strategy for personalized and precision medicine.

Natural compounds targeting YAP/TAZ axis in cancer: Current state of art and challenges.

Cancer has become a burgeoning global healthcare concern marked by its exponential growth and significant economic ramifications. Though advancements in the treatment modalities have increased the overall survival and quality of life, there are no definite treatments for the advanced stages of this malady. Hence, understanding the diseases etiologies and the underlying molecular complexities, will usher in the development of innovative therapeutics. Recently, YAP/TAZ transcriptional regulation has been of immense interest due to their role in development, tissue homeostasis and oncogenic transformations. YAP/TAZ axis functions as coactivators within the Hippo signaling cascade, exerting pivotal influence on processes such as proliferation, regeneration, development, and tissue renewal. In cancer, YAP is overexpressed in multiple tumor types and is associated with cancer stem cell attributes, chemoresistance, and metastasis. Activation of YAP/TAZ mirrors the cellular "social" behavior, encompassing factors such as cell adhesion and the mechanical signals transmitted to the cell from tissue structure and the surrounding extracellular matrix. Therefore, it presents a significant vulnerability in the clogs of tumors that could provide a wide window of therapeutic effectiveness. Natural compounds have been utilized extensively as successful interventions in the management of diverse chronic illnesses, including cancer. Owing to their capacity to influence multiple genes and pathways, natural compounds exhibit significant potential either as adjuvant therapy or in combination with conventional treatment options. In this review, we delineate the signaling nexus of YAP/TAZ axis, and present natural compounds as an alternate strategy to target cancer.

Transmembrane protein 25 abrogates monomeric EGFR-driven STAT3 activation in triple-negative breast cancer.

In wild-type cells, TMEM25 physically associates with EGFR monomer and suppresses the EGFR-mediated STAT3 phosphorylation, which results in the sequestration of unphosphorylated STAT3 in the cytoplasm. In TMEM-/- cells, EGFR monomer phosphorylates STAT3 at the basal level.

c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy.

BACKGROUND: c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS: The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS: The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.

SKP2 promotes the metastasis of pancreatic ductal adenocarcinoma by suppressing TRIM21-mediated PSPC1 degradation.

Despite significant advances in diagnostic techniques and treatment approaches, the prognosis of pancreatic ductal adenocarcinoma (PDAC) is still poor. Previous studies have reported that S-phase kinase-associated protein 2 (SKP2), a subunit of the SCF E3 ubiquitin ligase complex, is engaged in the malignant biological behavior of some tumor entities. However, SKP2 has not been fully investigated in PDAC. In the present study, it was observed that high expression of SKP2 significantly correlates with decreased survival time. Further experiments suggested that SKP2 promotes metastasis by interacting with the putative transcription factor paraspeckle component 1 (PSPC1). According to the results of coimmunoprecipitation and ubiquitination assays, SKP2 depletion resulted in the polyubiquitination of PSPC1, followed by its degradation. Furthermore, the SKP2-mediated ubiquitination of PSPC1 partially depended on the activity of the E3 ligase TRIM21. In addition, inhibition of the SKP2/PSPC1 axis by SMIP004, a traditional inhibitor of SKP2, impaired the migration of PDAC cells. In summary, this study provides novel insight into the mechanisms involved in PDAC malignant progression. Targeting the SKP2/PSPC1 axis is a promising strategy for the treatment of PDAC.

Molecular panorama of therapy resistance in prostate cancer: a pre-clinical and bioinformatics analysis for clinical translation.

Prostate cancer (PCa) is a malignant disorder of prostate gland being asymptomatic in early stages and high metastatic potential in advanced stages. The chemotherapy and surgical resection have provided favourable prognosis of PCa patients, but advanced and aggressive forms of PCa including CRPC and AVPC lack response to therapy properly, and therefore, prognosis of patients is deteriorated. At the advanced stages, PCa cells do not respond to chemotherapy and radiotherapy in a satisfactory level, and therefore, therapy resistance is emerged. Molecular profile analysis of PCa cells reveals the apoptosis suppression, pro-survival autophagy induction, and EMT induction as factors in escalating malignant of cancer cells and development of therapy resistance. The dysregulation in molecular profile of PCa including upregulation of STAT3 and PI3K/Akt, downregulation of STAT3, and aberrant expression of non-coding RNAs are determining factor for response of cancer cells to chemotherapy. Because of prevalence of drug resistance in PCa, combination therapy including co-utilization of anti-cancer drugs and nanotherapeutic approaches has been suggested in PCa therapy. As a result of increase in DNA damage repair, PCa cells induce radioresistance and RelB overexpression prevents irradiation-mediated cell death. Similar to chemotherapy, nanomaterials are promising for promoting radiosensitivity through delivery of cargo, improving accumulation in PCa cells, and targeting survival-related pathways. In respect to emergence of immunotherapy as a new tool in PCa suppression, tumour cells are able to increase PD-L1 expression and inactivate NK cells in mediating immune evasion. The bioinformatics analysis for evaluation of drug resistance-related genes has been performed.

Concurrent inhibition of pBADS99 synergistically improves MEK inhibitor efficacy in KRASG12D-mutant pancreatic ductal adenocarcinoma.

Therapeutic targeting of KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) has remained a significant challenge in clinical oncology. Direct targeting of KRAS has proven difficult, and inhibition of the KRAS effectors have shown limited success due to compensatory activation of survival pathways. Being a core downstream effector of the KRAS-driven p44/42 MAPK and PI3K/AKT pathways governing intrinsic apoptosis, BAD phosphorylation emerges as a promising therapeutic target. Herein, a positive association of the pBADS99/BAD ratio with higher disease stage and worse overall survival of PDAC was observed. Homology-directed repair of BAD to BADS99A or small molecule inhibition of BADS99 phosphorylation by NCK significantly reduced PDAC cell viability by promoting cell cycle arrest and apoptosis. NCK also abrogated the growth of preformed colonies of PDAC cells in 3D culture. Furthermore, high-throughput screening with an oncology drug library to identify potential combinations revealed a strong synergistic effect between NCK and MEK inhibitors in PDAC cells harboring either wild-type or mutant-KRAS. Mechanistically, both mutant-KRAS and MEK inhibition increased the phosphorylation of BADS99 in PDAC cells, an effect abrogated by NCK. Combined pBADS99-MEK inhibition demonstrated strong synergy in reducing cell viability, enhancing apoptosis, and achieving xenograft stasis in KRAS-mutant PDAC. In conclusion, the inhibition of BADS99 phosphorylation enhances the efficacy of MEK inhibition, and their combined inhibition represents a mechanistically based and potentially effective therapeutic strategy for the treatment of KRAS-mutant PDAC.

Cannabidiol activates MAPK pathway to induce apoptosis, paraptosis, and autophagy in colorectal cancer cells.

Mitogen-activated protein kinase (MAPK) activation by natural compounds is known to be involved in the induction of apoptosis, paraptosis, and autophagy. Cannabidiol (CBD), a bioactive compound found in Cannabis sativa, is endowed with many pharmacological activities. We investigated the cytotoxic effect of CBD in a panel of colorectal cancer (CRC) cells (HT-29, SW480, HCT-116, and HCT-15). CBD induced significant cytotoxicity as evidenced by the results of MTT  assay, live-dead assay, and flow cytometric analysis. Since CBD displayed cytotoxicity against CRC cells, we examined the effect of CBD on apoptosis, paraptosis, and autophagy. CBD decreased the expression of antiapoptotic proteins and increased the Annexin-V-positive as well as TUNEL-positive cells suggesting that CBD induces apoptosis. CBD increased the expression of ATF4 (activating transcription factor 4) and CHOP (CCAAT/enhancer-binding protein homologous protein), elevated endoplasmic reticulum stress, and enhanced reactive oxygen species levels indicating that CBD also promotes paraptosis. CBD also induced the expression of Atg7, phospho-Beclin-1, and LC3 suggesting that CBD also accelerates autophagy. Since, the MAPK pathway is a common cascade that is involved in the regulation of apoptosis, paraptosis, and autophagy, we investigated the effect of CBD on the activation of JNK, p38, and ERK pathways. CBD activated all the forms of MAPK proteins and pharmacological inhibition of these proteins reverted the observed effects. Our findings implied that CBD could induce CRC cell death by activating apoptosis, paraptosis, and autophagy through the activation of the MAPK pathway.

Phytostilbenes in lymphoma: Focuses on the mechanistic and clinical prospects of resveratrol, pterostilbene, piceatannol, and pinosylvin.

Lymphoma is a cancer affecting the lymphatic system that fights infections and diseases. In addition to surgery, radiotherapy, and chemotherapy, novel approaches have recently been investigated, such as phytostilbenes in treating lymphoma. Phytostilbenes are natural compounds present in various plants and have been shown to have different therapeutic effects, including anticancer properties. Resveratrol is a main phytostilbene with various derivates followed by pterostilbene and piceatannol. Studies have revealed that phytostilbenes can suppress the growth and proliferation of lymphoma cells by inducing apoptosis and inhibiting specific enzyme activity in cancer cell survival. The compounds also have antiinflammatory effects contributing to reducing lymphoma-associated inflammation. Additionally, phytostilbenes have been shown to increase the immune system's ability to fight cancer cells by activating immune cells (T-cells and natural killer cells). This review investigates the potential therapeutic effects of phytostilbenes, including resveratrol, pterostilbene, piceatannol, and pinosylvin, against lymphoma.

Delineating the role of nuclear receptors in colorectal cancer, a focused review.

Colorectal cancer (CRC) stands as one of the most prevalent form of cancer globally, causing a significant number of deaths, surpassing 0.9 million in the year 2020. According to GLOBOCAN 2020, CRC ranks third in incidence and second in mortality in both males and females. Despite extensive studies over the years, there is still a need to establish novel therapeutic targets to enhance the patients' survival rate in CRC. Nuclear receptors (NRs) are ligand-activated transcription factors (TFs) that regulate numerous essential biological processes such as differentiation, development, physiology, reproduction, and cellular metabolism. Dysregulation and anomalous expression of different NRs has led to multiple alterations, such as impaired signaling cascades, mutations, and epigenetic changes, leading to various diseases, including cancer. It has been observed that differential expression of various NRs might lead to the initiation and progression of CRC, and are correlated with poor survival outcomes in CRC patients. Despite numerous studies on the mechanism and role of NRs in this cancer, it remains of significant scientific interest primarily due to the diverse functions that various NRs exhibit in regulating key hallmarks of this cancer. Thus, modulating the expression of NRs with their agonists and antagonists, based on their expression levels, holds an immense prospect in the diagnosis, prognosis, and therapeutical modalities of CRC. In this review, we primarily focus on the role and mechanism of NRs in the pathogenesis of CRC and emphasized the significance of targeting these NRs using a variety of agents, which may represent a novel and effective strategy for the prevention and treatment of this cancer.

Therapeutic potential of tocotrienols as chemosensitizers in cancer therapy.

Chemoresistance is the adaptation of cancer cells against therapeutic agents. When exhibited by cancer cells, chemoresistance helps them to avoid apoptosis, cause relapse, and metastasize, making it challenging for chemotherapeutic agents to treat cancer. Various strategies like dosage modification of drugs, nanoparticle-based delivery of chemotherapeutics, antibody-drug conjugates, and so on are being used to target and reverse chemoresistance, one among such is combination therapy. It uses the combination of two or more therapeutic agents to reverse multidrug resistance and improve the effects of chemotherapy. Phytochemicals are known to exhibit chemosensitizing properties and are found to be effective against various cancers. Tocotrienols (T3) and tocopherols (T) are natural bioactive analogs of vitamin E, which exhibit important medicinal value and potential curative properties apart from serving as an antioxidant and nutrient supplement. Notably, T3 exhibits a variety of pharmacological activities like anticancer, anti-inflammatory, antiproliferative, and so on. The chemosensitizing property of tocotrienol is exhibited by modulating several signaling pathways and molecular targets involved in cancer cell survival, proliferation, invasion, migration, and metastasis like NF-κB, STATs, Akt/mTOR, Bax/Bcl-2, Wnt/ß-catenin, and many more. T3 sensitizes cancer cells to chemotherapeutic drugs including cisplatin, doxorubicin, and paclitaxel increasing drug concentration and cytotoxicity. Discussed herewith are the chemosensitizing properties of tocotrienols on various cancer cell types when combined with various drugs and biological molecules.

Exploring the nexus of nuclear receptors in hematological malignancies.

Hematological malignancies (HM) represent a subset of neoplasms affecting the blood, bone marrow, and lymphatic systems, categorized primarily into leukemia, lymphoma, and multiple myeloma. Their prognosis varies considerably, with a frequent risk of relapse despite ongoing treatments. While contemporary therapeutic strategies have extended overall patient survival, they do not offer cures for advanced stages and often lead to challenges such as acquisition of drug resistance, recurrence, and severe side effects. The need for innovative therapeutic targets is vital to elevate both survival rates and patients' quality of life. Recent research has pivoted towards nuclear receptors (NRs) due to their role in modulating tumor cell characteristics including uncontrolled proliferation, differentiation, apoptosis evasion, invasion and migration. Existing evidence emphasizes NRs' critical role in HM. The regulation of NR expression through agonists, antagonists, or selective modulators, contingent upon their levels, offers promising clinical implications in HM management. Moreover, several anticancer agents targeting NRs have been approved by the Food and Drug Administration (FDA). This review highlights the integral function of NRs in HM's pathophysiology and the potential benefits of therapeutically targeting these receptors, suggesting a prospective avenue for more efficient therapeutic interventions against HM.

Harnessing Sulforaphane Potential as a Chemosensitizing Agent: A Comprehensive Review.

Recent advances in oncological research have highlighted the potential of naturally derived compounds in cancer prevention and treatment. Notably, sulforaphane (SFN), an isothiocyanate derived from cruciferous vegetables including broccoli and cabbage, has exhibited potent chemosensitizing capabilities across diverse cancer types of bone, brain, breast, lung, skin, etc. Chemosensitization refers to the enhancement of cancer cell sensitivity to chemotherapy agents, counteracting the chemoresistance often developed by tumor cells. Mechanistically, SFN orchestrates this sensitization by modulating an array of cellular signaling pathways (e.g., Akt/mTOR, NF-κB, Wnt/ß-catenin), and regulating the expression and activity of pivotal genes, proteins, and enzymes (e.g., p53, p21, survivin, Bcl-2, caspases). When combined with conventional chemotherapeutic agents, SFN synergistically inhibits cancer cell proliferation, invasion, migration, and metastasis while potentiating drug-induced apoptosis. This positions SFN as a potential adjunct in cancer therapy to augment the efficacy of standard treatments. Ongoing preclinical and clinical investigations aim to further delineate the therapeutic potential of SFN in oncology. This review illuminates the multifaceted role of this phytochemical, emphasizing its potential to enhance the therapeutic efficacy of anti-cancer agents, suggesting its prospective contributions to cancer chemosensitization and management.

Extracellular vesicle-mediated ferroptosis, pyroptosis, and necroptosis: potential clinical applications in cancer therapy.

Extracellular vesicles (EVs) have gained increasing recognition as significant regulators of intercellular communication in various physiological and pathological processes. These vesicles play a pivotal role in cancer progression by facilitating the transfer of diverse cargoes, including lipids, proteins, and nucleic acids. Regulated cell death (RCD), the orderly and autonomous death of cells, is controlled by a variety of biomacromolecules and, in turn, influences various biological processes and cancer progression. Recent studies have demonstrated that EV cargoes regulate diverse oncogenes and tumor suppressors to mediate different nonapoptotic forms of RCD, notably ferroptosis, pyroptosis, and necroptosis. Nevertheless, comprehensive exploration of EV-mediated nonapoptotic RCD forms in the context of cancer has not been performed. This review summarizes the progress regarding the biological functions and underlying mechanisms of EVs in mediating nonapoptotic RCD by delivery of cargoes to regulate tumor progression. Additionally, the review delves into the potential clinical applications of EV-mediated cell death and its significance in the areas of cancer diagnosis and therapy.