CD44/PD-L1-mediated networks in drug resistance and immune evasion of breast cancer stem cells: Promising targets of natural compounds.

Cancer stem cells (CSCs) significantly interfere with immunotherapy, leading to challenges such as low response rates and acquired resistance. PD-L1 expression is associated with the CSC population's overexpression of CD44. Mounting evidence suggests that the breast cancer stem cell (BCSC) marker CD44 and the immune checkpoint PD-L1 contribute to treatment failure through their networks. Natural compounds can overcome therapy resistance in breast cancer by targeting mechanisms underlying resistance in BCSCs. This review provides an updated insight into the CD44 and PD-L1 networks of BCSCs in mediating metastasis and immune evasion. The review critically examines existing literature, providing a comprehensive understanding of the topic and emphasizing the impact of natural flavones on the signaling pathways of BCSCs. Additionally, the review discusses the potential of natural compounds in targeting CD44 and PD-L1 in breast cancer (BC). Natural compounds consistently show potential in targeting regulatory mechanisms of BCSCs, inducing loss of stemness, and promoting differentiation. They offer a promising approach for developing alternative therapeutic strategies to manage breast cancer.

Neoantigens and cancer-testis antigens as promising vaccine candidates for triple-negative breast cancer: Delivery strategies and clinical trials.

Immunotherapy is gaining prominence as a promising strategy for treating triple-negative breast cancer (TNBC). Neoantigens (neoAgs) and cancer-testis antigens (CTAs) are tumor-specific targets originating from somatic mutations and epigenetic changes in cancer cells. These antigens hold great promise for personalized cancer vaccines, as supported by preclinical and early clinical evidence in TNBC. This review delves into the potential of neoAgs and CTAs as vaccine candidates, emphasizing diverse strategies and delivery approaches. It also highlights the current status of vaccination modalities undergoing clinical trials in TNBC therapy. A comprehensive understanding of neoAgs, CTAs, vaccination strategies, and innovative delivery methods is crucial for optimizing neoAg-based immunotherapies in clinical practice.

Revitalizing Cancer Treatment: Exploring the Role of Drug Repurposing.

Cancer persists as a global challenge necessitating continual innovation in treatment strategies. Despite significant advancements in comprehending the disease, cancer remains a leading cause of mortality worldwide, exerting substantial economic burdens on healthcare systems and societies. The emergence of drug resistance further complicates therapeutic efficacy, underscoring the urgent need for alternative approaches. Drug repurposing, characterized by the utilization of existing drugs for novel clinical applications, emerges as a promising avenue for addressing these challenges. Repurposed drugs, comprising FDA-approved (in other disease indications), generic, off-patent, and failed medications, offer distinct advantages including established safety profiles, cost-effectiveness, and expedited development timelines compared to novel drug discovery processes. Various methodologies, such as knowledge-based analyses, drug-centric strategies, and computational approaches, play pivotal roles in identifying potential candidates for repurposing. However, despite the promise of repurposed drugs, drug repositioning confronts formidable obstacles. Patenting issues, financial constraints associated with conducting extensive clinical trials, and the necessity for combination therapies to overcome the limitations of monotherapy pose significant challenges. This review provides an in-depth exploration of drug repurposing, covering a diverse array of approaches including experimental, re-engineering protein, nanotechnology, and computational methods. Each of these avenues presents distinct opportunities and obstacles in the pursuit of identifying novel clinical uses for established drugs. By examining the multifaceted landscape of drug repurposing, this review aims to offer comprehensive insights into its potential to transform cancer therapeutics.

Exploring the Gamma-Ray Enhanced NIR-Luminescence and Cytotoxic Potential of Lanthanide-Naphthalene Dicarboxylate based Metal-Organic Frameworks.

In this investigation, we explore the integration of lanthanides into Metal-Organic Frameworks (MOFs) to enable Near-Infrared (NIR) emission. Specifically, we focus on Lanthanide-Naphthalene Dicarboxylate based MOFs (Ln-MOFs), incorporating elements such as Praseodymium (Pr), Samarium (Sm), Dysprosium (Dy), and Erbium (Er). The synthesis of Ln-MOFs is achieved via the hydrothermal method. The structure, morphology, thermal stability, and luminescence properties of synthesized Ln-MOFs have been evaluated through different characterization techniques. Upon photoexcitation at 350 nm, Ln-MOFs show the emission in the Visible and NIR region. Further, the luminescence intensity of Ln-MOFs enhanced by 2-3 folds in the visible region and 6-8 folds in NIR region after exposing to Gamma irradiation at 150 kGy. Cytotoxic effect on the viability of MDA-MB 231 and MDA-MB 468 Triple negative breast cancer (TNBC) cells was evaluated by MTT assay. The results revealed that among all synthesized MOFs, Pr-MOF exhibited an aggressive cytotoxic effect. Additionally, analysis of phase-contrast microscopy data indicates that Pr-MOF induces alterations in the morphology of both MDA-MB 231 and MDA-MB 468 TNBC cells when compared to untreated controls. The findings in this study reveal the utilization of Ln-MOFs for studying cytotoxicity and highlight their ability to enhance near-infrared (NIR) emission when exposed to gamma radiation.

mRNA vaccines and their delivery strategies: A journey from infectious diseases to cancer.

mRNA vaccines have evolved as promising cancer therapies. These vaccines can encode tumor-allied antigens, thus enabling personalized treatment approaches. They can also target cancer-specific mutations and overcome immune evasion mechanisms. They manipulate the body's cellular functions to produce antigens, elicit immune responses, and suppress tumors by overcoming limitations associated with specific histocompatibility leukocyte antigen molecules. However, successfully delivering mRNA into target cells destroys a crucial challenge. Viral and nonviral vectors (lipid nanoparticles and cationic liposomes) have shown great capacity in protecting mRNA from deterioration and assisting in cellular uptake. Cell-penetrating peptides, hydrogels, polymer-based nanoparticles, and dendrimers have been investigated to increase the delivery efficacy and immunogenicity of mRNA. This comprehensive review explores the landscape of mRNA vaccines and their delivery platforms for cancer, addressing design considerations, diverse delivery strategies, and recent advancements. Overall, this review contributes to the progress of mRNA vaccines as an innovative strategy for effective cancer treatment.

Unleashing the Power of Yes-Associated Protein in Ferroptosis and Drug Resistance in Breast Cancer, with a Special Focus on Therapeutic Strategies.

The YAP protein is a critical oncogenic mediator within the Hippo signaling pathway and has been implicated in various cancer types. In breast cancer, it frequently becomes activated, thereby contributing to developing drug-resistance mechanisms. Recent studies have underscored the intricate interplay between YAP and ferroptosis within the breast tumor microenvironment. YAP exerts a negative regulatory effect on ferroptosis, promoting cancer cell survival and drug resistance. This review offers a concise summary of the current understanding surrounding the interplay between the YAP pathway, ferroptosis, and drug-resistance mechanisms in both bulk tumor cells and cancer stem cells. We also explore the potential of natural compounds alone or in combination with anticancer therapies for targeting the YAP pathway in treating drug-resistant breast cancer. This approach holds the promise of enhancing the effectiveness of current treatments and paving the way for developing novel therapeutics.

Obesity associated pancreatic ductal adenocarcinoma: Therapeutic challenges.

Obesity is a prominent health issue worldwide and directly impacts pancreatic health, with obese individuals exhibiting a significant risk for increasing pancreatic ductal adenocarcinoma (PDAC). Several factors potentially explain the increased risk for the development of PDAC, including obesity-induced chronic inflammation within and outside of the pancreas, development of insulin resistance and metabolic dysfunction, promotion of immune suppression within the pancreas during inflammation, pre- and malignant stages, variations in hormones levels (adiponectin, ghrelin, and leptin) produced from the adipose tissue, and acquisition of somatic mutations in tumor once- and suppressor proteins critical for pancreatic tumorigenesis. In this manuscript, we will explore the broad impact of these obesity-induced risk factors on the development and progression of PDAC, focusing on changes within the tumor microenvironment (TME) as they pertain to prevention, current therapeutic strategies, and future directions for targeting obesity management as they relate to the prevention of pancreatic tumorigenesis.

Exploring the role of CD151 in the tumor immune microenvironment: Therapeutic and clinical perspectives.

CD151 is a transmembrane protein implicated in tumor progression and has been shown to regulate various cellular and molecular mechanisms contributing to malignancy. More recently, the role of CD151 in the tumor immune microenvironment (TIME) has gained attention as a potential target for cancer therapy. This review aims to explore the role of CD151 in the TIME, focusing on the therapeutic and clinical perspectives. The role of CD151 in regulating the interactions between tumor cells and the immune system will be discussed, along with the current understanding of the molecular mechanisms underlying these interactions. The current state of the development of CD151-targeted therapies and the potential clinical applications of these therapies will also be reviewed. This review provides an overview of the current knowledge on the role of CD151 in the TIME and highlights the potential of CD151 as a therapeutic target for cancer treatment.

Complexity and diversity of FOXP3 isoforms: Novel insights into the regulation of the immune response in metastatic breast cancer.

FOXP3 is a key transcription factor in the regulation of immune responses, and recent studies have uncovered the complexity and diversity of FOXP3 isoforms in various cancers, including metastatic breast cancers (mBCs). It has dual role in the tumor microenvironment of mBCs. This review aims to provide novel insights into the complexity and diversity of FOXP3 isoforms in the regulation of the immune response in breast cancer. We discuss the molecular mechanisms underlying the function of FOXP3 isoforms, including their interaction with other proteins, regulation of gene expression, and impact on the immune system. We also highlight the importance of understanding the role of FOXP3 isoforms in breast cancer and the potential for using them as therapeutic targets. This review highlights the crucial role of FOXP3 isoforms in the regulation of the immune response in breast cancer and underscores the need for further research to fully comprehend their complex and diverse functions.

Proteomic profiling and ROC analysis identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug in resistant TNBC.

Triple-negative breast cancer is high heterogeneous, aggressive, and metastatic with poor prognosis. Despite of advances in targeted therapies, TNBC has been reported to cause high morbidity and mortality. A rare subpopulation within the tumor microenvironment organized into a hierarchy of cancer stem cells is responsible for therapy resistance and tumor recurrence. Repurposing of antiviral drugs for cancer treatment is gaining momentum due to reduced cost, labour, and research time, but limited due to lack of prognostic, and predictive markers. The present study investigates proteomic profiling and ROC analysis to identify CD151 and ELAVL1 as potential therapy response markers for the antiviral drug 2-thio-6-azauridine (TAU) in resistant TNBC. The stemness of MDA-MB 231 and MDA-MD 468 adherent cells was enriched by culturing them under non-adherent and non-differentiation conditions. Then, CD151+ subpopulation was isolated and characterized for the enrichment of stemness. This study found that CD151 has overexpressed in stemness enriched subpopulations, and also showed CD44 high and CD24 low expression along with stem cell-related transcription factors octamer-binding transcription factor 4 (OCT4) and Sex determining Y-box 2 (SOX2). This study also found that TAU induced significant cytotoxicity and genotoxicity in the CD151+TNBC subpopulation and inhibited their proliferation by inducing DNA damage, cell cycle arrest at the G2M phase, and apoptosis. Further, a proteomic profiling study showed that the expression of CD151 along with ELAVL1, an RNA-binding protein, was significantly reduced with TAU treatment. KM plotter showed correlation of CD151 and ELAVL1 gene expression with a poor prognosis of TNBC. ROC analysis predicted and validated CD151 and ELAVL1 as best therapy response marker for TAU in TNBC. These findings provide new insight into repurposing antiviral drug TAU for treatment of metastatic and drug resistant TNBC.

Tetraspanin-enriched Microdomain Containing CD151, CD9, and TSPAN 8 - Potential Mediators of Entry and Exit Mechanisms in Respiratory Viruses Including SARS-CoV-2.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which originated in Wuhan, the Hubei region of China, has become a pandemic worldwide. It can transmit through droplets and enter via oral, nasal, and eye mucous membranes. It consists of single-stranded RNA (positive-sense), nonstructural proteins including enzymes and transcriptional proteins, and structural proteins such as Spike, Membrane, Envelope, and Nucleocapsid -proteins. SARS-CoV-2 mediates S-proteins entry and exit via binding to host cell surface proteins like tetraspanins. The transmembrane tetraspanins, CD151, CD9, and tetraspanin 8 (TSPAN8), facilitate the entry of novel coronaviruses by scaffolding host cell receptors and proteases. Also, CD151 was reported to increase airway hyperresponsiveness to calcium and nuclear viral export signaling. They may facilitate entry and exit by activating the serine proteases required to prime S-proteins in tetraspanin-enriched microdomains (TEMs). This article updates recent advances in structural proteins, their epitopes and putative receptors, and their regulation by proteases associated with TEMs. This review furnishes recent updates on the role of CD151 in the pathophysiology of SARS-CoV-2. We describe the role of CD151 in a possible mechanism of entry and exit in the airway, a major site for infection of SARS-CoV-2. We also updated current knowledge on the role of CD9 and TSPAN 8 in the entry and exit mechanism of coronaviruses. Finally, we discussed the importance of some small molecules which target CD151 as possible targeted therapeutics for COVID-19. In conclusion, this study could identify new targets and specific therapeutics to control emerging virus infections.

Cancer Stem Cells and Circulatory Tumor Cells Promote Breast Cancer Metastasis.

Breast cancer (BC) is a highly metastatic, pathological cancer that significantly affects women worldwide. The mortality rate of BC is related to its heterogeneity, aggressive phenotype, and metastasis. Recent studies have highlighted that the tumor microenvironment (TME) is critical for the interplay between metastasis mediators in BC. BC stem cells, tumor-derived exosomes, circulatory tumor cells (CTCs), and signaling pathways dynamically remodel the TME and promote metastasis. This review examines the cellular and molecular mechanisms governing the epithelial to mesenchymal transition (EMT) that facilitate metastasis. This review also discusses the role of cancer stem cells (CSCs), tumor-derived exosomes, and CTs in promoting BC metastasis. Furthermore, the review emphasizes major signaling pathways that mediate metastasis in BC. Finally, the interplay among CSCs, exosomes, and CTCs in mediating metastasis have been highlighted. Therefore, understanding the molecular cues that mediate the association of CSCs, exosomes, and CTCs in TME helps to optimize systemic therapy to target metastatic BC.

Insight into drug sensitizing effect of diallyl disulfide and diallyl trisulfide from Allium sativum L. on paclitaxel-resistant triple-negative breast cancer cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Ayurvedic practitioners and herbal healers in India and China have extensively used garlic (Allium sativum L.) to treat cancers. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are major volatile organosulfur phytochemical constituents found in garlic. AIM OF THE STUDY: To find new insight into the drug sensitizing effect of DADS and DATS on paclitaxel (PTX)-resistant triple-negative breast cancer cells (TNBC/PR). MATERIALS AND METHODS: This study estimates the non-toxic concentration of DADS and DATS against normal healthy breast epithelial cell line (MCF-12A) by using a trypan blue viability assay. Also, it evaluates the effect of DADS and DATS on the sensitization of established stable TNBC/PR cell clones (MDA-MB 231 PR and MDA-MB 468 PR) by MTT, BrdU incorporation, intracellular ROS, cell cycle, and apoptosis assays. RESULTS: The results show that DADS and DATS are non-cytotoxicity against MCF-12A cells. Nevertheless, DADS and DATS have shown significantly high cytotoxicity against MDA-MB 231 PR and MDA-MB 468 PR cells. They also inhibited PTX-resistant cell proliferation by blocking the cell cycle. Further, they induced apoptosis by activation of caspase 3 and 9. N-acetyl cysteine pre-treatment inhibited DADS and DATS-induced intracellular ROS release. In silico study shows that DADS and DATS interact with a large extracellular loop (LEL) of CD151 with a binding energy of -4.0 kcal/mol and transmembrane domain (TM) with a binding affinity of 11.7 and 13.6 kcal/mol, respectively. They also inhibited the surface expression of CD151 in TNBC/PR cells. CONCLUSION: This study implies that DADS and DATS could be considered for sensitizing drug-resistant breast cancers.

Diallyl disulfide and diallyl trisulfide in garlic as novel therapeutic agents to overcome drug resistance in breast cancer.

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide. It is a cancer that originates from the mammary ducts and involves mutations in multiple genes. Recently, the treatment of breast cancer has become increasingly challenging owing to the increase in tumor heterogeneity and aggressiveness, which gives rise to therapeutic resistance. Epidemiological, population-based, and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer. Diallyl disulfide (DADS) and diallyl trisulfide (DATS) are the main allyl sulfur compounds present in garlic, and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation, tumor metastasis, and angiogenesis. The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer. This review discusses the potential anticancer activities of DADS and DATS, with emphasis on drug resistance in triple-negative breast cancer (TNBC). Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mechanisms of TNBC, especially in clinical studies.

Tumor-associated macrophages: Potential target of natural compounds for management of breast cancer.

A large body of experimental research reveals that tumor-associated macrophages (TAMs) are the major immunosuppressor cells in the breast tumor microenvironment (TME). The infiltration of macrophages is correlated with inverse outcomes like disease-free survival and overall survival of cancer patients. They are responsible for heterogeneity, metastasis, and drug resistance. Further, their density in tumor beds is correlated with stage and therapy response. The current review is aimed at summarizing mechanisms and signaling pathways that modulate immune-suppressive phenotype and expansion of TAMs. The review presents an overview of the interdependence of tumor cells and TAMs in TME to promote metastasis, drug resistance and immune suppressive phenotype. This review also presents the potential natural compounds that modulate the immune-suppressive functions of TAMs and their signaling pathways. Finally, this review provides nanotechnology approaches for the targeted delivery of natural products. This review shed light on BC management including clinical studies on the prognostic relevance of TAMs and natural compounds that sensitizes BC.

Current Overview on the Potency of Natural Products for Modulating Myeloid-derived Suppressor Cells Dependent Cold Tumors.

Ample data pertaining to the use of MDSCs have been documented. However, the potency of natural products in targeting MDSCs in the light of the tumor immune microenvironment (TME) has not been discussed vividly. The current review is an amalgamation of the documented literature pertaining to the effectiveness of various natural products supported by in silico experimental data. The combination of bioinformatics to wet bench experimentation with natural products against cancer specifically targeting MDSCs can be a promising approach to mitigate cancer.

Diallyl disulfide and diallyl trisulfide in garlic as novel therapeutic agents to overcome drug resistance in breast cancer / 药物分析学报

Breast cancer is one of the leading causes of cancer-related deaths in women worldwide.It is a cancer that originates from the mammary ducts and involves mutations in multiple genes.Recently,the treatment of breast cancer has become increasingly challenging owing to the increase in tumor het-erogeneity and aggressiveness,which gives rise to therapeutic resistance.Epidemiological,population-based,and hospital-based case-control studies have demonstrated an association between high intake of certain Allium vegetables and a reduced risk in the development of breast cancer.Diallyl disulfide(DADS)and diallyl trisulfide(DATS)are the main allyl sulfur compounds present in garlic,and are known to exhibit anticancer activity as they interfere with breast cancer cell proliferation,tumor metastasis,and angiogenesis.The present review highlights multidrug resistance mechanisms and their signaling pathways in breast cancer.This review discusses the potential anticancer activities of DADS and DATS,with emphasis on drug resistance in triple-negative breast cancer(TNBC).Understanding the anticancer activities of DADS and DATS provides insights into their potential in targeting drug resistance mecha-nisms of TNBC,especially in clinical studies.

Reactive oxygen species (ROS): Critical roles in breast tumor microenvironment.

Increases in Reactive oxygen species (ROS) have been reported in breast tumors and their surrounding tumor microenvironment (TME) cells. ROS are critical factors in breast TME as they ensure bidirectional communication among various components and mediate multi-faceted roles in tumor progression and metastasis. This paper presents a detailed and comprehensive review of the studies exploring ROS and various forms of oxidative stress in cancer progression, specifically breast cancer (BC), its microenvironment and associated cell types. The paper focuses on several diverse aspects of cellular and molecular biology of cancer, with pharmacological implications of phytochemicals in BC. We also describe the role of ROS in the genetic and epigenetic reprogramming of the TME, metastasis, and drug resistance as well as regulators of BC TME. Additionally, we discuss ROS-mediated TME therapy and the therapeutic conundrum of breast TME. These contributions could prompt the development of personalized anti-cancer drugs for the treatment of highly complex and aggressive BCs.

E6 and E7 Oncoproteins: Potential Targets of Cervical Cancer.

Cervical cancer (CC) is the fourth leading cancer in women in the age group of 15-44 years globally. Experimental as well as epidemiological studies identified that type16 and 18 HPV cause 70% of precancerous cervical lesions as well as cervical cancer worldwide by bringing about genetic as well as epigenetic changes in the host genome. The insertion of the HPV genome triggers various defense mechanisms including the silencing of tumor suppressor genes as well as activation of oncogenes associated with cancer metastatic pathway. E6 and E7 are small oncoproteins consisting of 150 and 100 amino acids, respectively. These oncoproteins affect the regulation of the host cell cycle by interfering with p53 and pRb. Further, these oncoproteins adversely affect the normal functions of the host cell by binding to their signaling proteins. Recent studies demonstrated that E6 and E7 oncoproteins are potential targets for CC. Therefore, this review discusses the role of E6 and E7 oncoproteins in metastasis and drug resistance as well as their regulation, early oncogene mediated signaling pathways. This review also uncovers recent updates on molecular mechanisms of E6 and E7 mediated phytotherapy, gene therapy, immune therapy, and vaccine strategies as well as diagnosis through precision testing. Therefore, understanding the potential role of E6/E7 in metastasis and drug resistance along with targeted treatment, vaccine, and precision diagnostic strategies, could be useful for the prevention and treatment of cervical cancer.

Molecular modeling and in vitro study on pyrocatechol as potential pharmacophore of CD151 inhibitor.

CD151 has been recognized as a prognostic marker, the therapeutic target of breast cancers, but less explored for small molecule inhibitors due to lack of a validated model. The 3-D structure of CD151 large extracellular loop (LEL) was modeled using the LOMETS server and validated by the Ramachandran plot. The validated structure was employed for molecular docking and structure-based pharmacophore analysis. Druglikeness was evaluated by the ADMET description protocol. Antiproliferative activity was evaluated by MTT, BrdU incorporation, flow cytometry, and cell death ELISAPLUS assay. This study predicted the best model for CD151-LEL with 94.1% residues in favored regions and Z score -2.79 kcal/mol using the threading method. The web-based receptor cavity method identified one functional target site, which was suitable for the binding of aromatic and heterocyclic compounds. Molecular docking study identified pyrocatechol (PCL) and 5-fluorouracil (FU) as potential leads of CD151-LEL. The pharmacophore model identified interaction points of modeled CD151-LEL with PCL and FU. Also, the analysis of ADMET properties revealed the drug-likeness of PCL and FU. The viability of MDA-MB 231 cells was significantly reduced with PCL and FU but less affected MCF-12A, normal healthy breast epithelial cell line. With 50% toxic concentration, both PCL and FU significantly inhibited 82.46 and 87.12% proliferation, respectively, of MDA-MB 231 cells by altering morphology and inducing G1 cell cycle arrest and apoptosis. In addition, PCL and FU inhibited the CD151 expression by 4.5-and 4.8-folds, respectively. This study suggests the further assessment of pyrocatechol as a potential lead of CD151 in breast cancer at the molecular level.