Search Results (129)

The natural, highly lipophilic bicyclic sesquiterpenes, Beta-Caryophyllene (BCP), was highlighted in several recent preclinical studies to enhance chemo-sensitization in chemo-resistant tumors and to efficiently inhibit angiogenesis and cancer cells’ ability to invade and metastasize. Previous studies have researched the reasons for the synergistic effect of Beta-Caryophyllene in combination therapy and its role as a chemosensitizer and an inhibitor of angiogenesis through investigating the involved mechanisms and signaling molecules. These include the lipophilic nature of BCP, the selective interaction of BCP with CB2, the binding affinity of BCP to the receptor binding sites at the angiogenic vascular endothelial growth factor, and the upstream effect on JAK1/STAT3 pathway and other signaling pathways. Herein, the BCP role in enhancing chemo-sensitization of chemo-resistant tumors and in inhibiting angiogenesis and cancer cells’ ability to invade and metastasize are highlighted. Beta-Caryophyllene appears to be a promising candidate in treating cancer when co-supplemented with drugs such as cisplatin, gemcitabine and sorafenib. Clinical trials are needed to validate the potential therapeutic effect of BCP as a co-supplementary drug in cancer therapy, helping to sensitize cancer response to drugs, modulating signaling pathways, and lowering the drugs’ doses besides working as anti-angiogenetic drug. Full article

Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness in older adults. Its pathogenesis involves multiple factors, including aging, environmental influences, genetic predisposition, oxidative stress, metabolic dysfunction, and immune dysregulation. Currently, AMD treatment focuses primarily on wet AMD, managed through repeated intravitreal injections of anti-vascular endothelial growth factor (VEGF) therapies. While anti-VEGF agents represent a major breakthrough in wet AMD care, repeated injections may lead to incomplete responses or resistance in some patients, and carry a risk of progressive fibrosis. Artemisinin (ART) and its derivatives, originally developed as antimalarial drugs, exhibit a broad spectrum of pleiotropic activities beyond their established use, including anti-inflammatory, anti-angiogenic, antioxidant, anti-fibrotic, mitochondrial regulatory, lipid metabolic, and immunosuppressive effects. These properties position ART as a promising therapeutic candidate for AMD. A growing interest in ART-based therapies for AMD has emerged in recent years, with numerous studies demonstrating their potential benefits. However, no comprehensive review has systematically summarized the specific roles of ART and its derivatives in AMD pathogenesis and treatment. This paper aims to fill the knowledge gap by synthesizing the therapeutic efficacy and molecular mechanisms of ART and its derivatives in AMD, thereby providing a foundation for future investigations. Full article

Glioblastoma (GBM) is one of the most invasive central nervous system tumors, with rising global incidence. Therapy resistance and poor prognosis highlight the urgent need for new anticancer drugs. Plant alkaloids, a largely unexplored yet promising class of compounds, have previously contributed to oncology treatments. While past reviews provided selective insights, this review aims to collectively compare data from the last decade on (1) plant alkaloid-based anticancer drugs, (2) alkaloid transport across the blood–brain barrier (BBB) in vitro and in vivo, (3) alkaloid mechanisms of action in glioblastoma models (in vitro, in vivo, ex vivo, and in silico), and (4) cytotoxicity and safety profiles. Additionally, innovative drug delivery systems (e.g., nanoparticles and liposomes) are discussed. Focusing on preclinical studies of single plant alkaloids, this review includes 22 botanical families and 28 alkaloids that demonstrated anti-GBM activity. Most alkaloids act in a concentration-dependent manner by (1) reducing glioma cell viability, (2) suppressing proliferation, (3) inhibiting migration and invasion, (4) inducing cell death, (5) downregulating Bcl-2 and key signaling pathways, (6) exhibiting antiangiogenic effects, (7) reducing tumor weight, and (8) improving survival rates. The toxic and adverse effect analysis suggests that alkaloids such as noscapine, lycorine, capsaicin, chelerythrine, caffeine, boldine, and colchicine show favorable therapeutic potential. However, tetrandrine, nitidine, harmine, harmaline, cyclopamine, cocaine, and brucine may pose greater risks than benefits. Piperine’s toxicity and berberine’s poor bioavailability suggest the need for novel drug formulations. Several alkaloids (kukoamine A, cyclovirobuxine D, α-solanine, oxymatrine, rutaecarpine, and evodiamine) require further pharmacological and toxicological evaluation. Overall, while plant alkaloids show promise in glioblastoma therapy, progress in assessing their BBB penetration remains limited. More comprehensive studies integrating glioma research and advanced drug delivery technologies are needed. Full article

This review article aims to address the challenges associated with targeted therapy for the treatment of metastatic colorectal cancer (mCRC). We will first provide an overview of approved targeted therapies for treating mCRC, which include antiangiogenic therapy, as well as inhibitors of EGFR, BRAFV600E, HER2 inhibitors, and immune checkpoints. Second, we discuss the different mechanisms of primary resistance, including tumor heterogeneity, both as inter-patient and intra-patient heterogeneity, and mechanisms of secondary resistance which include: driver oncogene alterations, downstream or parallel bypass signaling, presence of co-dominant driver oncogenes, tumor lineage plasticity, and epithelial to mesenchymal transition. Resistance mechanisms towards the different drug classes targeting mCRC are discussed in detail. Strategies to overcome resistance primarily involve combination of therapies, although this approach is typically linked to increased drug toxicity, manifesting as on and off-target effects. Moreover, the cost and accessibility of targeted therapies pose significant challenges for diverse populations. Addressing these challenges necessitates further research efforts aimed at optimizing the use of targeted therapy in mCRC. Integration of genomic biomarkers, such as sequencing and liquid biopsy, into routine clinical practice holds promise in enhancing treatment outcomes. In conclusion, this comprehensive review underscores the complex challenges encountered in targeted therapy for mCRC. Full article

Vascular endothelial growth factor receptor-2 (VEGFR-2), a tyrosine kinase receptor (TKR), plays a crucial role in angiogenesis and is overexpressed in most cancers. It is important for tumor angiogenesis, facilitating essential angiogenic cellular processes, such as promoting endothelial cell survival, proliferation, migration, and vascular permeability. Consequently, VEGFR-2 has become one of the main targets for anti-angiogenic therapy, with its inhibition serving as a crucial strategy for developing new drugs to mitigate angiogenesis-dependent cancers. Small-molecule drugs targeting VEGFR-2, approved by the USFDA, are exhibiting the development of drug resistance during chemotherapy, with cardiac-related side effects being consistently reported. In conclusion, it is important to develop novel strategies to enhance the efficacy of VEGFR-2 inhibitors and eliminate their adverse effects. Multifunctional drugs that target multiple pathways present a promising strategy, enhancing efficacy while minimizing side effects. Sulfonamide derivatives are extensively used in medicinal chemistry and modern drug discovery due to their variety of pharmacological activities. The present review focuses on novel compounds endowed with potential VEGFR-2 inhibition, four of which additionally present carbonic anhydrase inhibitory activity. Full article

The poor prognosis for high-grade serous ovarian cancer (HGSOC), the dominant subtype of ovarian cancer, reflects its aggressive nature, late diagnosis, and the highest mortality rate among all gynaecologic cancers. Apart from late diagnosis, the main reason for the poor prognosis and its unsuccessful treatment is primarily the emergence of chemoresistance to carboplatin. Although there is a good response to primary treatment, the disease recurs in 80% of cases, at which point it is largely resistant to carboplatin. The introduction of novel targeted therapies in the second decade of the 21st century has begun to transform the treatment of HGSOC, although their impact on overall survival remains unsatisfactory. Targeting the specific pathways known to be abnormally activated in HGSOC is especially difficult due to the molecular diversity of its subtypes. Moreover, a range of molecular changes are associated with acquired chemoresistance, e.g., reversion of BRCA1 and BRCA2 germline alleles. In this review, we examine the advantages and disadvantages of approved targeted therapies, including bevacizumab, PARP inhibitors (PARPis), and treatments targeting cells with neurotrophic tyrosine receptor kinase (NTRK), B-rapidly accelerated fibrosarcoma (BRAF), and rearranged during transfection (RET) gene alterations, as well as antibody–drug conjugates. Additionally, we explore promising new targets under investigation in ongoing clinical trials, such as immune checkpoint inhibitors, anti-angiogenic agents, phosphatidylinositol-3-kinase (PI3K) inhibitors, Wee1 kinase inhibitors, and ataxia telangiectasia and Rad3-related protein (ATR) inhibitors for platinum-resistant disease. Despite the development of new targeted therapies, carboplatin remains the fundamental medicine in HGSOC therapy. The correct choice of treatment strategy for better survival of patients with advanced HGSOC should therefore include a prediction of patients’ risks of developing chemoresistance to platinum-based chemotherapy. Moreover, effective targeted therapy requires the selection of patients who are likely to derive clinical benefit while minimizing potential adverse effects, underscoring the essence of precision medicine. Full article

Chondrosarcoma (CS), the second most common malignant bone tumor after osteosarcoma, accounts for 20–30% of all malignant bone tumors. It mainly affects adults, middle-aged, and elderly people. The CS family includes various entities displaying peculiar biological, genetic, and epigenetic characteristics and clinical behaviors. Conventional CS is the most common subtype. High-grade, dedifferentiated, and mesenchymal CS, as well as unresectable and metastatic CS, exhibit poor prognoses due to their intrinsic resistance to radiotherapy and chemotherapy, underscoring the urgent need for novel therapeutic strategies. CS research is dealing with several challenges. Experimental studies can rely on animal and patient-derived models, but the paucity of representative near-patient preclinical models has hampered predictive drug screening research. This review describes the main clinical and molecular features of CS subtypes, discussing recent data on the genetic alterations and molecular mechanisms involved in CS pathogenesis and progression. The review provides an overview of the current in vitro and in vivo CS models, discusses their advantages and limitations, and highlights the recent efforts in the development of new targeted therapies against CS dependencies, including IDH1/2 mutations, NAD⁺ dependency, and SIRT1-HIF-2α axis, or exploring DR5 targeting, antiangiogenic therapies, epigenetic drugs, and immunological approaches. All such strategies, in combination with advanced preclinical modeling and personalized multi-omic profiling, hold promise for improving the survival of patients with advanced CS. Full article

Cancer remains one of the most formidable diseases globally and continues to be a leading cause of mortality. While chemotherapeutic agents are crucial in cancer treatment, they often come with severe side effects. Furthermore, the development of acquired drug resistance poses a significant challenge in the ongoing battle against cancer. Combining these chemotherapeutic agents with plant-derived phenolic compounds offers a promising approach, potentially reducing side effects and counteracting drug resistance. Phytochemicals, the bioactive compounds found in plants, exhibit a range of health-promoting properties, including anticarcinogenic, antimutagenic, antiproliferative, antioxidant, antimicrobial, neuroprotective, and cardioprotective effects. Their ability to enhance treatment, coupled with their non-toxic, multi-targeted nature and synergistic potential when used alongside conventional drugs, underscores the growing importance of natural therapeutics. In this study, we investigated the anticancer effects of olaparib (OL), a small-molecule PARP inhibitor that has shown promising results in both preclinical and clinical trials, and gallic acid (GA), a phenolic compound, in olaparib-resistant human osteosarcoma U2OS cells (U2OS-PIR). Both parental U2OS and U2OS-PIR cell lines were treated with increasing concentrations of olaparib and gallic acid, and their cytotoxic effects were assessed using the WST-1 cell viability assay. The synergistic potential of OL and GA, based on their determined IC₅₀ values, was further explored in combination treatment. A colony survival assay revealed the combination’s ability to significantly reduce the colony-forming capacity of cancer cells. Additionally, the apoptotic effects of OL and GA, both individually and in combination, were examined in U2OS-PIR cells using acridine orange/ethidium bromide dual staining. The anti-angiogenic properties were assessed through a VEGF ELISA, while the expression of proteins involved in DNA damage and apoptotic signaling pathways was analyzed via Western blot. The results of this study demonstrate that gallic acid effectively suppresses cell viability and colony formation, particularly when used in combination therapy to combat OL resistance. Additionally, GA inhibits angiogenesis and induces DNA damage and apoptosis by modulating key apoptosis-related proteins, including cPARP, Bcl-2, and Bax. These findings highlight gallic acid as a potential compound for enhancing therapeutic efficacy in overcoming acquired drug resistance. Full article

Non-small-cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, with epidermal growth factor receptor (EGFR) mutations present in a substantial proportion of patients. Third-generation EGFR tyrosine kinase inhibitors (EGFR TKI), exemplified by osimertinib, have dramatically improved outcomes by effectively targeting the T790M mutation—a primary driver of acquired resistance to earlier-generation EGFR TKI. Despite these successes, resistance to third-generation EGFR TKIs inevitably emerges. Mechanisms include on-target mutations such as C797S, activation of alternative pathways like MET amplification, histologic transformations, and intricate tumor microenvironment (TME) alterations. These resistance pathways are compounded by challenges in tolerability, adverse events, and tumor heterogeneity. In light of these hurdles, this review examines the evolving landscape of combination therapies designed to enhance or prolong the effectiveness of third-generation EGFR TKIs. We explore key strategies that pair osimertinib with radiotherapy, anti-angiogenic agents, immune checkpoint inhibitors, and other molecularly targeted drugs, and we discuss the biological rationale, preclinical evidence, and clinical trial data supporting these approaches. Emphasis is placed on how these combinations may circumvent diverse resistance mechanisms, improve survival, and maintain a favorable safety profile. By integrating the latest findings, this review aims to guide clinicians and researchers toward more individualized and durable treatment options, ultimately enhancing both survival and quality of life for patients with EGFR-mutated NSCLC. Full article

Background/Objectives: It remains challenging to treat recurrent ovarian cancer effectively as traditional interventions like chemotherapy and surgery have limited long-term efficacy, highlighting an urgent need for innovative approaches. Immunotherapy offers potential advantages in modulating the immune response against tumor cells and has emerged as a promising strategy in ovarian cancer management. This review discusses various immunotherapy modalities, including active and passive immune strategies, for recurrent ovarian cancer. Methods: We systematically reviewed recent immunotherapy advances for recurrent ovarian cancer, including the efficacy and mechanisms of single and dual immune checkpoint inhibitors, checkpoint inhibitor combinations with chemotherapy or radiotherapy, anti-angiogenic agents, PARP inhibitors, antibody–drug conjugates (ADC), tumor vaccines, and adoptive cell therapies (ACT). Additionally, we assessed emerging research on biomarkers predictive of immunotherapy responsiveness in ovarian cancer. Results: The findings indicate that immunotherapy, particularly combinations involving immune checkpoint inhibitors and other agents, demonstrates promising efficacy in recurrent ovarian cancer, with some therapies showing enhanced benefits in specific subtypes. The immune microenvironment in platinum-sensitive and -resistant cases exhibits distinct immunological profiles, influencing therapy outcomes. Several potential biomarkers have been identified, potentially aiding in patient stratification and treatment optimization. Conclusions: Immunotherapy significantly advances recurrent ovarian cancer treatment, with various combinations potentially improving outcomes. Further research on predictive biomarkers and immune microenvironment characteristics is crucial for personalizing immunotherapy approaches and enhancing their efficacy in managing recurrent ovarian cancer. Full article

Mutations of the von Hippel–Lindau (VHL) tumor suppressor gene occur frequently in clear cell renal cell carcinoma (RCC), the predominant histology of kidney cancer, and have been associated with its pathogenesis and progression. Alterations of VHL lead to impaired degradation of hypoxia-inducible factor 1α (HIF1α) and HIF2α promoting neoangiogenesis, which is pivotal for cancer growth. As such, targeting the VHL-HIF axis holds relevant potential for therapeutic purposes. Belzutifan, an HIF-2α inhibitor, has been recently indicated for metastatic RCC and other antiangiogenic drugs directed against HIF-2α are currently under investigation. Further, clinical and preclinical studies of combination approaches for metastatic RCC including belzutifan with cyclin-dependent kinase 4–6 inhibitors, tyrosine kinase inhibitors, or immune checkpoint inhibitors achieved promising results or are ongoing. This review aims to summarize the existing evidence regarding the VHL/HIF pathway, and the approved and emerging treatment strategies that target this pivotal molecular axis and their mechanisms of resistance. Full article

Objectives: This research aims to investigate the mechanisms of resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC), particularly focusing on the role of the epithelial–mesenchymal transition (EMT) within the tumor microenvironment (TME). Materials and Methods: We employed an in vitro three-dimensional organoid model that mirrors the physiology of human lung cancer. These organoids consist of lung cancer cells harboring specific EGFR mutations, human mesenchymal stem cells, and human umbilical vein endothelial cells. We analyzed EMT and drug resistance markers, and evaluated the effects of the anti-angiogenic agent Bevacizumab and micro-RNA miR200c. Results: The study identified a significant link between EMT and EGFR-TKI resistance. Notable findings included a decrease in E-cadherin and an increase in Zinc Finger E-Box Binding Homeobox 1 (ZEB1), both of which influenced EMT and resistance to treatment. Bevacizumab showed promise in improving drug resistance and mitigating EMT, suggesting an involvement of the Vascular Endothelial Growth Factor (VEGF) cascade. Transfection with miR200c was associated with improved EMT and drug resistance, further highlighting the role of EMT in TKI resistance. Conclusions: Our research provides significant insights into the EMT-driven EGFR-TKI resistance in NSCLC and offers potential strategies to overcome resistance, including the use of Bevacizumab and miR200c. However, due to the limitations in organoid models in replicating precise human cancer TME and the potential influence of specific EGFR mutations, further in vivo studies and clinical trials are necessary for validation. Full article

Background: Itraconazole (ITZ) is an antiangiogenic agent recognized as a potent suppressor of endothelial cell growth that suppresses angiogenesis. Nevertheless, its exploitation is significantly restricted by its low bioavailability and systematic side effects. The objective of this study was to utilize glycerosomes (GLY), glycerol-developed vesicles, as innovative nanovesicles for successful ITZ pulmonary drug delivery. Methods: The glycerosomes were functionalized with hyaluronic acid (HA-GLY) to potentiate the anticancer efficacy of ITZ and extend its local bio-fate. ITZ-HA-GLY were fabricated using soybean phosphatidylcholine, tween 80, HA, and sonication time via a thin-film hydration approach according to a 24 full factorial design. The impact of formulation parameters on ITZ-HA-GLY physicochemical properties, as well as the optimal formulation option, was evaluated using Design-Expert^®. Sulphorhodamine-B (SRB) colorimetric cytotoxicity assay of the optimized ITZ-HA-GLY versus ITZ suspension was explored in the human A549 cell line. The in vivo pharmacokinetics and bio-distribution examined subsequent to intratracheal administrations of ITZ suspension, and ITZ-HA-GLY were scrutinized in rats. Results: The optimized ITZ-HA-GLY unveiled vesicles of size 210.23 ± 6.43 nm, zeta potential of 41.06 ± 2.62 mV, and entrapment efficiency of 73.65 ± 1.76%. Additionally, ITZ-HA-GLY manifested a far lower IC50 of 13.03 ± 0.2 µg/mL on the A549 cell line than that of ITZ suspension (28.14 ± 1.6 µg/mL). Additionally, the biodistribution analysis revealed a higher concentration of ITZ-HA-GLY within the lung tissues by 3.64-fold as compared to ITZ suspension. Furthermore, the mean resistance time of ITZ-HA-GLY declined more slowly with 14 h as compared to ITZ suspension, confirming the accumulation of ITZ inside the lungs and their promising usage as a target for the treatment of lung disease. Conclusions: These data indicate that the improved ITZ-HA-GLY demonstrates significant promise and represents an exciting prospect in intratracheal delivery systems for lung cancer treatment, meriting further investigation. Full article

Backgrounds/Objectives: Abnormal platelet functions are associated with human morbidity and mortality. Platelets have emerged as critical regulators of numerous physiological and pathological processes beyond their established roles in hemostasis and thrombosis. Maintaining physiological platelet function is essential to hemostasis and preventing platelet-associated diseases such as cardiovascular disease, cancer metastasis, immune disorders, hypertension, diabetes, sickle cell disease, inflammatory bowel disease, sepsis, rheumatoid arthritis, myeloproliferative disease, and Alzheimer’s disease. Platelets become hyperactive in obesity, diabetes, a sedentary lifestyle, hypertension, pollution, and smokers. Platelets, upon activation, can trawl leukocytes and progenitor cells to the vascular sites. Platelets release various proinflammatory, anti-inflammatory, and angiogenic factors and shed microparticles in the circulation, thus promoting pathological reactions. These platelet-released factors also maintain sustained activation, further impacting these disease processes. Although the mechanisms are unknown, multiple stimuli induce platelet hyperreactivity but involve the early pathways of platelet activation. The exact mechanisms of how hyperactive platelets contribute to these diseases are still unclear, and antiplatelet strategies are inevitable for preventing these diseases. Reducing platelet function during the early stages could significantly impact these diseases. However, while this is potentially a worthwhile intervention, using antiplatelet drugs to limit platelet function in apparently healthy individuals without cardiovascular disease is not recommended due to the increased risk of internal bleeding, resistance, and other side effects. The challenge for therapeutic intervention in these diseases is identifying factors that preferentially block specific targets involved in platelets’ complex contribution to these diseases while leaving their hemostatic function at least partially intact. Since antiplatelet drugs such as aspirin are not recommended as primary preventives, it is essential to use alternative safe platelet inhibitors without side effects. Methods: A systematic search of the PUBMED database from 2000 to 2023 was conducted using the selected keywords: “functional foods”, “polyphenols”, “fatty acids”, “herbs”, fruits and vegetables”, “cardioprotective agents”, “plant”, “platelet aggregation”, “platelet activation”, “clinical and non-clinical trial”, “randomized”, and “controlled”. Results: Potent natural antiplatelet factors have been described, including omega-3 fatty acids, polyphenols, and other phytochemicals. Antiplatelet bioactive compounds in food that can prevent platelet hyperactivity and thus may prevent several platelet-mediated diseases, including cardiovascular disease. Conclusions: This narrative review describes the work during 2000–2023 in developing functional foods from natural sources with antiplatelet effects. Full article

This review article explores the fundamental role of receptor targeting in overcoming drug resistance in cancer therapy, an area of critical concern given the persistently high rates of cancer morbidity and mortality globally. We highlight how receptor biology intersects with the development of therapeutic resistance with a specific focus on anti-angiogenic agents, immune checkpoint inhibitors, and monoclonal antibodies, which directly or indirectly influence receptor pathways. We also explore how other receptor tyrosine kinases can initially suppress tumor growth, yet often lead to resistance, underscoring the need for novel combinatorial approaches that incorporate advanced receptor modulation techniques. Further, the review delves into the mechanisms by which modulation of the tumor microenvironment and immune system via receptor pathways can overcome resistance to traditional immunotherapies. Additionally, emerging technologies in receptor-targeted nanomedicine are also highlighted, showcasing their potential to revolutionize drug delivery and improve therapeutic outcomes by targeting specific receptor interactions. Ultimately, this review calls for a deeper understanding of receptor dynamics to develop more precise interventions, including insights from various healthcare settings that can prevent or circumvent drug resistance, thus enhancing patient outcomes in oncology. Full article