Flavonoids are a large class of natural polyphenolic substances ubiquitously synthesized in the plant kingdom. When entering the human body, these compounds can exert a wide range of biological activities, including immunomodulatory, antiinflammatory, and anticancer effects. Over the recent years, the mechanisms underlying these actions have become increasingly clear, also indicating the important involvement of G protein-coupled receptors (GPCRs), such as adenosine receptors, in signal transduction networks. In this perspective article, the potential role of flavonoids as adenosine receptor antagonists on the development, progression, and spread of glioblastoma is discussed, blocking the tumor-promoting and immunosuppressive actions of elevated levels of endogenous adenosine. Therefore, flavonoids can be considered as structural leads for developing novel antiglioblastoma agents, applied either alone or as boosters of chemo- or immunotherapy to improve the quality of life and outcome of patients. The importance of these studies is, in turn, emphasized by the current lack of effective treatment strategies for this highly aggressive and fast-growing brain tumor, associated with poor prognosis.

Murine Double Minute 2 (MDM2) inhibition is recognized as a potential preventive and therapeutic approach for several malignant neoplasms in humans. Targeting MDM2 is a viable strategy for cancer treatment, as it can be regulated by both p53-mediated and p53-independent pathways. Despite MDM2’s crucial role in carcinogenesis, research into pharmacological MDM2 inhibitors has been challenging. Since there are currently no FDA-approved MDM2 inhibitors available on the market, more research in this field is necessary. In several human cancer models, various natural substances have demonstrated the ability to inhibit MDM2. They include Glycyrrhizic Acid (GA), Parthenolide (PTL), chalcones, hoiamides, Isokotomolide A (IKA), Genistein (GT), Flavopiridol, Theaflavin (TF), Curcumin, Camellia sinensis (C.sinensis), and Sesquiterpene Lactones (STLs). Natural extracts have also been investigated as possible lead sources for pharmacological MDM2 inhibitors, in addition to particular molecules. The goal of this review is to provide a comprehensive analysis of natural MDM2 inhibitors, including their pharmacokinetic properties, binding mechanisms, and challenges in their development. Possible methods to enhance their effectiveness and therapeutic applications are also explored.

Cancer remains a major global health challenge, with rising incidence and persistent therapy resistance highlighting the need for new multi-targeted therapeutic agents. Pinocembrin (5,7-dihydroxyflavanone), a naturally occurring flavanone found in honey, propolis, and several medicinal plants, has gained increasing attention for its broad-spectrum anticancer potential. Recent studies demonstrate that pinocembrin modulates multiple hallmarks of cancer by regulating the PI3K/Akt/mTOR, STAT3, and NF-κB pathways, resulting in antiproliferative, pro-apoptotic, anti-metastatic, and anti-inflammatory effects. Evidence from diverse cancer models—including breast, prostate, colon, lung, ovarian, and melanoma—shows that pinocembrin induces cell-cycle arrest, activates intrinsic and extrinsic apoptotic pathways, inhibits angiogenesis, and suppresses epithelial–mesenchymal transition. Structure–activity relationship (SAR) analyses further reveal that modifications such as hydroxylation, esterification, and glycosylation enhance its bioavailability and anticancer activity. Despite its therapeutic promise, the clinical utility of pinocembrin is limited by poor solubility and rapid metabolic clearance. Recent nanotechnology-based formulations, including polymeric micelles, liposomes, nanoparticles, and nanoemulsions, have significantly improved their stability, bioavailability, and tumor-targeted delivery. Pinocembrin also exhibits synergistic effects with conventional chemotherapeutics while maintaining low toxicity toward normal cells, underscoring its suitability for combination therapy and chemoprevention. Preliminary clinical data indicate a favorable safety profile, although long-term toxicity, optimal dosing, and pharmacokinetic parameters require further investigation. This review synthesizes current knowledge on the anticancer mechanisms, SAR-driven insights, nanotechnology-enhanced delivery, synergistic actions, and safety considerations of pinocembrin. By integrating recent findings and highlighting research gaps, it provides a comprehensive foundation for advancing pinocembrin toward future preclinical and clinical applications in oncology.

Gastrointestinal cancers represent a major global health burden and are associated with high morbidity and mortality worldwide. Despite advances in conventional therapies, treatment outcomes remain limited due to therapy resistance, toxicity, and poor long-term efficacy, highlighting the need for novel and complementary therapeutic strategies. Magnolol, a biphenolic lignan isolated from Magnolia officinalis, has attracted considerable attention due to its reported anticancer activity in multiple gastrointestinal malignancies. This review systematically summarizes current preclinical evidence on the anticancer effects of magnolol in oral, esophageal, gastric, colorectal, pancreatic, and liver cancers. Available studies demonstrate that magnolol inhibits cancer cell proliferation, migration, invasion, angiogenesis, and epithelial-mesenchymal transition, while inducing cell cycle arrest and apoptosis. These effects are mediated through modulation of key cancer-associated signaling pathways, including PI3K/Akt/NF-κB, MAPK/JNK, ERK, TGF-β/Smad, and caspase-dependent apoptotic pathways. The review further highlights recent insights into the structure-activity relationship of magnolol and its semi-synthetic derivatives, emphasizing how targeted chemical modifications influence anticancer potency and mechanistic specificity. In addition, challenges related to magnolol's poor aqueous solubility, rapid metabolism, and limited bioavailability are discussed, with particular focus on nanotechnology-based delivery systems developed to improve its pharmacokinetic profile and therapeutic performance. This current review provides an integrated overview of magnolol's molecular mechanisms, chemical optimization strategies, and translational limitations in gastrointestinal cancer therapy, and outlines future research directions necessary to support its progression toward clinical application.

MicroRNAs (miRNAs) are pivotal post-transcriptional regulators that orchestrate gene expression programs governing cancer initiation, progression, metastasis, and therapeutic resistance. Among their many targets, the WNT signaling pathway, a key driver of malignancy, is tightly controlled by miRNAs, forming intricate feedback loops that shape tumor behavior. Concurrently, flavonoids, naturally occurring plant-derived polyphenols, are emerging as promising anticancer agents that can modulate both WNT signaling and miRNA expression. This review highlights miRNAs as the central regulators of oncogenic signaling, focusing on their dualistic role in cancer biology and their modulation by flavonoids. We explore the mechanistic frameworks underpinning miRNA-WNT interactions and the therapeutic potential of flavonoid-mediated miRNA reprogramming for precision miRNA targeting. Unraveling this regulatory axis offers a promising avenue for developing multi-targeted therapies and personalized cancer treatment strategies.

The retinoblastoma gene (RB1), which is located on chromosome 13q14.2, is mutated in retinoblastoma (RB), the most common malignant intraocular tumor in children. About 8000 new cases of retinoblastoma are diagnosed globally each year, accounting for approximately 1 in 17,000 live births. RB is prototypically considered hereditary by nature as thirty to forty percent of cases have autosomal dominant inheritance, and the remaining sixty to seventy percent have non-inherited sporadic inheritance. RB is the most treatable juvenile malignancy, with a high percentage of survival; nevertheless, advanced tumors restrict the amount of globe salvage and are frequently linked to high-risk histological characteristics that indicate spread. Investigating the disease’s molecular causes has also helped to understand its subsequent processes, which has resulted in the identification of biomarkers and relevant targeted treatments. Additionally, advancements in molecular biology techniques facilitated the creation of effective strategies for early disease detection, genetic counseling, and prevention. In the present review, we discuss the risk factors, epidemiology, pathology, and therapeutic approaches for retinoblastoma. We specifically focus on the genetic and molecular characteristics of retinoblastoma, including mutations that cause key signaling pathways involved in the DNA repair, cellular plasticity, and cell proliferation to become dysregulated.

Harmine is a β-carboline alkaloid derived from Peganum harmala, showing a solid antitumor potential in different types of human cancer cells. Unfortunately, the clinical application of this natural alkaloid has been impeded till now by severe toxic side effects, especially neurotoxicity, besides its poor water solubility. Therefore, over the recent years, several semisynthetic derivatives of harmine have been prepared and studied concerning their abilities to inhibit tumor cell proliferation, survival, angiogenesis, migration, and invasion in diverse preclinical models. This review article summarizes the anticancer effects of harmine and its synthetic derivatives, demonstrating their high potential to be developed as novel anticancer drugs to supplement our current therapeutic arsenal in the fight against the globally increasing rate of malignant disorders.

For a long time, the family of receptor tyrosine kinases, including epidermal growth factor receptor and insulin-like growth factor 1 receptor, was regarded as the main players stimulating cell proliferative signaling. Today, it is increasingly clear that many G protein-coupled receptors (GPCRs) are also involved in controlling the hallmarks of cancer by activating diverse intracellular signaling networks. GPCRs can therefore be considered as promising drug targets for fighting against diverse types of human malignancies. Although plant polyphenols, flavonoids, are well known for their diverse anticancer effects inhibiting the growth, proliferation, migration, and invasion of malignant cells, involvement of GPCRs in these activities has still remained largely unelucidated. Therefore, in this review article, the current knowledge about the role of GPCRs in anticancer action of structurally varied flavonoids is compiled, highlighting the ability of these natural polyphenols to modulate the expression levels of GPCRs but also suppress the action of endogenous ligands and downstream tumor-promoting events. These data show that targeting the respective GPCRs by specific flavonoids may open new perspectives in the therapeutic intervention in human malignancies.

Diabetes and cancer are two chronic metabolic diseases with ever-increasing incidence rates worldwide. These disorders can often occur together, as diabetes presents an important risk factor for cancer and some cancers could in turn lead to diabetes. In this perspective article, many more commonalities between diabetes and cancer are highlighted, including the role of lifestyle and environmental factors in the pathogenesis, the presence of a rather long latency period before clinical diagnosis of invasive disease, as well as the ultimate progression to diabetic complications or malignant metastases. Moreover, both of these devastating disorders still lack curative treatment options, whereas several currently approved antidiabetic and anticancer drugs have been originally derived from different natural sources. However, while in the case of diabetes, the main therapeutic goal is to maintain the pancreatic islet mass by preserving β-cells survival, the major purpose of cancer therapy is to kill malignant cells and reduce the neoplastic mass of solid tumors. It is expected that both diabetes and cancer, two systemic diseases with epidemic proportions, would be managed more effectively through an integral approach, considering many different aspects related to their pathogenesis, including also lifestyle changes and dietary modifications.

Over the past few decades, it has become clear that an excessive activity of matrix metalloproteinases (MMPs) can accelerate the progression and fatal outcomes of several serious age-related diseases, including atherosclerotic coronary heart disorders and various types of malignancies. These proteolytic enzymes mediate the degradation and remodeling of the extracellular matrix through cleaving its various components, thereby affecting many critical functions of surrounding cells and intercellular communication. Consequently, the low expression levels of MMPs can be important in the prevention and treatment of such chronic life-threatening pathologies, contributing to the better quality of life and longer life expectancy. In this review article, the pathogenic proteolytic roles of MMPs are examined in more detail, especially in the cases of heart attack and stroke as well as cancer invasion and metastasis, showing that these enzymes can be considered not only as diagnostic and prognostic biomarkers but also as important therapeutic targets in the fight against many age- and lifestyle-related serious disorders. The identification and development of suppressing agents with a selective activity towards specific MMPs have, however, still remained a complex and complicated challenge, in which natural plant-derived compounds are increasingly recognized as promising leads for the new-generation inhibitors.

Angiogenesis is a process involved in the formation of new blood capillaries from pre-existing ones. It is regulated by several anti-angiogenic molecules involved in tumor growth and metastasis. The endothelial angiopoietin Ang-Tie/PI3K/AKT growth receptor pathway is necessary for healthy vascular development. The activation of AKT is controlled by a multistep process involving phosphoinositide 3-kinase (PI3K). This article aims to provide an overview of the role and mechanism of the Ang-Tie/PI3K/AKT signaling pathways and the potential of flavonoids as anti-angiogenic drugs. Flavonoids have shown great potential in preventing angiogenesis by targeting signaling pathways and exhibit additional anti-cancer properties. Research studies have revealed that the currently available anti-angiogenic drugs do not meet the safety and efficacy standards for treating tumor growth. Phytocompounds have long been a valuable resource for the development of novel therapeutic drugs. This article explores recent findings explaining the role and mechanism of the Ang-Tie/PI3K/AKT signaling pathways, as well as the interaction of flavonoids with angiogenic signaling pathways as a novel therapeutic approach. Several investigations have shown that synergistic studies of natural phytocompounds have great potential to target these pathways to inhibit tumor growth. Therefore, flavonoid-based medications may offer a more effective synergistic strategy to treat cancer.

GPR87 is a G protein-coupled seven-transmembrane receptor first described as an orphan receptor in 2001. Despite its high structural homology to several extracellular nucleotide-activated P2Y receptors and sharing conserved sequence motifs in transmembrane regions, identification of endogenous ligands from the class of nucleotides and their analogues has failed for GPR87. Although lysophosphatidic acid was proposed to be a natural ligand for this cell surface receptor, these data are preliminary and inconsistent, and IUPHAR is currently considering GPR87 as an orphan receptor. Thus, the endogenous ligands and physiological functions of GPR87 are still required to be determined and/or confirmed. The remarkably higher expression of GPR87 in human malignant tissues compared to the normal healthy ones clearly suggests that this receptor may be involved in the development and progression of cancerous neoplasms. Therefore, in this review article, the main focus is placed on the oncogenic role of GPR87 in various human malignancies, presenting it as a potential novel target site for therapeutic interventions using both humanized monoclonal antibodies and gene therapy but also selective antagonists which are still waiting for their identification. Furthermore, the importance of the expression of GPR87 as a predictive biomarker for evaluating the prognosis and overall survival of cancer patients is also highlighted.

Alzheimer’s disease, a progressive and irreversible neurodegenerative disorder, is the most prevalent form of dementia with an increasingly growing incidence rate worldwide. As no effective therapeutic modalities are still available for the treatment of this serious disabling condition, lifestyle modifications, especially nutritional interventions, have been shown to be important in its prevention and symptomatic alleviation. In this short perspective article, an inverse association between the intake of sunflower seeds and the mortality from Alzheimer’s disease and dementia is proposed, showing that in the countries with the highest consumption of sunflower seeds, the death rate from this neurodegenerative disorder is low. The bioactive ingredients of sunflower seeds and their possible neuroprotective mechanisms are further unraveled, highlighting the potent antioxidant, antiinflammatory and neurotrophic effects of tocopherols, unsaturated fatty acids and phytosterols. Among the latter agents, β-sitosterol might be particularly important in combating Alzheimer’s disease by enhancing the levels of nerve growth factor and thereby promoting neurite formation. If future epidemiological studies will confirm the proposed inverse association between the intake of sunflower seeds and the development of Alzheimer’s disease and dementia, it is easy to include appropriate sunflower seed products in the everyday diet to protect against the pathogenesis and progression of this neurodegenerative disorder, especially in individuals with a genetic predisposition. Considering the rather long latency period before clinical manifestation of Alzheimer’s disease, nutritional approaches with specific foods might be a promising strategy for fighting against dementia.