Search Results (317)

Background: The treatment landscape for multiple myeloma (MM) has significantly evolved in recent decades with novel therapies like proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies. However, MM remains incurable, necessitating new pharmacological strategies. Mitotic kinases, such as Aurora proteins, have emerged as potential targets. Selective inhibitors of Aurora A and B,- alisertib (MLN8237) and barasertib (AZD1152), respectively, have shown anti-myeloma activity in preclinical studies, with alisertib demonstrating modest efficacy in early clinical trials. Methods and Results: This study investigated the mechanisms of action of alisertib and barasertib and their combination with antitumor agents in a panel of five MM cells lines. Both drugs induced cell cycle arrest phase and abnormal nuclear morphologies. Alisertib caused prolonged mitotic arrest, whereas barasertib induced transient arrest, both resulting in the activation of mitotic catastrophe. These findings revealed three potential outcomes: cell death, senescence, or polyploidy. High mitochondrial reactive oxygen species (mROS) were identified as possible drivers of cell death. Caspase inhibition reduced caspase-3 activation but did not prevent cell death. Interestingly, alisertib at low doses remained toxic to Bax/Bak^DKO cells, although mitochondrial potential disruption and cytochrome c release were observed. Sequential combinations of high-dose Aurora kinase inhibitors with BH3-mimetics, and in specific cases with panobinostat, showed a synergistic effect. Conversely, the simultaneous combination of alisertib and barasertib showed mostly antagonistic effects. Conclusions: Alisertib and barasertib emerge as potential in vitro candidates against MM, although further studies are needed to validate their efficacy and to find the best combinations with other molecules. Full article

Essential oils are lipophilic secondary metabolites produced in various parts of aromatic plants and stored in specialized secretory structures. They play a vital role in plant defense, offering protection against microorganisms and herbivores. These oils are known for a wide range of biological activities, including antibacterial, anti-inflammatory, antitumor, analgesic, antioxidant, and immunomodulatory effects. Given the increasing interest in natural alternatives to synthetic drugs, this review explored the therapeutic relevance of Pinus-derived essential oils as promising candidates in modern phytotherapy. Species of the genus Pinus have been widely investigated for their phytochemical composition and biological potential, with a focus on their medicinal and pharmaceutical applications. This review aimed to assess the biological properties of Pinus species commonly used in traditional medicine. In this paper, thorough insight into the chemical composition, as well as into the antimicrobial and antioxidant activities of essential oils obtained from the different parts of Pinus species, was given. Although recognized for their antimicrobial activity against a wide range of bacterial strains, including both Gram-positive and Gram-negative bacteria, the practical application of Pinus essential oils is often limited by their physicochemical instability and volatility. Therefore, this review highlighted the advances in formulation strategies, particularly encapsulation techniques, as the possible direction of future research concerning essential oils. Full article

Cancer treatment remains a formidable challenge globally. Natural products, particularly natural alkaloids, have emerged as significant resources for the development of novel anti-tumor drugs due to their structural diversity and unique biological activities. Our team previously isolated an alkaloid, 6-hydroxymethyldihydrochelerythrine (6-HMDN), from Zanthoxylum ailanthoides. Subsequent in vitro and in vivo activity screenings, utilizing cell-based assays and a zebrafish xenograft model, revealed that 6-HMDN significantly inhibited the proliferation of HepG2 and MCF7 cells and effectively suppressed HepG2 cell migration. Mechanistic studies indicated that 6-HMDN induced tumor cell apoptosis by modulating the Bcl-2/Bax protein balance and activating the caspase cascade. Furthermore, 6-HMDN augmented intracellular reactive oxygen species (ROS) levels, thereby promoting ferroptosis, as evidenced by lipid ROS accumulation and glutathione (GSH) depletion. Additionally, 6-HMDN attenuated focal adhesion kinase (FAK) phosphorylation, leading to the inhibition of tumor cell migration. In vivo experiments further substantiated the capacity of 6-HMDN to effectively suppress tumor proliferation and metastasis. These findings demonstrate that 6-HMDN exhibits potent anti-tumor activity, exerting its effects through multiple mechanisms involving the regulation of apoptosis, ferroptosis, and the FAK signaling pathway. Therefore, 6-HMDN may be considered a promising candidate for anti-tumor drug development. Full article

Withanolides are a class of naturally occurring C-28 ergostane steroidal lactones with an abundance of biological activities, and their members are promising candidates for antineoplastic drug development. The ADMET properties of withanolides are still largely unknown, and in silico predictions can play a crucial role highlighting these characteristics for drug development, shortening time and resources spent on the development of a drug lead. In this work, ADMET properties of promising antitumoral withanolides were assessed. Each chemical structure was submitted to the prediction tools: SwissADME, pkCSM–pharmacokinetics, admetSAR v2.0, and Molinspiration Cheminformatics. The results indicate a good gastrointestinal absorption rate, inability to cross the blood–brain barrier, CYP3A4 metabolization, without inhibition of other P450 cytochromes, high interaction with nuclear receptors, and a low toxicity. It was also predicted for the inhibition of pharmacokinetics transporters and some ecotoxicity. This demonstrates a viability for oral drug development, with low probabilities of side effects. Full article

Formononetin is widely used in anti-tumor research, but its poor water solubility leads to low absorption and poor utilization efficiency in vivo, limiting further development. The triphenylphosphine cation was partially attached to the 7-position hydroxyl group of formononetin to specifically target it into the mitochondria of tumor cells to enhance the anti-tumor effect. Detailed structural characterization via ¹H-NMR and ¹³C-NMR analysis confirmed the physical properties and chemical structures of 21 newly synthesized derivatives. The effects of these derivatives on tumor cells were assessed by in vitro and computational methods. MTT results from four tumor cell lines showed that formononetin derivatives containing triphenylphosphine had stronger anti-tumor activity than formononetin and exhibited more cytotoxic effects in cancer cells than in normal cells. In particular, the final product 2c (IC₅₀ = 12.19 ± 1.52 μM) showed more potent anti-tumor activity against A549 cells. It was also superior to formononetin and 5-FU. To identify the potential biological targets, the core-expressed gene SHMT2 in lung cancer mitochondria was screened using network pharmacology technology, and molecular docking analysis confirmed the stable binding of the end products to the amino acid residues of the core genes through the formation of hydrogen bonds and via other interactions. In addition, molecular docking simulations further confirmed that the end product exhibited excellent stability when bound to SHMT2. These results suggest that triphenylphosphine-containing formononetin derivatives are worthy of further exploration in the search for novel drug candidates for the treatment of cancer. Full article

Background: Germline alleles near genes encoding certain immune checkpoints (CTLA4, CD200) are associated with autoimmune/autoinflammatory disease and cancer, but in opposite ways. This motivates a systematic search for additional germline alleles with this pattern with the aim of identifying potential cancer immunotherapeutic targets using human genetics. Methods: Pairwise fixed effect cross-disorder meta-analyses combining genome-wide association studies (GWAS) for breast, prostate, ovarian and endometrial cancers (240,540 cases/317,000 controls) and seven autoimmune/autoinflammatory diseases (112,631 cases/895,386 controls) coupled with in silico follow-up. Results: Meta-analyses followed by linkage disequilibrium clumping identified 312 unique, independent lead variants with p < 5 × 10⁻⁸ associated with at least one of the cancer types at p < 10⁻³ and one of the autoimmune/autoinflammatory diseases at p < 10⁻³. At each lead variant, the allele that conferred autoimmune/autoinflammatory disease risk was protective for cancer. Mapping led variants to nearest genes as putative functional targets and focusing on immune-related genes implicated 32 genes. Tumor bulk RNA-Seq data highlighted that the tumor expression of 5/32 genes (IRF1, IKZF1, SPI1, SH2B3, LAT) was each strongly correlated (Spearman’s ρ > 0.5) with at least one intra-tumor T/myeloid cell infiltration marker (CD4, CD8A, CD11B, CD45) in every one of the cancer types. Tumor single-cell RNA-Seq data from all cancer types showed that the five genes were more likely to be expressed in intra-tumor immune versus malignant cells. The five lead SNPs corresponding to these genes were linked to them via the expression of quantitative trait locus mechanisms and at least one additional line of functional evidence. Proteins encoded by the genes were predicted to be druggable. Conclusions: We provide population-scale germline genetic and functional genomic evidence to support further evaluation of the proteins encoded by IRF1, IKZF1, SPI1, SH2B3 and LAT as possible targets for cancer immunotherapy. Full article

Stilbenes are plant secondary metabolites with remarkable antidiabetic, anti-inflammatory, antimicrobial, antioxidant, antitumor, and neuroprotective properties. As these compounds are valuable constituents in healthcare products and promising drug candidates, exploring new sources of stilbenes is essential for therapeutic advancement. The present study reports the isolation of two stilbene glycosides, resveratroloside and pinostilbenoside, from Pinus cembra L. bark. Their antioxidant activity and cytotoxic effects against HeLa cells were evaluated in comparison to the raw bark extract. The structures of resveratroloside and pinostilbenoside were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS) data analyses. Antioxidant activity was assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging and reducing power assays. Cell viability, apoptosis, cell proliferation, and cell cycle assays were used to evaluate the cytotoxic potential against HeLa cells. Resveratroloside and pinostilbenoside exhibited lower activity as free radical scavengers and reducing agents. However, they showed greater efficacy in reducing viability and suppressing proliferation in human cervical carcinoma HeLa cells. Given the promising findings of our study, the therapeutic potential of resveratroloside and pinostilbenoside should be further investigated. Full article

Titanium (Ti)-based metallic biomaterials (MBs) are traditionally employed as mechanical supports and constraints in clinical practice, owing to their superb comprehensive mechanical properties, great corrosion resistance, and good biocompatibility. Recently, Ti-based MBs have emerged as promising candidates for antitumor applications. These developments focus on the functionalization of Ti-based MBs to inhibit tumor propagation and recurrence. This work systematically examines the antitumor approaches of Ti-based MBs and categorizes them into physical and chemical approaches. Physical strategies, such as the photothermal and photocatalytic techniques, are usually related to material-specific properties. Chemical approaches often employ controlled local drug delivery (LDD) systems. Ti-based LDD systems enable the targeted release of chemotherapeutics, metal ions, or immunomodulatory agents at tumor sites. This review highlights the efficacy of these surface-functionalized Ti-based MBs against diverse tumors. Additionally, the challenges and prospects of antitumor Ti-based MBs are also discussed. Full article

Lichenized fungi, recognized as an ecologically vital and pharmaceutically promising resource, hold substantial value in both environmental conservation and medicinal applications. As the second largest subclass within the lichen-forming fungi of Lecanoromycetes, Ostropomycetidae emerged as a critical reservoir of bioactive secondary metabolites. Current research has revealed that these secondary metabolites demonstrate remarkable bioactivities, positioning them as potential sources for novel pharmaceutical compounds. Despite considerable progress in characterizing chemical constituents and evaluating bioactivities within this subclass, a systematic summary of these discoveries remains absent. This review synthesizes the lichenochemical research progress, providing critical evaluations of 202 structurally characterized compounds from Ostropomycetidae lichen species over recent decades. These Ostropomycetidae-derived compounds cover the phenols, polyketides, fatty acids, terpenoids, steroids, and non-ribosomal peptides, and exhibit diverse bioactivities including antitumor, anti-inflammatory, antibacterial, antifungal, antiviral, antioxidant, anti-angiogenic, anti-neurodegenerative diseases, antitubercular, anti-herbivore, and antitrypanosomal, and so on. The aim of this review is to establish a robust chemodiversity framework and to offer strategic guidance for targeted exploration of lichen-derived drug candidates in the biological resources of Ostropomycetidae lichens. Full article

Towards the efforts to expand the bioactivity and to reduce toxic and adverse properties of known metal-based drugs, various multinuclear complexes have recently been studied. They have shown enhancement of target specificity and selectivity. Different from small organic compounds and traditional metal-based complexes with anticancer activity, iridium(III) multinuclear or heteronuclear metallodrugs have confirmed potential advantages due to their unique biological and chemical diversities, better activity and different anticancer mechanisms. Ir(III) coordination compounds, similar to most Pt group compounds, are of excessive interest because of their potential cytotoxic activity, effective cellular uptake and tolerance by healthy cells. Although mononuclear Ir(III) complex compounds have been extensively studied as promising candidates for antitumor application, the research on the antineoplastic potential of homo- or hetero-multinuclear iridium(III) complexes is not as abundant; nevertheless, intensive investigations have been conducted in the recent years towards developing complexes that are anticipated to have improved therapeutic potential and biotarget selectivity. Multimetallic iridium(III) frameworks have offered interesting possibilities for designing new antitumor agents by exploiting the action of different metal cations at the same time. This method was very successful in the design of homo- and hetero-multinuclear cyclometalated and half-sandwich organometallic Ir(III) compounds. In the described background, many homonuclear and heteronuclear Ir(III) complexes have been estimated and have exposed promising advantages in cancer therapy. This review intends to summarize newly reported innovative and promising multinuclear Ir(III)-based complexes and to afford a wide-ranging overview of current development and perspectives for the practical impact of these complexes in the tumor therapy field. It is anticipated that this analysis will provide significant direction for the further progress of active homonuclear and heteronuclear iridium-based anticancer agents. Full article

Scolopendra subspinipes, commonly known as the Chinese red-headed centipede, has been utilized in traditional East Asian medicine for centuries to treat conditions such as chronic pain, inflammation, convulsions, and infections. Recent pharmacological investigations have uncovered a wide array of bioactive molecules—including peptides, alkaloids, and polysaccharide–protein complexes—from both venom and whole-body extracts. This review synthesizes findings from 45 in vitro, in vivo, and clinical studies investigating the pharmacological effects of venom-derived and whole-body-derived compounds from S. subspinipes across multiple domains, including analgesic, anti-inflammatory, antimicrobial, antifungal, antioxidant, antitumor, antithrombotic, anti-fibrotic, and neuroprotective activities, along with a brief scoping review of clinical practice guidelines. Key venom-derived compounds such as the peptide SsmTX-I, immunomodulatory antimicrobial peptide scolopendrasin IX, and antitumor peptide scolopentide exhibit strong mechanistic rationale and preclinical efficacy, positioning them as lead candidates for clinical development. Compounds derived from whole-body extracts, including alkaloids and polysaccharide–protein complexes, also demonstrate promising therapeutic potential. Mechanistic studies suggest these compounds operate via distinct pathways—such as ion-channel inhibition, NF-κB suppression, and apoptosis induction—offering potential advantages over existing therapies. However, current evidence remains primarily preclinical, and challenges such as extract variability, immunogenicity, and lack of standardized dosing must be addressed. Future research should prioritize isolation and structural optimization of key peptides, standardized formulation development, toxicological profiling, and early-phase human trials. The integration of traditional knowledge and modern pharmacological insights underscores the potential of venom- and whole-body-derived S. subspinipes agents to enrich the drug discovery, particularly for conditions with unmet therapeutic needs. Full article

Background/Objectives: The thiazolo [5,4-d]pyrimidine scaffold is a class of drugs known for its anticancer, antitumor, anti-inflammatory, and antimicrobial properties. In this study, the electrochemical properties of novel thiazolo [5,4-d]pyrimidine derivatives and their interactions with DNA were characterized for the first time using voltammetric methods. Determining the interactions of new drug candidate molecules with DNA is crucial for drug development studies and is the main objective of this research. Methods: Both molecules were immobilized on the surface of the electrodes by passive adsorption, and their electrochemical properties were determined by voltammetric methods through reduction currents. Their interactions with DNA were carried out in the solution phase and examined by the changes in the oxidation peak potential and current of the guanine base. Results: For both molecules, it was determined that the electrochemical reduction processes are diffusion-controlled and irreversible, with an equal number of protons and electrons being transferred during this process. The detection limits for TP-NB (4-chloro-N-(5-chlorothiazolo [5,4-d]pyrimidin-2-yl)-3-nitrobenzamide) and TP-PC (1-(2-(4-(4-carbamoylpiperidin-1-yl)-3-nitrobenzamido)thiazolo [5,4-d]pyrimidin-5-yl)piperidine-4-carboxamide) were determined to be 12 µg/mL and 16 µg/mL, respectively. As a result of the interaction between both molecules with DNA, the guanine oxidation current decreased. It was found that TP-NB could act as an intercalator, while TP-PC could affect DNA electrostatically, both showing toxic effects on DNA. Conclusions: An electrochemical method was developed for the rapid, cost-effective, and sensitive detection of both molecules and their DNA interactions. Both compounds exhibited notable affinity towards DNA, as evidenced by significant changes in oxidation peak currents, shifts in peak potentials, and calculated toxicity values. These findings suggest their potential use as DNA-interacting drugs, such as anticancer and antimicrobial agents. Our study offers a quick, cost-effective, and reliable electrochemical approach for the evaluation of drug–DNA interactions. Full article

β-glucan, a promising drug candidate for immuno-antitumor therapy, holds tremendous potential for clinical applications. However, the absence of highly sensitive quantitative methods for polysaccharides, attributed to their complicated chemical structures and susceptibility to endogenous interference, has posed significant challenges for their clinical development. Here, we report a highly sensitive and reliable analytical strategy for quantifying β-1, 3/1, 6-glucan derived from Durvillaea antarctica (BG136) in various biological matrices. This approach integrates targeted depolymerization and derivatization, followed by oligosaccharide isomer fingerprinting using ultra-high-performance liquid chromatography-triple quadrupole tandem mass spectrometry (UHPLC-MS/MS). The absolute quantification of BG136 relied on the abundance of the structure-specific trisaccharide (Glc-β1, 6-Glc-β1, 3-Glc) generated. This methodology not only facilitates prototype-based BG136 administration but also exhibits remarkable sensitivity. Following method optimization and validation, we successfully explored the in vivo fate of BG136 across multiple models, including cellular uptake and release kinetics, as well as preclinical and clinical pharmacokinetics. These achievements provide insight into the “black box” of BG136 from administration to elimination in vivo. This work marks the first practical application of this strategy in complex biological matrices, offering methodological support for the successful execution of the BG136 Phase I clinical trial. Full article

Despite improvements in therapeutic approaches like immunotherapy and gene therapy, cancer still remains a serious threat to world health due to its high incidence and mortality rates. Limitations of conventional therapy include suboptimal targeting, multidrug resistance, and systemic toxicity. A major challenge in current oncology therapies is the development of new delivery methods for antineoplastic drugs that act directly on target. One approach involves the complexation of antitumor drugs with cyclodextrins (CDs) and chitosan (CS) as an attempt to counteract their primary limitations: low water solubility and bioavailability, diminished in vitro and in vivo stability, and high dose-dependent toxicity. All those drawbacks may potentially exclude some therapeutic candidates from clinical trials, thus their integration into smart delivery systems or drug-targeting technologies must be implemented. We intended to overview new drug delivery systems based on chitosan or cyclodextrins with regard to the current diagnosis and cancer management. This narrative review encompasses full-length articles published in English between 2019 and 2025 (including online ahead of print versions) in PubMed-indexed journals, focusing on recent research on the encapsulation of diverse antitumor drugs within those nanosystems that exhibit responsiveness to various stimuli such as pH, redox potential, and folate receptor levels, thereby enhancing the release of bioactive compounds at tumor sites. The majority of the cited references focus on the most notable research, studies of novel applications, and scientific advancements in the field of nanostructures and functional materials employed in oncological therapies over the last six years. Certainly, there are additional stimuli with research potential that can facilitate the drug’s release upon activation, such as reactive oxygen species (ROS), various enzymes, ATP level, or hypoxia; however, our review exclusively addresses the aforementioned stimuli presented in a comprehensive manner. Full article

The liver, as the primary metabolic organ, is susceptible to an array of factors that can harm liver cells and give rise to different liver diseases. Epigallocatechin gallate (EGCG), a natural compound found in green tea, exerts numerous beneficial effects on the human body. Notably, EGCG displays antioxidative, antibacterial, antiviral, anti-inflammatory, and anti-tumor properties. This review specifically highlights the pivotal role of EGCG in liver-related diseases, focusing on viral hepatitis, autoimmune hepatitis, fatty liver disease, and hepatocellular carcinoma. EGCG not only inhibits the entry and replication of hepatitis B and C viruses within hepatocytes, but also mitigates hepatocytic damage caused by hepatitis-induced inflammation. Furthermore, EGCG exhibits significant therapeutic potential against hepatocellular carcinoma. Combinatorial use of EGCG and anti-hepatocellular carcinoma drugs enhances the sensitivity of drug-resistant cancer cells to chemotherapeutic agents, leading to improved therapeutic outcomes. Thus, the combination of EGCG and anti-hepatocellular carcinoma drugs holds promise as an effective approach for treating drug-resistant hepatocellular carcinoma. In conclusion, EGCG possesses hepatoprotective properties against various forms of liver damage and emerges as a potential drug candidate for liver diseases. Full article