M. Barel, M. Balbo, M. Le Romancer and R. Frade, "Activation of Epstein-Barr Virus/C3d Receptor (gp140, CR2, CD21) on Human Cell Surface Triggers pp60src and Akt-GSK3 Activities Upstream and Downstream to PI 3-Kinase, Respectively," European Journal of Immunology 33, no. 9 (2003): 2557-2566, https://doi.org/10.1002/eji.200324059. This Expression of Concern is for the above article, published online on 18 August 2003 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editors-in-Chief, Matteo Iannacone and Nadja Bakocevic, and Wiley-VCH GmbH, Weinheim. The Expression of Concern has been issued after duplicated bands were identified between the anti‑nucleolin panels presented in Figures 1A2 and 3C2. Due to the time elapsed since publication, the authors were unable to provide supporting raw data. While the journal considers it unlikely that the conclusions of the article are affected, this Expression of Concern is published to inform readers of the issue.
Lower limb transient ischemia (LLTI)-induced hepatic injury is intricately linked to redox disequilibrium, inflammation, and emerging modalities of regulated cell death, including ferroptosis. The renin-angiotensin system (RAS), particularly its non-canonical arm, has been implicated in tissue protection, yet its crosstalk with ferroptosis remains underexplored. This study investigated the hepato-therapeutic potential of xanthenone (XNT), an ACE2 activator, in a LLTI-induced liver injury model, with a focus on the Ang-(1-9)/AT2R axis and ferroptosis regulation. Accordingly, male Wistar rats were subjected to LLTI and treated with XNT, with or without the AT2R antagonist PD123319. Hepatic function, oxidative stress markers, ferroptotic signals, and RAS components were assessed using molecular modeling, biochemical, and histopathological techniques. XNT improved liver architecture and reduced ALT/AST levels to confer hepatoprotection. Mechanistically, XNT shifted RAS signaling to the protective ACE2/Ang-(1-9)/AT2R pathway, leading to suppression of Ang-II and enhancement of Ang-I/Ang-(1-9) contents. This shift activated the AKT/Nrf2/HO-1 antioxidant cascade and restored homeostasis of the central anti-ferroptotic system SLC7A11/GSH/GPX4, inhibited ACSL4 expression, thereby reducing ROS, and lipid peroxidation. Importantly, XNT also mitigated ferroptosis by downregulating Fe3+/TfR1, Fe2+, and ferritin accumulation, while modulating the ferritinophagy axis through upregulation of HERC2 and suppression of NCOA4. These effects were largely abolished by PD123319, indicating AT2R dependency. In conclusion, XNT protects against LLTI-induced hepatic injury by orchestrating a dual antioxidant and anti-ferroptotic response via the Ang-(1-9)/AT2R axis. These findings unveil a novel crosstalk between RAS modulation and ferroptosis regulation, positioning AT2R activation as a promising therapeutic strategy for ischemia/reperfusion-related liver damage.
Infectious diseases remain a major global health challenge, accounting for millions of deaths annually and placing an increasing burden on healthcare systems worldwide. The rapid emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacterial strains, together with recurrent outbreaks of viral infections such as SARS-CoV-2, Ebola, Zika, Monkeypox, and influenza, underscores the urgent need for novel therapeutic agents with diverse mechanisms of action. In this context, indolizines, isoindoles, and isoindolinones represent promising scaffolds in anti-infective drug discovery due to their unique structural features, versatile reactivity, and ability to engage multiple biological targets. This review provides an updated overview of the medicinal chemistry of indolizine and isoindoles, with particular emphasis on compounds demonstrating activities against infectious pathogens. Representative examples are highlighted to illustrate structure-activity relationships (SARs), scaffold-based optimization strategies, and emerging mechanistic insights. Relevant synthetic methodologies are discussed only in the context of biologically active compounds to provide a framework for rational design. Collectively, this review underscores the therapeutic potential of indolizine- and isoindole-derived scaffolds as versatile frameworks for anti-infective drug development and highlights opportunities for further chemical and biological exploration.
Oxadiazole derivatives represent a promising scaffold for drug discovery, offering therapeutic potential, notably against neurodegenerative diseases and microbial infections. Based on molecular hybridisation approach utilising bioactive oxadiazoles, pyridine-, quinoline- and nitrophenyl-based compounds, we designed novel 1,3,4- and 1,2,4-oxadiazole derivatives containing nitro group(s), evaluated their enzyme inhibition, antimicrobial, and antioxidant properties, and analysed their structure-activity relationships (SAR). Comprehensive activity assessments of them and their synthetic precursors revealed robust inhibitory activity against acetylcholinesterase with IC50 values as low as 1.47 µM and butyrylcholinesterase (IC50 ≥ 45.09 μM), outperforming rivastigmine in several cases. Mechanistic insights via molecular docking unveiled unique binding modes for cholinesterases inhibition. Antimicrobial screening demonstrated potent activity (MIC ≥ 2 μM) of several compounds against Mycobacterium tuberculosis, atypical mycobacteria, Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, and mould Trichophyton interdigitale. The antioxidant evaluation identified derivatives' free-radical scavenging potential. SAR analysis identified essential structural features, favouring 3,5-dinitrophenyl moiety and 1,3,4-oxadiazoles over 1,2,4-isomers and 1,2-diacylhydrazine precursors. In summary, novel candidates for addressing challenges in treating infectious diseases and disorders related to insufficient acetylcholine transmission were identified.
To evaluate the safety and effectiveness of intravascular lithotripsy (SEISMIQ intravascular lithotripsy [IVL] system; Boston Scientific Corporation, Marlborough, Massachusetts) for treating calcified above-the-knee (ATK) lesions in patients with peripheral artery disease. RESTORE ATK was a prospective, single-arm study that enrolled from 10 sites between January 20, 2023, and December 13, 2023. Ninety-five patients with de novo, moderate to severe calcifications of the femoropopliteal segments were treated using the tested device to modify calcium. Adjunctive drug-eluting technology was not permitted. Primary endpoints were <50% residual diameter stenosis after IVL treatment (by independent core laboratory-adjudicated angiography) and 30-day incidence of major adverse events (MAEs): death, clinically driven target lesion revascularization (CD-TLR), or major amputation. Secondary endpoints included patency, ankle-brachial index, and Rutherford classification (RC) through 6 months. Baseline RC included RC2 (23.2%), RC3 (70.5%), or RC4 (6.3%). Lesions averaged 96.0 mm in length, with 93.7% severely calcified and a mean baseline diameter stenosis of 93.7%. Postprocedural residual stenosis of <50% was achieved in all patients, meeting the predefined performance goal. Three patients (3.2%) received provisional stent placement. Patients had a mean residual stenosis of 21.2% and acute luminal gain of 3.2 mm. No MAEs occurred through 30-day follow-up. At 6 months, target lesion patency was 66.3%, and freedom from CD-TLR was 97.9%. A high proportion of patients demonstrated ≥1 RC improvement at 30-day (93.5%) and 6-month (91.2%) follow-up. This IVL system demonstrated effective treatment of calcified ATK lesions by successfully reducing calcific stenoses with minimal complications and sustained clinical improvement through 6 months.
Proteolysis targeting chimeras (PROTACs) and molecular glues induce ligand-mediated ternary complexes between an E3 ubiquitin ligase and a protein of interest, but their in silico modeling remains challenging due to conformational flexibility and weak protein-protein interfaces. Recent diffusion-based AI structure prediction models enable the direct prediction of protein-ligand complexes. Here we benchmarked AlphaFold 3 and Boltz-2 for predicting PROTAC- and molecular glue-mediated ternary complexes using a reproducible evaluation workflow. We curated a dataset of 40 experimentally resolved complexes from the Protein Data Bank, including 25 PROTAC and 15 molecular glue systems. Structural accuracy was assessed using complex RMSD and DockQ scores relative to the corresponding crystal structures and compared to model-internal confidence metrics. Both models outperform other current approaches in both accuracy and runtime. Boltz-2 shows higher prediction accuracy assessed by complex RMSD and DockQ scores. Predictions are generally more accurate for VHL-based PROTACs than for CRBN-based PROTACs. Predictions for molecular glue complexes show good overall accuracy. Error analysis indicates that prediction failures predominantly arise from misoriented global arrangements and twisting in flexible ternary complexes, while individual protein and ligand structures are often accurately modeled. Limitations in the generalizability of the models could also be observed, especially for more recently released structures. These findings suggest that diffusion-based AlphaFold-type models show promise in the structure-based prediction of PROTAC- and molecular glue-mediated ternary complexes.
Inspired by the structural insights of the reported kinase inhibitor Sorafenib, two new series comprising 19 benzimidazole-based compounds incorporating isatin and thiourea motifs were rationally designed as a novel VEGFR-2-targeting anti-cancer chemotype. These compounds were synthesized and evaluated for their anti-cancer activity using the NCI single-dose antiproliferative assay against 60 cancer cell lines. The most potent and broad-spectrum compounds 8e, 9b, 9d, 9e, 9g, 9h, and 9i were further selected by NCI for the five-dose assay panel. These compounds were then assessed for anti-angiogenic activity against VEGFR-2, where compound 9i revealed promising activity (IC50 = 58 nM) compared to Sorafenib (IC50 = 72 nM), while the rest of the compounds gave an IC50 range of 96-981 nM. The most active compound 9i showed considerable safety toward normal human WI-38 cells (IC50 = 28.847 µM vs. Sorafenib IC50 = 13.497 µM) and arrested cell growth in the G1/S phase with total apoptotic induction of 37.65%. Molecular docking studies revealed favorable binding modes of the designed compounds within the VEGFR-2 active site. Molecular dynamics (MD) simulation confirmed the high stability of VEGFR-2-9i complex. Physicochemical properties and bioavailability radar plot disclosed adequate drug-likeness properties. Collectively, a new benzimidazole-isatin/thiourea chemotype was introduced as a promising VEGFR-2-targeting anti-cancer scaffold, demonstrating enhanced potency and improved safety relative to Sorafenib, and providing a rational basis for further lead optimization.
Gastrointestinal (GI) cancers represent a major global health burden due to their high incidence and mortality. Brusatol has emerged as a promising natural anticancer agent with potent activity against diverse malignancies. It exerts antitumor effects by inhibiting the nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway, modulating redox homeostasis, and sensitizing tumor cells to oxidative stress and chemotherapeutics. This review summarizes the current understanding of the molecular mechanisms of brusatol in GI cancers, and its synergistic potential with conventional therapies as well as nanotechnology-based delivery systems. We highlight the future directions for safer and more selective brusatol derivatives for GI cancer therapy.
After vessel preparation, using different strategies such as balloon angioplasty, specialty balloons, atherectomy or intravascular lithotripsy, definitive treatment has emerged as a key feature in endovascular treatment strategies. Based on current guidelines, endovascular treatment is the most common treatment option in patients with claudication. In patients with chronic limb-threatening ischemia (CLTI), on the other hand, the best treatment modality, including bypass surgery and endovascular revascularization, needs to be selected by an interdisciplinary team, focusing on individual anatomic and patient-specific characteristics, on the availability of a vein graft and on cardiovascular and other comorbidities of the patients. With endovascular therapy, currently, a plethora of options are available for the treatment of femoropopliteal lesions, which are increasingly gaining in complexity. Therefore, a practical systematic case-based approach, entailing contemporary treatment options, like drug-coated balloon (DCB) angioplasty tools, self-expanding bare-metal stents (BMSs), drug-eluting stents (DESs), interwoven stents and covered stents, is crucial. Generally, most endovascular operators adhere to the 'leave nothing behind' concept, meaning that, after proper lesion preparation, lesions can be treated with DCBs, avoiding the implantation of permanent metallic implants. However, in the case of severe dissections or significant recoil, stent implantation becomes necessary to achieve adequate limb perfusion. The selection between long versus spot stenting and the different stent options depends on the current scientific evidence, guidelines and expert opinion statements. An interdisciplinary expert consensus was recently compiled on how these modalities should be used in specific lesions and patients in the femoropopliteal segment. Herein we present a practical case-based approach, which is based on this algorithm and aims at harmonization of endovascular treatment strategies in daily practice and ultimately at further improvements in limb and patient outcomes.
AXL and c-Met have been identified as pivotal oncogenic factors in non-small cell lung cancer (NSCLC), their downstream signaling pathways exhibit substantial cross-talk, and the simultaneous inhibition of both factors has demonstrated substantial anti-tumor efficacy. Molecular targeted therapy is characterized by its high precision and low toxicity, which confers a significant advantage in the management of NSCLC. Extensive research has explored the co-targeting of AXL and c-Met in both preclinical and clinical contexts, primarily emphasizing small-molecule inhibitors. This review systematically examines the structure, function, regulatory mechanisms, and signaling pathways of AXL and c-Met. It then highlights recent advancements in small molecule co-targeted inhibitors of AXL and c-Met, detailing their mechanisms of action in NSCLC treatment, and summarizes the results of relevant clinical trials. AXL and c-Met significantly influence NSCLC cell proliferation, migration and invasion, epithelial-mesenchymal transition (EMT), and drug resistance, all of which adversely affect patient prognosis. Co-targeting of AXL and c-Met is considered a promising therapeutic strategy for NSCLC.
Chalcones are versatile scaffolds with broad pharmacological relevance, particularly as anti-inflammatory and anti-malarial agents. In the current investigation, a series of (3-arylediene-1-phenyl-1H-pyrazol-4-yl)acryloyl-4-hydroxy-6-methyl-2H-pyran-2-one analogs/1,3-diarylprop-2-en-1-ones were successfully synthesized, leveraging dehydroacetic acid (DHA) as the precursor molecule. The choice of DHA is strategic as it is a bioactive and highly versatile scaffold bearing a 4-hydroxy-6-methyl-2H-pyran-2-one moiety, which enhances structural diversity and provides multiple reactive sites for functionalization. Its inherent anti-microbial, anti-inflammatory, and anti-malarial potential offers an added advantage over conventional precursors, thereby increasing the likelihood of generating pharmacologically active chalcone hybrids. The synthetic protocol employed in this study involved the implementation of a Claisen condensation reaction, wherein DHA was reacted with formyl pyrazole to afford the corresponding chalcones, with yields ranging from moderate to good. The synthesized compounds were subjected to a rigorous characterization protocol, involving a battery of analytical techniques, including 1H-NMR, 13C-NMR, FT-IR, and HRMS analyses. Biological evaluation focused on anti-malarial and anti-inflammatory activities, while molecular docking (PyRx 0.8) was performed to explore binding interactions with cyclooxygenase-2 (COX-2; PDB ID: 3LN1) and enoyl-acyl-carrier-protein reductase (EACPR; PDB ID: 1NHG). Notably, compound 3c emerged as the most potent one within the synthesized series, exhibiting remarkable anti-inflammatory and anti-malarial potency, as evidenced by its IC50 values of 7.05 ± 0.17 µM and 0.95 ± 0.06 µM, respectively. Docking studies revealed strong binding affinities and favorable molecular interactions, supporting the observed bioactivities. This study highlights chalcone-pyrazole hybrids as promising therapeutic scaffolds. In particular, compound 3c emerges as a compelling lead candidate for further optimization and preclinical investigation as a dual-action agent against malaria and inflammation.
The pyrazolopyrimidines are a significant category of heterocyclic fused compounds that have gained growing interest owing to their wide range of biological functions as well as their synthetic all-purpose. The review draws attention to the current advances (2019-2025) in the synthesis, structural rearrangement, and pharmacological assessments of pyrazolopyrimidines with particular focus on pyrazolo[3,4-d]pyrimidine and pyrazolo[1,5-a]pyrimidine derivatives. The latter scaffolds have also been efficiently and sustainably approached through recent synthetic methodologies, such as multicomponent reactions, microwave-assisted synthesis, and green chemistry methodologies. Several derivatives have been shown to have strong anticancer, antimicrobial, anti-inflammatory, and antiviral effects, usually through the action on important enzymes, including CDK2, FLT3, VEGFR-2, PIM-1, and Topoisomerase IIa.
The first BODIPY-allopregnanolone conjugates have been synthesized by selecting the C21 position for labeling. The steroidal moiety and BODIPY fluorophores were coupled through flexible amino acid-derived linkers, designed with rotatable bonds and a variable carbon chain length. Сonjugates were characterized, with quantum yields of up to 79% and high extinction coefficients. All compounds showed a reasonable ability to potentiate GABA-evoked currents in isolated cerebellar Purkinje neurons. Interactions of the conjugates with the GABAA receptor were investigated by molecular docking calculations, which predicted that the BODIPY fluorophore linked to 3α5αTHP via the C21 atom does not prevent the binding of the 3α5αTHP moiety at the neurosteroid site on the β(+)/α(-) intersubunit interfaces. Fluorescence microscopy studies demonstrated that the BODIPY-3α5αTHP III effectively stains Purkinje neurons in cerebellar slices and preferentially labels neuronal populations amidst coexisting astroglia in hippocampal tissue slices.
Comprehending the intricate mechanisms of apoptosis and its interaction with cytotoxic, antioxidant, and HDAC activities is imperative for devising effective cancer therapies. Sulfonamides and Schiff bases are compounds of pharmacological importance with known anticancer activity. Our study aimed to investigate the cytotoxic, antioxidant, HDAC, and apoptotic activities of new sulfonamide-Schiff bases in human colon cancer cells (DLD-1 and HT-29). New sulfonamide-derived Schiff base compounds (3a-d) were synthesized from the condensation of sulfamethoxypyridazine (1) and various aromatic aldehydes, and were characterized by FTIR, NMR (1H and 13C/APT), UV-Vis., and mass spectroscopy. Sulfonamide-derived Schiff bases 3a-d and compound 1 exhibited significant anticancer activity against colorectal cancer cell lines (DLD-1, HT-29). In the MTT assay, 3c was most active in DLD-1 (viability: 37.7%, IC₅₀ = 3.94 µM) and 3b in HT-29 (viability: 46.6%, IC₅₀ = 3.26 µM). In the WST-8 assay, 3c was strongest in DLD-1 (viability: 45.9%, IC₅₀ = 17.95 µM). None of the compounds showed toxicity in normal colon cells (CCD-18Co). qRT-PCR revealed upregulation of apoptotic (BAX, p53, Caspase-3/8/9) and antioxidant (SOD-1/2, CAT, GSS) genes, notably by 3a in DLD-1 and 3d in HT-29, while 3c reduced BCL-2 in HT-29 cells. ELISA confirmed strong antioxidant induction (3a: 70% in DLD-1) and HDAC inhibition (3d: 69% in HT-29). Western blot showed 3a increased p38/MAPK expression sevenfold in DLD-1 and fourfold in HT-29, while decreasing ERK1. Overall, 3c and 3d emerged as the most promising candidates, combining cytotoxic, antioxidant, HDAC inhibitory, and apoptotic effects, and may act as selective therapeutic agents by targeting the p38/MAPK-ERK1 pathway in colorectal cancer.
Gout and hyperuricemia, prevalent metabolic disorders, are driven by elevated serum uric acid (UA) levels and subsequent monosodium urate crystal deposition, which provoke inflammatory responses and joint damage. Current therapeutic options remain unsatisfactory, underscoring the urgent need for novel agents with improved efficacy and safety profiles. In this study, we aimed to discover a new lead compound capable of concurrently addressing both hyperuricemia and associated inflammatory pain. Two novel compounds were designed and synthesized, among which C2 was identified as a promising candidate. In vitro, C2 exhibited potent dual inhibitory activity against transient receptor potential vanilloid 1 (TRPV1)-a key mediator of inflammatory pain signaling-and urate transporter 1 (URAT1), which regulated renal UA reabsorption, with IC₅₀ values of 78.52 ± 14.50 nM and 598.6 ± 115.5 nM, respectively. In vivo, oral administration of C2 (20 mg/kg) significantly reduced serum UA levels in a hyperuricemic mouse model, demonstrating efficacy comparable to dotinurad. Furthermore, in a formalin-induced inflammatory pain model, C2 produced dose-dependent antinociceptive effects. Mechanistic investigations revealed that C2 suppressed NLRP3 inflammasome activation in THP-1 cells, as indicated by reduced IL-1β secretion. Additionally, C2 ameliorated dextran sulfate sodium-induced colitis in mice, accompanied by improved histopathological scores. Collectively, these results establish C2 as a multi-target lead compound that acts simultaneously on UA transport, nociceptive signaling, and the NLRP3 inflammasome pathway, providing a strong rationale for its further development as a novel therapeutic strategy for gout and hyperuricemia.
β-Carboline alkaloids, such as harmine (1), have demonstrated notable anticancer properties, making them attractive candidates for anticancer drug development. This study evaluated the antiproliferative activity of compound 1 and thirty-three N9-substituted derivatives across a panel of cancer cell lines representing various histotypes. Among these, derivative 6, a harmine analog bearing a 3,5-dimethylbenzyl substituent, was the most potent, showing enhanced cytotoxicity and selectivity toward cancer cells. Compound 6 exhibited IC50 values below 10 µM in all tested cancer cell lines, while its IC50 in non-cancerous cells exceeded 100 µM. Viability assays and xCELLigence real-time monitoring confirmed a concentration-dependent inhibition of cancer cell growth with minimal effects on non-malignant cells. Flow cytometry demonstrated G1 phase arrest in MOLT-4 cells, supported by Western blot data showing reduced phosphorylated Rb and increased p27 protein levels. Apoptosis induction was confirmed through Annexin V/PI staining, TUNEL assays, and caspase activation studies. These revealed the involvement of both intrinsic (caspase-9) and extrinsic (caspase-8) apoptotic pathways, along with activation of caspases 3/7. Western blot analysis also showed a concentration-dependent increase in the Bax/Bcl-2 ratio. Immunofluorescence microscopy visualization indicated DNA damage through elevated levels of PAR and γH2AX, consistent with single- and double-strand DNA breaks. Importantly, compound 6 exhibited low inhibitory activity against monoamine oxidase A (MAO-A) and did not promote reactive oxygen species (ROS) generation, minimizing potential off-target effects. Together, these findings support the potential of compound 6 as a selective and effective candidate for antileukemia therapy.
Halogens are utilized in drug discovery and development due to their ability to precisely tune the molecular properties of drug candidates. The halogen substituents play a crucial role in determining the stability, lipophilicity, and receptor binding, as well as significantly influencing the metabolic fate of the drug candidates. Literature insights reveal that 30% of all small molecules approved by the USFDA carry a halogen as a substituent. Considering the vital importance of halogen-containing substituents, we have compiled concise information on halogen-containing US FDA-approved drugs over the last decade (2019-2024). The articles provide information on pharmacological conditions, targets, available formulations, and pharmacokinetic details for each approved drug that possesses a halogen as a substituent, along with its corresponding chemical structure. The analysis revealed that 37 new drugs were approved to combat cancer (13), followed by rare diseases (6), viral infections (3), and other conditions during the analysis period. Furthermore, the chemistry of halogens, along with their medicinal applications, provides key evidence on how halogens have been explored to enhance the pharmacokinetics and pharmacodynamics of drug candidates. The analysis of approved dosage forms revealed that 23 were solid dosage forms, comprising 24 tablet forms, 8 capsules, and 1 powder. CYP3A4 is a major contributor in the metabolism of 6 drugs, followed by CYP3A (3), CYP1A2 (2), CYP3A4/5 (2), and one each by CYP2C9, UGT1A9, CYP2C8, aldehyde oxidase, and other non-CYP enzymes. The present medicinal chemistry perspective is thus expected to be a valuable read for the medicinal and allied sciences community.
Selective estrogen receptor modulators (SERMs) are an important class of drugs mainly useful in the treatment of breast cancer as they act as estrogen antagonists in the breast tissue but have an agonistic activity in bone and the cardiovascular system (CVS). ER-positive breast cancer, driven by estrogen signaling, is the most prevalent subtype worldwide. SERMs remain essential therapeutics, antagonizing estrogen activity in breast tissue while retaining agonist effects in bone and CVS. While traditional reviews have focused on triphenylethylene and benzothiophene scaffolds, this review provides a novel, insightful comprehensive analysis of emerging heterocyclic SERMS-including indole, benzimidazole, coumarin, benzopyran, organometallic, and phytoestrogen derivatives-linking chemical diversity with tissue-selective mechanisms and structure-activity relationships. Major limitations include incomplete receptor subtype selectivity, metabolic instability, partial agonism in nontarget tissues, and acquired endocrine resistance driven by ER mutations and growth factor signaling. This work uniquely integrates structural, mechanistic, and therapeutic insights and highlights innovative strategies, including dual SERM-SERD scaffolds, combination with aromatase inhibitors, and computationally guided subtype-selective design to overcome resistance, improve potency, and optimize clinical outcomes in ER-positive breast cancer therapy.
Paclitaxel is a frequently employed chemotherapeutic agent for nasopharyngeal carcinoma (NPC) patients, and tumor cell resistance to paclitaxel poses a significant challenge to NPC treatment. This study investigated the impact and potential mechanisms of folate-receptor 1 (FOLR1) on paclitaxel resistance in NPC cells. Levels of FOLR1 in NPC tissues and cells were measured using RT-qPCR. Protein expression was analyzed by Western blot. IC50 of paclitaxel-treated NPC cells was assessed by CCK-8. EdU and Colony formation assay detected cell proliferation. Apoptosis and pyroptosis were evaluated utilizing flow cytometry. Expression and localization of ITCH and FOLR1 were detected by immunofluorescence staining. Interaction between ITCH and FOLR1 was tested by co-immunoprecipitation (Co-IP). The immunoprecipitation assay evaluated FOLR1 ubiquitination levels. An NPC xenograft model was constructed in nude mice. FOLR1 was overexpressed in NPC and correlates with a poor prognosis in NPC patients. Low levels of cell pyroptosis and elevated FOLR1 expression were strongly associated with paclitaxel resistance in NPC. Knockdown of FOLR1 reduced the chemoresistance of 5-8 F/paclitaxel cells to paclitaxel. ITCH was associated with FOLR1 and enhanced its degradation through ubiquitination. ITCH reduced paclitaxel resistance in NPC cells via downregulation of FOLR1. FOLR1 increased resistance to paclitaxel by suppressing pyroptosis in NPC through an NLRP3-dependent mechanism. FOLR1 inhibited pyroptosis by inhibiting the mTOR pathway and promoting autophagy. Lowering FOLR1 expression suppressed tumor growth and boosted paclitaxel sensitivity in mice. FOLR1 plays a significant role in promoting chemoresistance of NPC cells to paclitaxel through NLRP3 signaling.
Sideroxylonal B, a natural dimeric acylphloroglucinol, demonstrates promising anticancer potential through a dual mechanism of action involving both cytotoxicity and selective enzyme inhibition. In preliminary screening against the NCI 60 human tumor cell line panel at a concentration of 10-5M, sideroxylonal B exhibited moderate but selective antiproliferative activity, particularly against leukemia (CCRF-CEM, RPMI-8226), breast (MCF7), and renal (CAKI-1) cancer cell lines. Notably, sideroxylonal B selectively inhibits tumor-associated carbonic anhydrase isoforms hCA IX and XII (Ki  = 28.1 and 44.4 µM), with minimal inhibition of isoforms hCA I and II. Molecular docking and MM-GBSA binding energy simulations corroborated its selective interaction profile, highlighting its preferential binding to the more accommodating active sites of hCA IX and XII via hydrogen bonds and π-π interactions. The compound showed no antiviral activity against coxsackievirus B3 (CVB3) or Human Herpes virus type 1 (HHV-1). These findings suggest sideroxylonal B as a novel and selective natural carbonic anhydrase inhibitor with a unique structural scaffold, to be further explored for its potential application in targeted cancer therapy.