To enhance the skin permeability and retention of Sapindus saponins, cationic liposomes are fabricated via a thin-film dispersion method followed by electrostatic cross-linking with chitosan. The Franz diffusion cell method is used to evaluate the transdermal performance, while molecular dynamics (MD) simulations (50 ns) are employed to elucidate the self-assembly mechanism and intermolecular interactions. The optimized preparation conditions are determined as Sapindus saponin extract concentration of 15 mg/mL, soybean lecithin dosage of 350 mg, lecithin: stigmasterol mass ratio of 4:1, and hydration temperature of 55 °C. Under these conditions, the liposomes achieve an encapsulation efficiency of 87.89 ± 2.85%. Upon modification with chitosan (volume ratio of 0.8), the ζ potential reverses to positive (+39.9 ± 1.7 mV). Transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC) confirm the formation of a core-shell structure and the amorphization of the encapsulated components. Notably, the cationic liposomes exhibit a 24 h cumulative permeation rate of 63.92% (2.08 times that of conventional liposomes) and, more importantly, a skin retention rate of 7.09% (5.0 times higher), demonstrating a significant local drug reservoir effect. MD simulation results reveal that the system self-assembles into vesicular complexes driven by van der Waals forces, hydrogen bond networks, and strong electrostatic anchoring. Specifically, robust electrostatic attractions form between the phosphate groups of lipids and the amino groups of chitosan, while a diffuse hydrogen bond network creates a rigid protective coating. These interactions serve as the core forces, maintaining the structural stability and preventing drug leakage.

Natural products, especially diterpenoids, are widely used for clinical treatments with commercially available drugs. For the purpose of finding much more bioactive diterpenoids, twelve 8,15-seco-ent-kaurane-type diterpenoids including 9 new ones, caesalactones A-I (1-9), along with 3 new natural products (10-12) were obtained from the leaves and stems of Caesalpinia enneaphylla. Their planar structures were established based on the comprehensive investigations of one dimensional nuclear magnetic resonance (1D NMR), 2D NMR and high resolution electrospray ionization mass spectrometry (HR-ESI-MS) data. The absolute configurations of compounds 1 and 2 were established by single-crystal X-ray diffraction, whereas those for the others were established by circular dichroism (CD) data analysis. Compounds 1-12 were identified as a group of rare 8,15-seco-ent-kaur16-en-8,15-olides. Hitherto, only five representative structures of this type have been found among ent-kaurane derivatives. Cytotoxic activities evaluation revealed that compound 8 exhibited significant cytotoxicity superior to the positive control cisplatin against MDA-MB-231, MCF-7 and HCT-116 cell lines with IC50 values of 7.03, 26.8 and 7.76 mu M, respectively. This study suggested the isolation of 8,15-seco-ent-kaurane diterpenoids from C. enneaphylla had new potential applications in pharmaceutical industry.

The hyperactivation of the PI3K pathway in head and neck squamous cell carcinoma (HNSCC) suggests that targeting PI3K is a potential therapeutic strategy. CYH33 is a novel PI3Kα-selective inhibitor discovered by our group, which is currently undergoing a phase I clinical trial (NCT03544905) for the treatment of advanced solid tumors including HNSCC. However, there is an urgent need to elucidate its mechanism of action and improve its efficacy against HNSCC. In this study, we found that CYH33 displayed promising but variable therapeutic activity against HNSCC. Inhibition of PI3K/Akt pathway by CYH33 was not sufficient for its activity against HNSCC. Tandem-Mass-Tag (TMT) phosphoproteomics were performed to reveal comprehensive regulation of kinome by CYH33. Particularly, attenuation of Erk phosphorylation was associated with the sensitivity of HNSCC cells to CYH33. Mechanistically, inhibition of PI3K by CYH33 blocked the PIP3 production and attenuated the membrane localization and phosphorylation of GAB1, resulting in reduced Erk phosphorylation and ultimately inhibition of cell proliferation in sensitive HNSCC cells. Meanwhile, activation of EGFR induced GAB1 phosphorylation independent of PI3K in HNSCC cells. Concurrent inhibition of EGFR synergistically potentiated the activity of CYH33 against HNSCC. These findings revealed the insight mechanism of CYH33 against HNSCC and provided rational combination regimen for HNSCC treatment.

One new stilbene, trans-3,2 '-dihydroxy-3 ',4 ',5-trimethoxy stilbene (1), together with seven known ones (2-8) were isolated from the leaves and stems of Cassia nodosa Buch.-Ham. ex Roxb (Fabaceae). The structure of the new compound was elucidated via analyses of NMR (1 D and 2 D) and HRESIMS data. To the best of our knowledge, all the known compounds were isolated from the genus Cassia for the first time. Cytotoxicity and anti-neuroinflammatory activities assay of the isolated compounds revealed that 1 exhibited significant cytotoxicity superior to the positive control cisplatin against MDA-MB-231 and MCF-7 cell lines. Furthermore, the chemotaxonomic significance of the isolates was also discussed, building upon our previous studies on flavonoids, anthraquinones, terpenoids, and flavan derivatives from C. nodosa, which collectively enrich the phytochemical profile of this species and support its classification within the genus Cassia.

A Pt(iv) prodrug of oxaliplatin incorporating the glycolysis inhibitor 3-bromopyruvic acid, BrPt3, was designed and investigated. The prodrug is reduced in the presence of ascorbic acid, releasing its active Pt(ii) species and axial ligand. In cytotoxicity studies, BrPt3 exhibited stronger anticancer activity than oxaliplatin against all tested cancer cell lines, particularly in oxaliplatin-resistant A549/OXP cells. By effectively inhibiting glycolysis, BrPt3 induced greater DNA damage in tumor cells. It arrested the cell cycle at the G0/G1 phase, leading to increased apoptosis and significantly reduced cell invasiveness. BrPt3 resulted in higher platinum accumulation in the genomic DNA of MKN28, HCT116, and HT29 cells, though no significant difference in DNA-platinum adduct formation was observed in A549/OXP cells. Compared to oxaliplatin, BrPt3 more effectively impaired the glycolytic capacity of tumor cells, as evidenced by significantly reduced levels of pyruvate, lactate, ATP, and HK2 enzyme expression. In vivo studies using an HCT116 xenograft tumor mouse model demonstrated that BrPt3 achieved a higher tumor inhibition rate and lower toxicity than oxaliplatin. Although gavage administration resulted in a lower tumor inhibition rate than intraperitoneal administration, it still exhibited substantial antitumor activity. Overall, this Pt(iv) prodrug holds potential for development as an oral anticancer agent through its dual mechanisms of inducing DNA damage and inhibiting glycolysis.

This study investigates key microscopic regions involved in colorectal cancer liver metastasis (CRLM), focusing on the crucial role of cancer-associated fibroblasts (CAFs) in promoting tumor progression and providing molecular- and metabolism-level insights for its diagnosis and treatment using multi-omics. We followed 12 fresh surgical samples from 2 untreated CRLM patients. Among these, 4 samples were used for spatial transcriptomics (ST), 4 for spatial metabolomics, and 4 for single-cell RNA sequencing (scRNA-seq). Additionally, 92 frozen tissue samples from 40 patients were collected. Seven patients were used for immunofluorescence and RT-qPCR, while 33 patients were used for untargeted metabolomics. ST revealed that the spatial regions of CRLM consists of 7 major components, with fibroblast-dominated regions being the most prominent. These regions are characterized by diverse cell-cell interactions, and immunosuppressive and tumor growth-promoting environments. scRNA-seq identified that SPP1+ fibroblasts interact with CD44+ tumor cells, as confirmed through immunofluorescence. Spatial metabolomics revealed suberic acid and tetraethylene glycol as specific metabolic components of this structure, which was further validated by untargeted metabolomics. In conclusion, an SPP1+ fibroblast-rich spatial region with metabolic reprogramming capabilities and immunosuppressive properties was identified in CRLM, which potentially facilitates metastatic outgrowth through interactions with tumor cells.

Salidroside (Sal) is a natural active ingredient extracted from Crassulaceae plants, which has pharmacological effects such as anti-tumor, anti-oxidation, and cardiovascular protection. Potassium channel function in pulmonary artery smooth muscle cells (PASMCs) is crucial in the development of pulmonary arterial hypertension (PAH). This study explored the effects of Sal on large-conductance calcium-activated potassium channels (BKCa) in these cells, focusing on the mechanisms underlying its protective effect in PAH. A rat model of PAH was established using monocrotaline (MCT) alongside an in vitro model of primary PASMCs stimulated by platelet-derived growth factor-BB. This study thoroughly assesses Salidroside's impact on PAH across tissue function, molecular mechanisms, and electrophysiological characteristics. Our results show that Sal treatment reduced right ventricular pressure in MCT-induced PAH rats, ameliorated pulmonary vascular remodeling and right ventricular reconstruction, and enhanced pulmonary vasoconstriction and relaxation activity. It increased the expression of BKCa channel proteins on the membrane of PASMCs, inhibited the proliferation of PASMCs, promoted their apoptosis, and improved the electrophysiological remodeling of PASMCs and pulmonary vascular remodeling caused by PAH. Activation and excessive expression of PKC α markedly suppressed BKCa channel function. Sal was able to activate BKCa channels by inhibiting PKC α, leading to enhanced K+ efflux, cellular hyperpolarization, and vasodilation. In conclusion,by reinstating BKCa channel activity in PASMCs, Sal rectified the dysregulation between cell proliferation and apoptosis within the pulmonary vasculature. This mechanism, potentially mediated indirectly by Sal's modulation of PKC α, offers a novel therapeutic approach for PAH.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound MC1 for the treatment of AD. Utilizing the co-crystal structure of MCC950 in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of MC1 as the lead candidate. MC1 exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that MC1 significantly ameliorated cognitive deficits, surpassing the performance of MCC950. Importantly, MC1 showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that MC1 holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles.

Metastatic recurrence is still a major challenge in breast cancer treatment. Patients with triple negative breast cancer (TNBC) develop early recurrence and relapse more frequently. Due to the lack of specific therapeutic targets, new targeted therapies for TNBC are urgently needed. Phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway is one of the active pathways involved in chemoresistance and survival of TNBC, being considered as a potential target for TNBC treatment. Our present study identified ticagrelor, an anti-platelet drug, as a pan-PI3K inhibitor with potent inhibitory activity against four isoforms of class I PI3K. At doses normally used in clinic, ticagrelor showed weak cytotoxicity against a panel of breast cancer cells, but significantly inhibited the migration, invasion and the actin cytoskeleton organization of human TNBC MDA-MB-231 and SUM-159PT cells. Mechanistically, ticagrelor effectively inhibited PI3K downstream mTOR complex 1 (mTORC1) and mTORC2 signaling by targeting PI3K and decreased the protein expression of epithelial-mesenchymal transition (EMT) markers. In vivo, ticagrelor significantly suppressed tumor cells lung metastasis in 4T1 tumor bearing BALB/c mice model and experimental lung metastasis model which was established by tail vein injection of GFP-labeled MDA-MB-231 cells. The above data demonstrated that ticagrelor can inhibit the migration and invasion of TNBC both in vitro and in vivo by targeting PI3K, suggesting that ticagrelor, a pan-PI3K inhibitor, might represent a promising therapeutic agent for the treatment of metastatic TNBC.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, for the cell invasion and migration assay images shown for the A2780 cell line in Figs. 1 and Fig. 3 on p. 3433 and 3435 respectively, the same data panel had apparently been selected to show the results of the si‑NEAT1 experiment in Fig. 1 and the si‑TJP3 experiment in Fig. 3. After having re‑examined their original data, the authors have realized that the image correctly shown for Fig. 1 was inadvertently copied across to Fig. 3. The corrected version of Fig. 3, now correctly showing the data for the si‑TJP3 experiment with the A2780 cell line, is shown on the next page. Note that this error did not significantly affect the results or the conclusions reported in this paper. All the authors agree to the publication of this Corrigendum, are grateful to the Editor of Molecular Medicine Reports for allowing them the opportunity to correct this error, and apologize to the readership for any inconvenience caused. [Molecular Medicine Reports 22: 3429‑3439, 2020; DOI: 10.3892/mmr.2020.11428].

Background The clinical applications of platinum-based anticancer drugs are largely compromised by side effects and drug resistance. Therefore, novel platinum-based anticancer drugs with improved injected or oral therapeutic index and low resistance need to be developed.Objective This study aimed at the synthesis and anticancer activity testing of Pt(IV) prodrugs containing alpha-furancarboxylate as an axial ligand. This would pave the way for obtaining novel Pt(IV) prodrugs with better anticancer activity by comparing the anticancer activity with their parent platinum(II) complexes.Methods In this study, synthesis, in vitro cytoxicity assay, and in vivo anticancer activity evaluation of three Pt(IV) complexes, cis,trans,cis-[Pt(NH3)2(OH)(alpha-furancarboxylato)Cl2] (FPt-1), cis,trans,cis-[Pt(NH3)2(OH)(alpha-furancarboxylato)(1,1'-cylobutanedicarboxylato)] (FPt-2), and cis,trans,cis-[Pt(1R,2R-diaminocyclohexane)(OH)(alpha-furancarboxylato)(C2O4)] (FPt-3), were carried out.Results Three Pt(IV) complexes exhibited considerable cytoxicity against the tested human cancer cells (MCF-7, A549 and HCT116), which was found to be slightly lower than the corresponding Pt(II) drugs. However, FPt-1 and FPt-3 displayed comparable antitumor efficacy to cisplatin and oxaliplatin in the murine S180 sarcoma model after intraperitoneal administration. More importantly, the intragastric administration test indicated the antitumor efficacy of FPt-3 to be much greater than oxaliplatin.Conclusion FPt-3 has shown excellent oral antitumor activity and it could be administrated in an oral dosage form.

DNA topoisomerases are essential nuclear enzymes in correcting topological DNA errors and maintaining DNA integrity. Topoisomerase inhibitors are a significant class of cancer chemotherapeutics with a definite curative effect. Natural products are a rich source of lead compounds for drug discovery, including anti-tumor drugs. In this study, we found that narciclasine (NCS), an amaryllidaceae alkaloid, is a novel inhibitor of topoisomerase I (topo I). Our data demonstrated that NCS inhibited topo I activity and reversed its unwinding effect on p-HOT DNA substrate. However, it had no obvious effect on topo II activity. The molecular mechanism of NCS inhibited topo I showed that NCS did not stabilize topo-DNA covalent complexes in cells, indicating that NCS is not a topo I poison. A blind docking result showed that NCS could bind to topo I, suggesting that NCS might be a topo I suppressor. Additionally, NCS exhibited a potent anti-proliferation effect in various cancer cells. NCS arrested the cell cycle at G2/M phase and induced cell apoptosis. Our study reveals the antitumor mechanisms of NCS and provides a good foundation for the development of anti-cancer drugs based on topo I inhibition.

Supplementary Figure Legends and Supplementary Table. Supplementary Table. EGFRvIII receptors/cell quantification of U251vIII and D317

Esophageal squamous cell carcinoma (ESCC) is among the most prevalent causes of cancer-related death in patients worldwide. Resistance to immunotherapy and chemotherapy results in worse survival outcomes in ESCC. It is urgent to explore the underlying molecular mechanism of immune evasion and chemoresistance in ESCC. Here, we conducted RNA-sequencing analysis in ten ESCC tissues from cisplatin-based neoadjuvant chemotherapy patients. We found that DMRTA1 was extremely upregulated in the non-pathologic complete response (non-pCR) group. The proliferation rate of esophageal squamous carcinoma cells was markedly decreased after knockdown of DMRTA1 expression, which could increase cisplatin sensitivity in ESCC. Additionally, suppression of DMRTA1 could decrease the immune escape of esophageal squamous carcinoma cells. Further mechanistic studies suggest that DMRTA1 can promote its expression by binding to the promoter of SOX2, which plays important roles in the progression and chemoresistance of ESCC in the form of positive feedback. Therefore, DMRTA1 could be a potential target to suppress immune escape and overcome chemoresistance in ESCC.

9-nitrocamptothecin (9-NC), an active derivative of camptothecin (CPT), demonstrated antitumor effect on experimental tumors in mice by topoisomerase I (Topo I) inhibition. However, under human physiological conditions, the rapid opening of lactone ring of 9-NC resulting in the formation of inactive and high toxic carboxylate limited its clinical efficacy. Therefore, strategies aimed to maintain the active closed-lactone form of 9-NC in the plasma were developed, such as prodrugs. In our study, 9-nitro-20(S)-carbonate-camptothecin (NCP4), a novel prodrug of 9-NC, was designed and synthesized. A preclinical evaluation of the chemotherapeutic potential of NCP4 was performed in vitro and in vivo. In cytotoxicity assay against six human cancer cells, the cytotoxic effect of NCP4 was slightly weaker than 9-NC. In addition, our data showed that 9-NC can be converted from NCP4 in vivo, and that the intracellular conversion of NCP4 to its active metabolites was correlated well with its cytotoxicity, demonstrating that NCP4 could serve as a prodrug of 9-NC. In human hepatoma Bel-7402 xenografts, NCP4 by intravenous injection showed more potent antitumor efficacy than 9-NC. Mechanistically, NCP4 induced cell apoptosis by increasing the expressions of caspase-3 and Bax in tumor tissues. In human hepatoma Hep G2 xenografts, NCP4 by oral administration significantly inhibited tumor growth. Importantly, the toxic effect of NCP4 on mice was much lower than 9-NC, demonstrating improved safety of NCP4. Overall, our study indicated that NCP4 would be a promising anticancer candidate and worthy of further investigation.

Two new Pt(iv) complexes featuring mesylate as the outer sphere anion, cis,trans,cis-[PtCl2(OH2)2(NH3)2](CH3SO3)2 (SPt-1) and cis,trans,cis-[PtCl2(OH2)2(1R,2R-DACH)](CH3SO3)2 (SPt-2), were synthesized and characterized by elemental analysis, 1H and 13C NMR, IR, and ESI-MS. Both complexes have excellent water-solubility, high molar conductivity and good water stability. They exhibit an irreversible two-electron reduction event with the peak potentials (E p) for the processes being -0.40 V for SPt-1 and -0.52 V for SPt-2. The biological tests reveal that SPt-2 possesses high in vitro anticancer activity against three human cancer cell lines (HCT-116, A549 and MKN-1) and its overall anticancer activity is slightly greater than that of oxaliplatin, whereas SPt-1 is less active than cisplatin. Moreover, the antitumor efficacy of SPt-2 on human colon carcinoma HCT-116 xenografts in nude mice is also greater than that of oxaliplatin, suggesting that SPt-2 deserves further evaluation as a prodrug for oxaliplatin.

目的:利用Orphanet数据库筛选我国罕见病目录中的肿瘤类疾病,并对其进行学科分类,以期促进罕见病的多维度分类方法及数据库的建立.方法:以Orphanet数据库的分类方法为准,初步筛选出罕见肿瘤类疾病;通过权威期刊文献数据库检索其相关文献,整理学科分类数据,结合肿瘤类疾病的临床表现及症状进行分析.结果:共筛选出24种罕见肿瘤病,占罕见病目录的15.38％;根据罕见病的特殊性,提出以学科分类为依托的分类方法,适用性及可操作性强.结论:针对我国尚未有准确的罕见病分类标准,本研究从多维度对肿瘤类罕见病进行分类,有助于提高肿瘤类罕见病的辨认能力、促进进一步罕见病的分类研究.

传统抗肿瘤药物是指能够直接杀伤肿瘤细胞,抑制肿瘤细胞生长、增殖的一类细胞毒类化疗药物.由芥子气衍生而来的氮芥于1946年用于治疗淋巴瘤,揭开了现代肿瘤化学治疗的序幕.以氮芥为起始,包括烷化剂、抗代谢、抗癌抗生素和抗肿瘤植物药等多种类抗肿瘤药物被陆续开发用于临床治疗.传统抗肿瘤药物是肿瘤化疗的基石,在恶性肿瘤的综合治疗和新辅助治疗中占有重要地位.近年来,传统抗肿瘤药物通过与分子靶向治疗、免疫治疗及放射治疗的联合应用,极大地提高了肿瘤患者的生存率.随着对肿瘤基因组和肿瘤发生发展机制研究的不断深入,精准医学和个体化治疗的理念被提出并在临床实践中取得成功.在此背景下,传统抗肿瘤药物的个性化治疗策略也有待进一步研究和优化.本文综述了近年来传统抗肿瘤药物的临床应用情况和研究进展.

The treatment options for cancer include surgery, radiotherapy and chemotherapy. However, the traditional approach of high-dose chemotherapy brings tremendous toxic side effects to patients, as well as potentially causing drug resistance. Drug resistance affects cell proliferation, cell senescence and apoptosis. Cellular senescence refers to the process in which cells change from an active proliferative status to a growth-arrested status. There are multiple factors that regulate this process and cellular senescence is activated by various pathways. Senescent cells present specific characteristics, such as an increased cell volume, flattened cell body morphology, ceased cell division and the expression of β-galactosidase. Tumor senescence can be categorized into replicative senescence and premature senescence. Cellular senescence may inhibit the occurrence and development of tumors, serving as an innovative strategy for the treatment of cancer. The present review mainly focuses on senescent biomarkers, methods for the induction of cellular senescence and its possible application in the treatment of cancer.