Broad-spectrum Anti-tumor Drug Research Articles

Gastrodin Attenuates Colitis and Prevents Tumorigenesis in Mice by Interrupting TLR4/MD2/NF-κB Signaling Transduction.

Chronic inflammation is one of the causative factors for tumorigenesis. Gastrodin is a main active ingredient isolated from Gastrodia elata Blume, a famous medicinal herb with a long edible history. This study aimed to explore the effects of gastrodin on colitis-associated carcinogenesis (CRC) in mice and to elucidate its potential molecular mechanisms. Balb/c mice were induced with azoxymethane (AOM) and dextran sulfate sodium (DSS) for 12 weeks. Gastrodin (50 mg/kg) was administered via oral gavage three times per week until the end of the experiment. Disease indexes, including body weight, bloody diarrhea, colon length, histopathological score, and tumor size, were measured. Tumor cell proliferation was evaluated by BrdU incorporation assay and tumor cell cytotoxicity was assessed by cell counting kit (CCK-8). The expression levels of toll-like receptor 4 (TLR4)/nuclear factor kappa-B (NF-κB) signaling molecules, NF-κB luciferase, and pro-inflammatory cytokines were determined by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR), immunoblotting, immunohistochemistry (IHC), enzyme-linked immunosorbent assay (ELISA), or reporter gene assays. The binding affinity between gastrodin and myeloid differentiation protein-2 (MD2) was analyzed by molecular docking and cellular thermal shift assay (CETSA). Gastrodin administration was demonstrated to mitigate various CRC-related symptoms in mice, including weight loss, diarrhea, and tissue abnormalities. Notably, gastrodin suppressed tumor cell growth during colitis- associated tumorigenesis, resulting in fewer and smaller adenomas in the colon. Unlike irinotecan, a broadspectrum antitumor drug, gastrodin did not exhibit apparent cytotoxicity in various colorectal adenocarcinoma cell lines. Additionally, gastrodin downregulated TLR4/NF-κB signaling molecules and pro-inflammatory mediators in mice and macrophages. Molecular docking and CETSA experiments suggested that gastrodin binds to the MD2 protein, potentially interfering with the recognition of lipopolysaccharide (LPS) by TLR4, leading to NF-κB pathway inhibition. This study provides evidence for the first time that gastrodin attenuated colitis and prevented colitisrelated carcinogenesis in mice, at least partially, by diminishing tumor-promoting cytokines through the interruption of TLR4/MD2/NF-κB signaling transduction.

Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality

Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal–organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.

Predicting drug synergy using a network propagation inspired machine learning framework.

Combination therapy is a promising strategy for cancers, increasing therapeutic options and reducing drug resistance. Yet, systematic identification of efficacious drug combinations is limited by the combinatorial explosion caused by a large number of possible drug pairs and diseases. At present, machine learning techniques have been widely applied to predict drug combinations, but most studies rely on the response of drug combinations to specific cell lines and are not entirely satisfactory in terms of mechanism interpretability and model scalability. Here, we proposed a novel network propagation-based machine learning framework to predict synergistic drug combinations. Based on the topological information of a comprehensive drug-drug association network, we innovatively introduced an affinity score between drug pairs as one of the features to train machine learning models. We applied network-based strategy to evaluate their therapeutic potential to different cancer types. Finally, we identified 17 specific-, 21 general- and 40 broad-spectrum antitumor drug combinations, in which 69% drug combinations were validated by vitro cellular experiments, 83% drug combinations were validated by literature reports and 100% drug combinations were validated by biological function analyses. By quantifying the network relationships between drug targets and cancer-related driver genes in the human protein-protein interactome, we show the existence of four distinct patterns of drug-drug-disease relationships. We also revealed that 32 biological pathways were correlated with the synergistic mechanism of broad-spectrum antitumor drug combinations. Overall, our model offers a powerful scalable screening framework for cancer treatments.

Targeted Delivery of Arctigenin Using Sialic Acid Conjugate-Modified Liposomes for the Treatment of Breast Cancer.

Arctigenin (ATG) is a broad-spectrum antitumor drug with an excellent inhibitory effect on malignant tumors such as breast cancer, glioblastoma, liver cancer, and colon cancer. However, the clinical application of ATG is limited by its poor water solubility and quick hydrolysis in the liver, intestine, and plasma, which might hinder its application. Sialic acid (SA) recognizes selectin receptors overexpressed on the surface of tumor-associated macrophages. In this study, SA was conjugated with octadecylamine (ODA) to prepare SA-ODA, which was employed to prepare SA functionalized nanoliposomes (SA-Lip) to achieve breast cancer targeting. The formulations were finely optimized using the Box-Behnken design to achieve higher ATG loading. The size, ζ potential, entrapment efficiency, drug loading, and release behavior of ATG@SA-Lip were fully investigated in comparison with conventional ATG@Lip. The ATG@SA-Lip displayed more potent cytotoxicity and higher cellular internalization compared to ATG@Sol and ATG@Lip in both MCF7 and 4T1 cells. Notably, ATG@SA-Lip showed the lowest impact on the immune system. Our study demonstrates that SA-Lip has strong potential as a delivery system for the targeted delivery of ATG.

A pharmacovigilance study of etoposide in the FDA adverse event reporting system (FAERS) database, what does the real world say?

Introduction: Etoposide is a broad-spectrum antitumor drug that has been extensively studied in clinical trials. However, limited information is available regarding its real-world adverse reactions. Therefore, this study aimed to assess and evaluate etoposide-related adverse events in a real-world setting by using data mining method on the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database.Methods: Through the analysis of 16,134,686 reports in the FAERS database, a total of 9,892 reports of etoposide-related adverse drug events (ADEs) were identified. To determine the significance of these ADEs, various disproportionality analysis algorithms were applied, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS) algorithms.Results: As a result, 478 significant disproportionality preferred terms (PTs) that were identified by all four algorithms were retained. These PTs included commonly reported adverse events such as thrombocytopenia, leukopenia, anemia, stomatitis, and pneumonitis, which align with those documented in the drug’s instructions and previous clinical trials. However, our analysis also uncovered unexpected and significant ADEs, including thrombotic microangiopathy, ototoxicity, second primary malignancy, nephropathy toxic, and ovarian failure. Furthermore, we examined the time-to-onset (TTO) of these ADEs using the Weibull distribution test and found that the median TTO for etoposide-associated ADEs was 10 days (interquartile range [IQR] 2–32 days). The majority of cases occurred within the first month (73.8%) after etoposide administration. Additionally, our analysis revealed specific high-risk signals for males, such as pneumonia and cardiac infarction, while females showed signals for drug resistance and ototoxicity.Discussion: These findings provide valuable insight into the occurrence of ADEs following etoposide initiation, which can potentially support clinical monitoring and risk identification efforts.

Preparation and properties of tumor-targeting lentinan-oleic acid polymer micelles based on folic acid for adriamycin delivery

To develop a natural polysaccharide targeted nanomicelles drug delivery system loaded with the broad-spectrum anti-tumor drug adriamycin (ADM), FA-LNT-OA polymer was synthesized, the ADM/FA-LNT-OA polymer nanomicelles was prepared, and response surface approach was used to optimize the drug loading procedure of the ADM/FA-LNT-OA nanomicelles. Under the optimum conditions, the drug loading ratio was 14.36 ± 0.12% while the entrapment efficiency was 95.17 ± 0.13%. The drug-loaded micelles were spherical, with the size about 170 nm, and the size distribution was uniform. The CMC of ADM/FA-LNT-OA nanomicelles was 48 ± 0.46 μg/mL, their release was more sensitive to pH than that of ADM, and they had good stability. The FA-LNT-OA nanomicelles had good blood compatibility and cell compatibility. In vitro anti-tumor pharmacodynamic studies proved that the IC50 of ADM/FA-LNT-OA nanomicelles on Hela, ES-2 and A549 cells were 48.49 ± 0.25, 63.56 ± 0.68 and 105.93 ± 17.03 μg/mL respectively. Moreover, the plasma elimination half-life of ADM/FA-LNT-OA nanomicelles was 5.341 h, the Tmax was 0.083 h, the CL was 0.017 L/h/kg. Compared with the common ADM formulation, the ADM/FA-LNT-OA nanomicelles prolonged the clearance half-life of ADM, decreased the clearance rate, and extended the retention time of ADM in vivo. In conclusion, the above results laid the foundation for the increase of therapeutic effects and reduction of the clinical toxic and side effects of ADM.

Astragaloside IV Inhibits NLRP3 Inflammasome-Mediated Pyroptosis via Activation of Nrf-2/HO-1 Signaling Pathway and Protects against Doxorubicin-Induced Cardiac Dysfunction.

Doxorubicin (DOX) is an effective broad-spectrum antitumor drug, but its clinical application is limited due to the side effects of cardiac damage. Astragaloside IV (AS-IV) is a significant active component of Astragalus membranaceus that exerts cardioprotective effects through various pathways. However, whether AS-IV exerts protective effects against DOX-induced myocardial injury by regulating the pyroptosis is still unknown and is investigated in this study. The myocardial injury model was constructed by intraperitoneal injection of DOX, and AS-IV was administered via oral gavage to explore its specific protective mechanism. Cardiac function and cardiac injury indicators, including lactate dehydrogenase (LDH), cardiac troponin I (cTnI), creatine kinase isoenzyme (CK-MB), and brain natriuretic peptide (BNP), and histopathology of the cardiomyocytes were assessed 4 weeks post DOX challenge. Serum levels of IL-1β, IL-18, superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) and the expression of pyroptosis and signaling proteins were also determined. Cardiac dysfunction was observed after the DOX challenge, as evidenced by reduced ejection fraction, increased myocardial fibrosis, and increased BNP, LDH, cTnI, and CK-MB levels (p < 0.05, N = 3-10). AS-IV attenuated DOX-induced myocardial injury. The mitochondrial morphology and structure were also significantly damaged after DOX treatment, and these changes were restored after AS-IV treatment. DOX induced an increase in the serum levels of IL-1β, IL-18, SOD, MDA and GSH as well as an increase in the expression of pyroptosis-related proteins (p < 0.05, N = 3-6). Besides, AS-IV depressed myocardial inflammatory-related pyroptosis via activation of the expressions of nuclear factor E2-related factor 2 (Nrf-2) and heme oxygenase 1 (HO-1) (p < 0.05, N = 3). Our results showed that AS-IV had a significant protective effect against DOX-induced myocardial injury, which may be associated with the activation of Nrf-2/HO-1 to inhibit pyroptosis.

Low-Dose Taxol Promotes Neuronal Axons Extension and Functional Recovery after Spinal Cord Injury.

Axonal regeneration has been the research focus in the field of clinical treatment for spinal cord injury (SCI). The growth and extension of neuronal axons is a dynamic biological process mediated by the cytoskeleton, and microtubule plays an important role in axonal growth. Moderate stabilization of microtubule promotes axonal growth and eliminates various intra- and extracellular mechanisms that impede axonal regeneration. After SCI, the damaged axons rapidly form a growth cone, wherein the stability of tubulin decreases, impairing axonal regeneration. Taxol with proven clinical safety is commonly used as a broad-spectrum antitumor drug. Importantly, Taxol can promote axonal extension by enhancing and stabilizing the microtubule assembly. In our study, we systematically investigated the differentiation of neural stem cells (NSCs) in vitro and functional recovery in injured rats in vivo following Taxol treatment. Low-dose Taxol promoted differentiation of NSCs to neurons and significantly extended the axons in vitro. In vivo, Taxol promoted the expression of βIII-tubulin in the injured areas and motor function recovery after SCI. Low-dose Taxol is a promising clinical agent to promote axonal regeneration after SCI.

Cardioprotective effect of crude polysaccharide fermented by Trametes Sanguinea Lyoyd on doxorubicin-induced myocardial injury mice

Doxorubicin (DOX) is a broad-spectrum anti-tumor drug, but its clinical application is greatly limited because of the cardiotoxicity. Thus, exploration of effective therapies against DOX-induced cardiotoxicity is necessary. The aim of this study is to investigate the effects and possible mechanisms of Trametes Sanguinea Lyoyd fermented crude polysaccharide (TSLFACP) against DOX-induced cardiotoxicity. We investigated the protective effects of TSLFACP on myocardial injury and its possible mechanisms using two in vitro cells of DOX-treated cardiomyocytes H9C2 and embryonic myocardial cell line CCC-HEH-2 and a in vivo mouse model of DOX-induced myocardial injury. We found that TSLFACP could reverse DOX-induced toxicity in H9C2 and CCC-HEH-2 cells. Similarly, we found that when pretreatment with TSLFACP (200 mg/kg, i.g.) daily for 6 days, DOX-induced myocardial damage was attenuated, including the decrease in serum myocardial injury index, and the amelioration in cardiac histopathological morphology. Additionally, immunohistochemistry and western blotting were used to identify the underlying and possible signal pathways. We found that TSLFACP attenuated the expression of LC3-II, Beclin-1 and PRAP induced by DOX. In conclusion, our results demonstrated that TSLFACP could protect against DOX-induced cardiotoxicity by inhibiting autophagy and apoptosis.

Fabrication of Doxorubicin Nanoparticles Mediated by Folic Acid and Its Effect on the Wnt/β-Catenin Signaling to Improve Precancerous Lesions in Gastric Cancer

Doxorubicin hydrochloride (DOX) is an anthracycline broad-spectrum antitumor drug, but it can produce a wide range of cytotoxicities in the body. Intravenous injection of a high dose of DOX causes serious toxicity and side effects in the heart and spinal cord. These shortcomings limit the clinical adoption of DOX. In this work, folic acid was coupled to DOX albumin nanoparticles (NPs) by chemical modification so that the preparation could actively target tumor site accumulation and release DOX to inhibit tumor cells. Albumin NPs were prepared by the desolvation method, and the formulation and preparation process were optimized. The particle size and granularity were taken as evaluation indexes. The in vitro antitumor activity of folic acid-mediated DOX albumin NPs against human hepatoma cell HepG2 and human gastric cancer cell SGC7901 was evaluated by using the methyl tetrazolium (MTT) assay with commercial DOX as a reference. Twenty SD rats were utilized to participate in the efficacy analysis of folic acid-mediated DOX albumin NPs for gastric precancerous lesions (GPLs). The results showed that the average particle size of folate-mediated doxorubicin albumin NPs was 267.28±0.38 nm, and 90% of them were less than 280.00 nm, showing a uniform particle size distribution. The drug release rate of the NPs within 24 h was 27.3%, and the NPs had sustained release properties. The IC50 values of the NPs and DOX aqueous solution on the highly expressed HepG2 cells were 4.78 μmol/L and 5.26 μmol/L, respectively, and those on the SGC7901 cells were 4.62 μmol/L and 5.06 μmol/L, respectively. After the establishment of the GPL model, the gene levels in the Wnt/β-catenin signaling were markedly upregulated (P &lt;0.05). Folic acid-mediated doxorubicin albumin NPs greatly inhibited the abnormal expression of the above genes (P &lt;0.01), i.e., they could effectively prevent further precancerous lesions of gastric cancer.

PAE ameliorates doxorubicin-induced cardiotoxicity via suppressing NHE1 phosphorylation and stimulating PI3K/AKT phosphorylation

Doxorubicin (DOX), a broad-spectrum anti-tumor drug, has severe cardiotoxic side effects that limit its clinical application. Perillaldehyde (PAE) is the main component of volatile oil extracted from the stems and leaves of Herbaceous plant-perilla, which demonstrates antioxidant, anti-inflammatory, hypolipidemic, and other health functions. The present study aimed to explore the protective effect of perillaldehyde on DOX-induced cardiotoxicity in rats and to confirm its possible mechanism. The results showed that PAE could significantly improve cardiac function, alleviate myocardial fibrosis, and attenuate oxidative stress and inflammatory responses in DOX-induced cardiotoxicity in rats. Mechanistically, PAE could DOX-induced cardiotoxicity, which is related to its regulation of the PI3K/Akt signaling pathway and inhibition of NHE1 phosphorylation. Therefore, the finding demonstrates that perillaldehyde may be a promising cardioprotective agent for the prevention and treatment of cardiotoxicity caused by DOX.

Nitric oxide-releasing docetaxel prodrug nanoplatforms for effective cancer therapy

Docetaxel (DTX) is an important broad-spectrum antitumor drug, but poor water solubility and multidrug resistance often limit clinical application. A nitric oxide (NO) donor docetaxel prodrug (DISMN-DTX) was designed and synthesized, through a two-step procedure starting from isosorbide mononitrate. The novel amphiphilic small molecule prodrug is readily self-assembled into nanoplatforms, which effectively solves the significant obstacle of poor water solubility of DTX. Specifically, the DISMN-DTX nanoplatforms could trigger NO release at the intracellular reduction conditions to improve the chemosensitivity of DTX. Thus, our rationally designed prodrug nanoplatforms provide an efficient treatment option for drug-resistant tumors.

Design, synthesis of N9- acyl substituted β-carboline derivatives containing 5-phenyl-2-furan moiety as potent anticancer agents

β-Carbolines are of great interest due to their broad spectrum of biochemical effects and pharmaceutical functions, especially antitumor activity. The N9 position at β-carboline is a modification site for important antitumor activity. Several phenylfuran derivatives displayed significant antitumor activity in our previous work. Here, we designed and preparated a series of novel N9-acyl substituted β-carboline derivatives containing 5-phenyl-2-furan moiety as potent anticancer agents. All newly synthesized compounds and β-carboline were evaluated for antitumor activity on five cancer cells. β-Carboline had only weak antitumor activity, while the introduction of the phenylfuran fragment significantly improved the activity. The primary structure–activity relationship study showed that 4-substituted phenylfuran played a key role in anti-cancer activity and compound 8 displayed superior than Camptothecin in anti-proliferative activity against breast cancer cells MCF-7. Flow cytometry studied revealed that compounds 8 and 15 effectively mediated MCF-7 apoptosis. This study lays a working foundation for the research and development of new broad-spectrum antitumor drugs based on β-carboline and phenylfurans, compound 8 would be great promise as a hit antitumor candidate in the future study.

Co-delivery of doxorubicin and curcumin via cRGD-peptide modified PEG-PLA self-assembly nanomicelles for lung cancer therapy

Lung cancer is the most common malignancy in the world, with a high mortality rate. Nevertheless, therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin (DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical application. In this work, biodegradable methoxy poly(ethylene glycol)-poly(lactic acid) (MPEG-PLA) and cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) polypeptide modified PEG-PLA (cRGD-PEG-PLA) copolymers were used for the co-delivery of curcumin (CUR) and DOX (CUR-DOX/cRGD-M). The particle size of the self-assembled drug-loaded nanomicelle approximately was 27.4 nm and the zeta potential was −2.7 mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma (LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/cRGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/cRGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

Apocynum venetum leaf extract alleviated doxorubicin-induced cardiotoxicity through the AKT/Bcl-2 signaling pathway

BackgroundDoxorubicin (DOX) is a broad-spectrum anti-tumor drug that has been associated with cardiotoxicity. Plant extracts have been shown to confer protection against DOX-induced cardiotoxicity. Apocynum venetum L. belongs to the Apocynaceae family. Flavonoid extracted from Apocynum venetum L. possess various biological effects, such as lowering blood pressure levels, sedation, diuresis, anti-aging, and improving immunity. PurposeThis study investigated the mechanism by which dry leaf extract of Apocynum venetum L. (AVLE) alleviates DOX-induced cardiomyocyte apoptosis. MethodsHPLC-MS/MS and HPLC methods were used to analyze the components of AVLE. The effects of DOX and AVLE on apoptosis of H9c2 and HMC cells were assessed using the MTT assay. Calcein AM/PI, TUNEL, and flow cytometry were carried out to determine the effects of AVLE on DOX-induced apoptosis. The effect of AVLE on DOX-induced oxidative stress in cardiomyocytes was investigated using ELISA test. Mito-Tracker Red CMXRos, JC-1, and RT-qPCR assays were performed to evaluate the impact of AVLE on DOX-induced cardiomyocyte mitochondrial activity and membrane permeability. Western blot assay was carried out to determine the activation of multiple signaling molecules, including phosphorylated-protein kinase B (p-AKT), Cytochrome c, Bcl-2 family, and caspase family in the apoptosis pathway. The AKT inhibitor was used to block AKT/Bcl-2 signaling pathway to investigate the role of AKT in the protection conferred by AVLE against DOX-induced cardiotoxicity. ResultsA total of 8 compounds, including rutin, hyperoside, isoquercetin, unidentified compounds, myricetin, quercetin, quercetin-3-O-glucuronide and kaempferol, were detected in AVLE. Of note, DOX suppressed lactate dehydrogenase (LDH) levels, aggravated oxidative stress, and promoted cardiomyocyte apoptosis. It also upregulated the mRNA expression levels of voltage-dependent anion channel 1 (VDAC1), adenosine nucleotide transporter 1 (ANT1), and cyclophilin D (CYPD), while suppressing mitochondrial activity and mitochondrial membrane permeability. Treatment with DOX altered the expression levels of apoptosis-associated proteins, Bcl-2 and Bax. However, AVLE treatment alleviated DOX-induced effects on cardiomyocytes. In addition, application of AKT inhibitors promoted DOX-induced apoptosis and reversed the inhibitory effects of AVLE on DOX-induced apoptosis. ConclusionsAVLE confer cardio protection by suppressing oxidative stress and apoptosis of cardiomyocytes via AKT/Bcl-2 signaling pathway.

Analysis of Renal Platinum Content as a Novel Approach to Protect against Cisplatin Nephrotoxicity: A Review

Cisplatin (cis-diamine-dichloroplatinum (II), CDDP) is a prominent member of the effective broad-spectrum antitumor drugs. However, its clinical usage is restricted due to serious side effects particularly nephrotoxicity. The vulnerability of the kidney to CDDP is almost certainly related to its primary role in the excretion of the drug as intact CDDP and its platinum containing products are excreted mainly in the urine. There is a correlation between the level of platinum in urine and nephrotoxicity because of renal uptake of the drug. Some analytical methods were applied for the determination of platinum content in biological fluids such as plasma, urine, serum, and peritoneal fluid. Studies have not documented a strong correlation between the renoprotective mechanism and the diminution of renal platinum content.

A Network Pharmacology Approach to Reveal the Underlying Mechanisms of Artemisia annua on the Treatment of Hepatocellular Carcinoma.

Objective To investigate the potential active ingredients and underlying mechanisms of Artemisia annua (AA) on the treatment of hepatocellular carcinoma (HCC) based on network pharmacology. Methods In the present study, we used a network pharmacological method to predict its underlying complex mechanism of treating HCC. First, we obtained relative compounds of AA based on the traditional Chinese medicine systems pharmacology (TCMSP) database and collected potential targets of these compounds by target fishing. Then, we built HCC-related targets target by the oncogenomic database of hepatocellular carcinoma (OncoDB.HCC) and biopharmacological network (PharmDB-K) database. Based on the matching results between AA potential targets and HCC targets, we built a protein-protein interaction (PPI) network to analyze the interactions among these targets and screen the hub targets by topology. Furthermore, the function annotation and signaling pathways of key targets were performed by Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis using DAVID tools. Finally, the binding capacity between active ingredients and key targets was validated by molecular docking. Results A total of 19 main active ingredients of AA were screened as target prediction; then, 25 HCC-related common targets were seeked out via multiple HCC databases. The areas of nodes and corresponding degree values of EGFR, ESR1, CCND1, MYC, EGF, and PTGS2 were larger and could be easily found in the PPI network. Furthermore, GO and KEGG enrichment analysis showed that these key targets were significantly involved in multiple biological processes and pathways which participated in tumor cell proliferation, apoptosis, angiogenesis, tumor invasion, and metastasis to accomplish the anti-HCC activity. The molecular docking analysis showed that quercetin could stably bind to the active pocket of EGFR protein 4RJ5 via LibDock. Conclusion The anticancer effects of AA on HCC were predicted to be associated with regulating tumor cell proliferation, apoptosis, angiogenesis, tumor invasion, and metastasis via various pathways such as the EGFR signaling pathway, ESR1 signaling pathway, and CCND1 signaling pathway. It is suggested that AA might be developed as a broad-spectrum antitumor drug based on its characteristics of multicomponent, multipath, and multitarget.

Nephroprotective effect of umbelliferone against cisplatin-induced kidney damage is mediated by regulation of NRF2, cytoglobin, SIRT1/FOXO-3, and NF- kB-p65 signaling pathways.

Cisplatin (Cis) is one of the most potent and effective broad-spectrum antitumor drugs, but its use is limited due to nephrotoxicity. The current study investigated the renoprotective effect of umbelliferone (UMB) on Cis-induced nephrotoxicity in rats. Renal injury was induced by a single injection of Cis (7 mg/kg, ip). Our results exhibited that the injection of Cis significantly disrupted renal function biomarkers as well as KIM-1 expression. The expressions of TNF-α, IL-1β, NF-kB-p65, and IKKβ were elevated along with downregulation of IkBα expression. Also, Cis disrupted cellular oxidant/antioxidant balance through the reduction of glutathione (GSH), glutathione-S-transferase (GST), and superoxide dismutase (SOD) levels and elevation of malondialdehyde (MDA) content. On the contrary, the levels of renal function biomarkers, cytokines, NF-kB-p65, IkBα, IKKβ, and oxidant/antioxidant status have been improved after UMB treatment. Mechanistically, rats administered Cis only exhibited a significant decrease in NRF2 and cytoglobin expressions as well as the CREB, SIRT1, FOXO-3, and PPAR-γ genes. Treatment with UMB significantly upregulated NRF2 and cytoglobin proteins, as well as effectively increased the expression of CREB, SIRT1, FOXO-3, PPAR-γ, and NRF2 genes. Histopathological findings strongly supported our biochemical results, as evidenced by attenuation of renal hemorrhage, cast diffusion, and inflammatory cell infiltration. Interestingly, UMB significantly enhanced Cis cytotoxicity in both HL-60 and HeLa cells in a dose-dependent manner. Together, our results demonstrated that UMB can protect against Cis-induced nephrotoxicity in normal rats along with the enhancement of its in vitro antitumor activity. These findings suggested that UMB could be used as a potential adjuvant therapy in Cis chemotherapeutic protocols.

Deoxidized gulose moiety attenuates the pulmonary toxicity of 6'-deoxy-bleomycin Z without effect on its antitumor activity

Bleomycins (BLMs) are broad-spectrum antitumor drugs, but the dose-dependent lung toxicity has restricted their therapeutic applications. Many efforts have contributed to develop novel BLM analogues, but mainly focused on single functional domain owing to the structural complexity of BLM. Benefit from the engineered production of two novel analogues 6'-deoxy-BLM Z (6'-DO-BLM Z) and BLM Z, they together with clinical BLM-sulfate comprised a good model with varied sugar or C-terminal domain in any two of them, allowing us to study their structure-activity relationships pairwise. Our investigations suggested the biological activities of BLM or its analogues are mainly depended on the C-terminal amine, while the changed C-terminal amine endowed BLM Z with much higher pulmonary toxicity comparing to BLM-sulfate, whereas the deoxidized gulose unit with same C-terminal amine evidently attenuated the pulmonary toxicity of 6'-DO-BLM Z without effect on antitumor activity. Further mechanistic studies revealed that the alleviation of pulmonary toxicity in 6'-DO-BLM Z by a slight change in the sugar moiety could attribute to the decrease of ROS production and thereby reduce the subsequent caspase-1 activity and resulting inflammatory response. Therefore, the synergistic modifications on C-terminal amine and sugar moiety provide new insights to efficiently develop potential BLM candidate with good clinical performance.

Efficacy and safety of Brucea javanica oil emulsion for liver cancer: A protocol for systematic review and meta-analysis.

Background:Brucea javanica oil emulsion (BJOE), extracted from the Chinese herb Bruceae Fructus (Yadanzi), is a broad-spectrum anti-tumor drug and has been widely used for the treatment of liver cancer in China. The aim of this study is to systematically investigate the efficacy and safety of BJOE for the treatment of liver cancer.Methods:Seven electronic databases including the Cochrane Library, PubMed, Excerpt Medica Database, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, China Scientific Journal Database, and Wanfang Database will be systematically retrieved for data extraction from their inceptions to September 2020. Cochrane Risk of Bias tool will be used to assess the risk of bias of included studies. The RevMan 5.4 and Stata 16.0 software will be applied for statistical analyses. Statistical heterogeneity will be computed by I2 tests. Sensitivity analysis will be conducted to evaluate the stability of the results. The publication bias will be evaluated by funnel plots and Egger test. The quality of evidence will be assessed by the GRADE system.Results:The results of our research will be published in a peer-reviewed journal or presenting the findings at a relevant conference.Conclusion:The conclusion of this study will provide helpful evidence of the effect and safety of BJOE for the treatment of liver cancer in clinical practice.OSF registration number:10.17605/OSF.IO/UC8XQ