Good Antitumor Activity Research Articles

Insight into intermolecular binding mechanism of apatinib mesylate and human alpha-1-acid glycoprotein: combined multi-spectroscopic approaches with in silico

Apatinib mesylate (APM), an oral tyrosine kinase inhibitor, has a good anti-tumor activity in the treatment of various cancers, particularly in advanced non-small cell lung cancer. In this study, the intermolecular binding mechanism between APM and human alpha-1-acid glycoprotein (HAG) was investigated by combining multi-spectroscopic approaches with in silico techniques. The findings revealed that APM gave rise to the fluorescence quenching of HAG by forming a ground-state complex between APM and HAG with a stoichiometric ratio of 1:1, and APM has a moderate affinity for HAG as the binding constant of APM and HAG of approximately 105 M−1, which was larger than the APM-HAG complex. The findings from thermodynamic parameter analysis indicated that the dominant driving forces for the formation of the APM-HAG complex were van der Waals forces, hydrogen bonding and hydrophobic interactions, which were also verified with site-probe studies and molecular docking. The findings from in silico study indicated that APM inserted into the opening of the hydrophobic cavity of HAG, leads to a slight conformational change in the HAG, which was verified by circular dichroism (CD) measurements, that was, the beta sheet level of HAG decreased. Additionally, the results of synchronous and 3D fluorescence spectroscopies confirmed the decline in hydrophobicity of the microenvironment around Trp and Tyr residues. Moreover, some common metal ions such as Cu2+, Mg2+, Fe3+, Ca2+, and Zn2+ could cause the alteration in the binding constant of APM with HAG, leading to the change in the efficacy of APM. It will be expected that these study findings are to provide useful information for further understanding pharmacokinetic and structural modifications of APM. Communicated by Ramaswamy H. Sarma

Glycolysis, a new mechanism of oleuropein against liver tumor

BackgroundBenign and malignant liver tumors are prevalent worldwide. However, there is no effective and comprehensive treatment option for many patients with malignant tumors. Thus, it is critical to prevent benign tumors from worsening, increasing the number of treatment options and effective medications against malignant liver tumors. Oleuropein is a natural and non-toxic product and inhibits tumor growth in various ways. MethodsWe employed bioinformatics analysis and molecular docking to identify potential targets of oleuropein. Surface plasmon resonance (SPR) was used to determine the direct binding strength of the target and compounds. Essential functionalities of the targets were analyzed using gene interference approaches. Transcriptomic studies were performed to observe the global genomic alterations occurring inside cells. Changes in glycolytic metabolites and gene and protein expressions were also detected. The anti-tumor benefits of oleuropein in vivo were determined using a tumor-bearing mouse model. ResultsGlucose-6-phosphate isomerase (GPI) was found to be a direct target of oleuropein. GPI discontinuation in liver tumor cells altered the expression of many genes, causing glycogenolysis. GPI interference was associated with PYGM and PFKFB4 inhibitors to inhibit glycolysis in liver tumors. Oleuropein inhibited glycolysis and showed good anti-tumor activity in vivo without adverse side effects. ConclusionsGPI is a crucial enzyme in glycolysis and the immediate target of oleuropein. GPI expression inside tumor cells affects different physiological functions and signal transduction. Oleuropein has depicted anti-tumor action in vivo without harmful side effects. Moreover, it can control tumor glycolysis through GPI.

Absorbable 3D-printed pancreaticojejunostomy device with a dual-layer drug coating for the prevention of postoperative local recurrence of pancreatic cancer

The high local recurrence rate of pancreatic cancer after surgery is one of the important risk factors affecting patient survival. The traditionally used silicone tube stent is not only complicated to operate but also lacks antitumor properties. The purpose of this study was to develop a dual-layer drug-coated pancreaticojejunostomy device. The coating consisted of two layers, an outer basic fibroblast growth factor (bFGF) coating layer and an inner nanoparticle albumin-bound paclitaxel (nab-PTX) coating layer with chitosan as the drug-carrying medium. Due to the diffusion barrier from the outer coating, the release of nab-PTX from the inner layer was delayed and slowed down. We studied the degradation rates, mechanical properties, surface morphologies, drug release kinetics, promoting the growth of fibroblasts and antitumor properties of the coated stents. It was found that 100 ng of bFGF and 50 µg of nab-PTX were suitable drug concentrations that can effectively promote the growth of fibroblasts and inhibit pancreatic cancer cells. The results also confirmed that the dual-layer drug-coated pancreaticojejunostomy device showed good antitumor activity both in vitro and in vivo without obvious systemic toxicity. In addition, the device has a suitable degradation rate. In conclusion, this biodegradable dual-layer drug-coated pancreaticojejunostomy device can potentially inhibit the local recurrence of pancreatic cancer after surgery and promote the healing of pancreaticointestinal anastomosis. This device has great potential to treat pancreatic cancer in the future.

Establishment of recombinant Catharanthus roseus stem cells stably overexpressing ORCA4 for terpenoid indole alkaloids biosynthesis

Catharanthus roseus is a perennial herb of the Apocynaceae family, from which about 200 kinds of alkaloids have been characterized. Most alkaloids from C. roseus are terpenoid indole alkaloids (TIAs), such as vinblastine and vincristine, which are widely used in the clinic for their good antitumor activity. However, they were only biosynthesized in C. roseus, and their content in C. roseus is extremely low. The access to these valuable compounds is by plant extraction or chemical semisynthesis from their precursors catharanthine and vindoline. Since catharanthine and vindoline are also obtained from C. roseus, the supply of vinblastine and vincristine makes it difficult to meet market demands. Therefore, how to improve the yield of TIAs is an attractive issue. In this study, we compared the regulatory effect of two critical transcription factors, octadecanoid-derivative responsive Catharanthus AP2-domain protein 3 (ORCA3) and octadecanoid-derivative responsive Catharanthus AP2-domain protein 4 (ORCA4), on the biosynthesis of TIAs in C. roseus. The results showed that overexpressing both two transcription factors could increase the accumulation of TIAs. The effect was more significant when ORCA4 was overexpressed. To acquire C. roseus TIAs on a continuous and consistent basis, we then created and acquired C. roseus stem cells stably overexpressing ORCA4. This is the first time a recombinant C. roseus stem cell system with stable ORCA4 overexpression has been developed, which not only provides new ideas for future research in this area but also breaches new life into the industrial application of using plant cell culture to obtain natural products.

Modular Biomimetic Strategy Enabled Discovery of Simplified Pseudo-Natural Macrocyclic P-Glycoprotein Inhibitors Capable of Overcoming Multidrug Resistance.

Natural macrocycles have shown impressive activity to overcome P-glycoprotein (P-gp)-mediated multidrug resistance (MDR). However, the total synthesis and structural modification of natural macrocycles are challenging, which would hamper the deeper investigations of their structure-activity relationship (SAR) and drug likeness. Herein, we describe a modular biomimetic strategy to expeditiously achieve a new class of macrocycles featuring polysubstituted 1,3-diene, which efficiently inhibited P-gp and reversed MDR in cancer cells. The SAR analysis revealed that the size and linker of the macrocycles are important structural characteristics to restore activity. Particularly, 32 containing a naphthyl group and (d)-Phe moiety has higher potency with an excellent reversal fold than verapamil at a concentration of 5 μM, which induces conformational change of P-gp and inhibits its function instead of altering P-gp expression. Furthermore, 23 and 32 were identified to be attractive leads, which possess a good pharmacokinetic profile and antitumor activity in a KBV200 xenograft mouse model.

Novel thiourea derivative compounds: Thermal behavior, biological evaluation, Hirshfeld surfaces and frontier orbitals analyses, in silico ADMET profiling and molecular docking studies

This work reports synthesis and structural characterization of N-(allylcarbamothioyl)-2-chlorobenzamide (HL1, C11H11ClN2OS) and N-(allylcarbamothioyl)-2-methylbenzamide (HL2, C12H14N2OS). Structural characterization studies were made via elemental analysis, FT-IR, 1H NMR and single crystal XRD techniques. Thermal behavior of the synthesized compounds were investigated via TG/DTA. The cell similarity calculation was made. The Is value for HL1 and HL2 was found to be 86.9%. The HL1 and HL2 compounds were found to be thermally stable upto 136 and 132 °C, respectively. Anticancer activity of the compounds against MCF-7 breast cancer cells was studied via cell viability test and MTT. The role and the effect of different functional groups present in the compounds on anticancer activity were investigated. The IC50 values were found to be in the range 2.59 – 7.09 µmol.L−1. The HL1 compound showed good antitumor activity at 2.59 µmol.L−1 at 48 h. The Hirshfeld surfaces analyses of the compounds were made. The HOMO-LUMO energy levels of HL1 and HL2 were calculated. The compounds were thoroughly investigated in silico for their ADMET characteristics. The physicochemical, pharmacological, and ADMET characteristics of HL1 and HL2 were investigated together with drug similarity metrics. The compounds were observed to have good drug-like property. Furthermore, molecular docking experiments were carried out to evaluate the interactions between the compoundssynthesized in this study and BRAF (V600E -protein kinase). The acquired results revealed that the synthesized compounds had high binding affinity and inhibitory effect on the BRAF (V600E) protein kinase. The synthesized compounds can be considered potent anticancer agents, according to the data obtained using both in vitro and in silico techniques.

Fabrication of biocompatible magnetic maltose/MIL-88 metal–organic frameworks decorated with folic acid-chitosan for targeted and pH-responsive controlled release of doxorubicin

Recently, metal–organic frameworks (MOFs) have attracted tremendous attention as promising porous drug delivery systems for cancer treatment. In this work, for the first time, a novel magnetic maltose disaccharide molecule modified with MIL-88 metal–organic framework (Fe3O4@C@MIL-88) was prepared, and then this targeted system was used for the delivery of the doxorubicin (DOX) drug. Eventually, Fe3O4@C@MIL-88-DOX were successfully decorated with folic acid conjugated chitosan (Fe3O4@C@MIL-88-DOX-FC) as a new targeted and controlled release drug system for treatment of MCF-7 breast cancer. The encapsulation efficiency of the DOX in the Fe3O4@C@MIL-88 was obtained at ∼83.6%. The in vitro drug release profiles showed a pH-responsive controlled release of DOX in acidic pH confirming the performance of the systems in the cancerous environment. The DOX release mechanism from systems at pH 5 also showed that the kinetic data well fitted to the Korsmeyer-Peppas and Fickian diffusion. Furthermore, in vitro cytotoxicity and DAPI staining study clearly illustrated that the synthesized Fe3O4@C@MIL-88 system had low cytotoxicity and good biocompatibility against MCF-7 cancer cells and MCF-10A normal cells. Whereas, Fe3O4@C@MIL-88-DOX and Fe3O4@C@MIL-88-DOX-FC exhibited good antitumor activity as a result of targeted delivery of DOX, which indicated the MCF-7 cell death with apoptotic effects. Based on these findings, the resulting carriers could be used as promising targeted drug delivery systems for cancer therapy.

PKM2/PDK1 dual-targeted shikonin derivatives restore the sensitivity of EGFR-mutated NSCLC cells to gefitinib by remodeling glucose metabolism

Pyruvate kinase 2 (PKM2) and pyruvate dehydrogenase kinase 1 (PDK1) are two key enzymes in tumor glucose metabolism pathway that not only promote tumor growth and proliferation through accelerating aerobic glycolysis, but also contribute to drug resistance of non-small cell lung cancer (NSCLC). Considering that targeting PKM2 or PDK1 alone seems insufficient to remodel abnormal glucose metabolism to achieve significant antitumor activity, we proposed a “two-step approach” that regulates PKM2 and PDK1 synchronously. Firstly, we found that the combination of ML265 (PKM2 activator) and AZD7545 (PDK1 inhibitor) could synergistically inhibit proliferation and induce apoptosis in H1299 cells. Base on this, we designed a series of novel shikonin (SK) thioether derivatives as PKM2/PDK1 dual-target agents, among which the most potent compound E5 featuring a 2-methyl substitution on the benzene ring exerted significantly increased inhibitory activity toward EGFR mutant NSCLC cell H1975 (IC50 = 1.51 μmol/L), which was 3 and 17-fold more active than the lead compound SK (IC50 = 4.56 μmol/L) and the positive control gefitinib (IC50 = 25.56 μmol/L), respectively. Additionally, E5 also showed good anti-tumor activity in xenografted mouse models, with significantly lower toxicity side effects than SK. Moreover, E5 also inhibited the entry of PKM2 into nucleus to regulate the transcriptional activation of oncogenes, thus restoring the sensitivity of H1975 cell to gefitinib. Collectively, these data demonstrate that E5, a dual inhibitor of PKM2/PDK1, may be a promising adjunct to gefitinib in the treatment of EGFR-TKIs resistant NSCLC, deserving further investigation.

Antitumor Activity of Bioactive Compounds from Rapana venosa against Human Breast Cell Lines.

This study is the first report describing the promising antitumor activity of biologically active compounds isolated from the hemolymph of marine snail Rapana venosa-a fraction with Mw between 50 and 100 kDa and two structural subunits (RvH1 and RvH2), tested on a panel of human breast cell lines-six lines of different molecular subtypes of breast cancer MDA-MB-231, MDA-MB-468, BT-474, BT-549, SK-BR-3, and MCF-7 and the non-cancerous MCF-10A. The fraction with Mw 50-100 kDa (HRv 50-100) showed good antitumor activity manifested by a significant decrease in cell viability, altered morphology, autophagy, and p53 activation in treated cancer cells. An apparent synergistic effect was observed for the combination of HRv 50-100 with cis-platin for all tested cell lines. The combination of HRv 50-100 with cisplatin and/or tamoxifen is three times more effective compared to treatment with classical chemotherapeutics alone. The main proteins in the active fraction, with Mw at ~50 kDa, ~65 kDa, ~100 kDa, were identified by MALDI-MS, MS/MS analyses, and bioinformatics. Homology was established with known proteins with antitumor potential detected in different mollusc species: peroxidase-like protein, glycoproteins Aplysianin A, L-amino acid oxidase (LAAO), and the functional unit with Mw 50 kDa of RvH. Our study reveals new perspectives for application of HRv 50-100 as an antitumor agent used alone or as a booster in combination with different chemotherapies.

Antitumor activity and mechanism of cucurbitacin B in A549/DDP cells.

Cucurbitacin B (CuB) is a class of tetracyclic triterpenoids isolated from Cucurbitaceae with a wide range of anti-inflammatory and anti-tumor activities, mainly used in hepatitis and hepatocellular carcinoma, while there is relatively little research and application of this drug for lung cancer. In this study, CuB was administered on A549/DDP cells to observe how it affected the cells and their mechanism of action. CuB demonstrated good anti-tumor activity against A549/DDP cells in a dose-dependent manner and caused changes in the hedgehog (Hh) pathway. The results showed that CuB greatly inhibits the proliferation and the invasion of A549/DDP cells, and promoted apoptosis of A549/DDP cells. Meanwhile, it changed the expression of p53-related genes at the RNA and protein level. In conclusion, this experiment provides a theoretical basis for new applications of CuB and new thoughts on the mechanism of its anti-tumor activity, and provides a direction for deep research.

Liujunzi decoction exerts potent antitumor activity in oesophageal squamous cell carcinoma by inhibiting miR-34a/STAT3/IL-6R feedback loop, and modifies antitumor immunity

BackgroundLiujunzi decoction (LJZD), a traditional herbal formula and one of the most commonly used adjuvant medications for the treatment of oesophageal squamous cell carcinoma (ESCC), exerts good antitumor and immunomodulatory activity. However, its specific mechanism of action remains largely unclear. PurposeIn order to examine the potential primary and adjuvant antitumor mechanisms of LJZD, both in vitro and in vivo. MethodsIL-6 and miR-34a inhibitors were used to activate the miR-34a/STAT3/IL-6R feedback loop to observe the effects of LJZD. A humanised mouse model with a functional human immune system was constructed to evaluate the antitumor efficacy of LJZD in vivo on xenograft tumours, which was compared to that of the positive control drug anti-PD-1 monoclonal antibodies (mAb). Finally, a co-culture system of peripheral blood mononuclear and tumour cells in vitro was used to analyse the cytotoxic activity of LJZD on T cells. ResultsLJZD significantly interfered with IL-6-induced activation of the miR-34a/STAT3/IL-6R feedback loop in ESCC by restoring the expression of the tumour suppressor miR-34a, and inhibited the proliferation of EC109 oesophageal cancer cells in a dose-dependant manner. Furthermore, LJZD effectively suppressed oesophageal tumour growth in vivo and alleviated organ injury and visceral index. Furthermore, LJZD boosted antitumor immunity by increasing IFN-γ expression and CD8+tumour-infiltrating lymphocytes (TILs) infiltration in the peripheral blood and tumour tissues, respectively, which may be related to a decrease in PD-1, but not PD-L1 expression. Finally, we confirmed that LJZD strengthens the killing ability of T cells by suppressing PD-1 expression in a co-culture system in vitro. ConclusionLJZD exerts excellent antitumor effect by interfering with the miR-34a/STAT3/IL-6R feedback loop and augmenting antitumor immune responses. Which provides new insights into mechanisms for LJZD and sheds light on the multifaceted role of phytomedicine in cancer.

Novel anthraquinone derivatives trigger endoplasmic reticulum stress response and induce apoptosis.

Background: Endoplasmic reticulum (ER) stress is a therapeutic target in cancer given its regulation of bioenergetics and cell death. Methodology & results: We synthesized 14 ER stress-triggered anthraquinone derivatives by introducing an amino group at the 3-position side chain of the lead compound obtained previously. Most of the anthraquinone derivatives exhibited good antitumor activity due to their ability to induce ER damage through cytoplasmic vacuoles. The mechanisms of ER stress caused by compound KA-4c were related to increasing the expression levels of the ATF6 and Bip proteins and upregulating CHOP and cleaved PARP. Conclusion: Compound KA-4c triggers ER stress response and induces apoptosis via the ATF6-CHOP signaling pathway.

Experimental evaluation of the antioxidant and antitumor activities of thyme and basil essential oils and their phenolic constituents: theoretical antioxidant evaluation

BackgroundIdentifying specific biological activities of natural products are of the main concerns worldwide for the use in safe functional food manufacture; essential oils and their components are good candidates in this respect. The present work aims to evaluate the biological activities of basil and thyme oils as well as their phenolic constituents. Using computational methods to predict biological activities are currently effective tools in minimizing and explaining experimental works.ResultsChemical composition of thyme and basil oils were determined using GC–MS. The identified phenolic components were thymol (28.21%) and carvacrol (0.47%) in thyme oil and eugenol (11.37%) in basil oil. The antioxidant activity of both oils and their phenolic constituents as expressed by EC50 value were 535.01, 134.37, 176.57, 407.89 and 2.29 µg/mL against DPPH and 131.95, 56.65, 57.15, 82.71and 32.80 µg/mL against hydrogen peroxide, respectively. The order of activity is basil oil > thyme oil while phenolic compound order is eugenol > thymol > carvacrol; reducing power showed the same order. Basil oil showed also higher and good antitumor activity where it reduces the surviving fraction to 38.4% of brain tumor cells (U251) and 61.3% of liver tumor cells (HEPG2) at concentration 10 µg/mL. The antioxidant activity were evaluated theoretically according to the main three mechanisms, Hydrogen-Atom-Transfer (HAT), Single Electron Transfer–Proton Transfer (SET-PT) and the Sequential Proton Loss Electron-Transfer (SPLET); the results proved the experimental order of antioxidant and biological activities, and explained the remarkably higher activities of basil oil and its main phenolic component, eugenol.ConclusionTheoretical calculation can be used successfully to explain and predict the experimental biological activity results. Basil oil and its main phenolic component, eugenol, were found effective as antioxidants. Basil oil was also efficient in reducing the surviving fraction of liver and brain cancer cells where it reduces brain cells even lower than cells treated by doxorubicin, a known anti-cancer agent; thus, basil oil and its main phenolic components, eugenol, can be used safely in food preservation and functional food production.Graphical

Highly Biocompatible Apigenin-Loaded Silk Fibroin Nanospheres: Preparation, Characterization, and Anti-Breast-Cancer Activity

Breast cancer is among the most common fatal diseases among women. Low-toxicity apigenin (AGN) is of interest due to its good antitumor activity, but its clinical application is severely limited due to its poor water solubility and low bioavailability. An effective strategy to enhance the anti-breast-cancer activity of AGN is to develop it as a nanodelivery system. Silk fibroin (SF) is an ideal drug carrier with good biocompatibility, biodegradability, and a simple extraction process. This paper develops a novel and efficient apigenin-loaded silk fibroin nanodelivery system (SF-AGN) by nanoprecipitation with SF as a carrier. The system was characterized in terms of morphology, zeta potential, particle size, ultraviolet (UV), infrared (IR), and synchronous thermal analyses (TG-DSC), and the in vitro cytotoxicity and in vivo pharmacokinetics were examined. Finally, the chronic toxicity of SF-AGN in mice was studied. The SF-AGN nanodelivery system has good dispersibility, a hydrated particle size of 163.35 nm, a zeta potential of -18.5 mV, an average drug loading of 6.20%, and good thermal stability. MTT studies showed that SF-AGN significantly enhanced the inhibitory effect of AGN on 4T1 and MDA-MB-231 cells. Pharmacokinetic studies have demonstrated that SF-AGN can dramatically improve the bioavailability of AGN. The results of toxicity experiments showed that SF-AGN is biocompatible and does not alter normal tissues or organs. In sum, the SF-AGN nanodelivery system is a promising drug-delivery system for the clinical treatment of breast cancer.

Inhibiting the growth of ovarian cancer cells in vitro and in vivo by a small molecular inhibitor targeting La-RNA interactions

ObjectiveTo identify small molecules blocking La-RNA interactions by using structural dynamics, molecular biology, and in vivo efficacy experiments. MethodsA docking virtual assay on the Chemdiv database was used to screen La binders, and their affinity were measured by surface plasmon resonance (SPR). A novel fluorescence polarization (FP) assay referring to the binding of La protein and 3’UUUOH was established to identify the inhibitors. Their activity on ovarian cancer cell proliferation, apoptosis and cell cycle were evaluated using Cell Counting Kit 8 (CCK8) and flow cytometry assay, respectively. Their in vivo efficacy against ovarian cancer growth were evaluated in a cell line-derived xenograft (CDX) model of A2780 cells. ResultsFrom a total of 20 compounds with high potential binding activity with La protein, two small molecule compounds 4424-1120 and 8017-5932 with relatively stronger inhibition ability on La-RNA interactions were identified. These two compounds shared the same active centers with hydroxyimidazole and hydroxybenzene to interact with La protein through residues ARG57, GLN20 and GLN136. The in vitro assays showed that 4424-1120 and 8017-5932 effectively cause G0/G1 cell cycle arrest, inhibit cell proliferation, reduce cell invasion and promote apoptosis in ovarian cancer cells. In a CDX model on BALB/C Nude mice, we found that the growth rate of the tumor was inhibited by 4424-1120. ConclusionOur results demonstrated compound 4424-1120 shows good antitumor activity and safety in vitro and in vivo, and it provides a new idea for the discovery of antitumor lead compounds from small drug-like molecules.

Visible light-promoted transition metal-free direct C3-carbamoylation of 2H-Indazoles.

We reported a general transition metal-free transformation to access C3-carbamoylated 2H-indazoles via visible light-induced oxidative decarboxylation coupling, in the presence of oxamic acids as the coupling sources, 4CzIPN as the photocatalyst, and Cs2CO3 as the base. The great application potential of this mild condition is highlighted by the late-stage modification of drugs, N-terminal modification of peptides, and the good antitumor activity of the novel desired product.

PD-1/LAG-3 bispecific antibody potentiates T cell activation and increases antitumor efficacy.

Several clinical studies demonstrate that there exist other immune checkpoints overexpressed in some PD-1 inhibitor-resistant tumor patients. Among them, Lymphocyte-activation gene 3 (LAG-3) is one of the important immune checkpoint molecules and has been clinically demonstrated to have synergistic anti-tumor effects in combination with PD-1 antibody. In this study, we designed a novel 'knob-in-hole' PD-1/LAG-3 bispecific antibody (BsAb) YG-003D3. In conclusion, the BsAb maintained the similar affinity and thermal stability to the parental antibody, and the BsAb structure can be independent of each other in the process of double-target recognition, and the recognition activity will not be affected. Moreover, the BsAb can not only target PD-1 and LAG-3 on single cell simultaneously, but also bridge the two kinds of cells expressing PD-1 and LAG-3, so as to release the 'brake system of immune checkpoints' and activate immune cells to exert anti-tumor effects more effectively. Especially in the PBMCs activation assay, YG-003D3 induced stronger IFN-γ, IL-6, and TNF-α secretion compared to anti-PD-1 or anti-LAG-3 single drug group or even combined drug group. In the tumor killing experiment of PBMC in vitro, YG-003D3 has a better ability to activate PBMC to kill tumor cells than anti-PD-1 or anti-LAG-3 single drug group or even combined drug group, and the killing rate is as high as 20%. In a humanized PD-1/LAG-3 transgenic mouse subcutaneous tumor-bearing model, YG-003D3 showed good anti-tumor activity, even better than that of the combination group at the same molar concentration. Further studies have shown that YG-003D3 could significantly alter the proportion of immune cells in the tumor microenvironment. In particular, the proportion of CD45+, CD3+ T, CD8+ T cells in tumor tissue and the proportion of CD3+ T, CD8+ T, CD4+ T cells in peripheral blood were significantly increased. These results suggest that YG-003D3 exerts a potent antitumor effect by activating the body 's immune system. In summary, the BsAb YG-003D3 has good anti-tumor activity, which is expected to become a novel drug candidate for cancer immunotherapy.

Preparation and pharmacodynamics of Niclosamide-hydroxypropyl-β-cyclodextrin inclusion complex

Niclosamide (NIC) has been found to have good antitumor activity in recent years, but its poor water solubility has limited its use in the treatment of tumors. In this study, NIC-Hydroxypropyl-β-cyclodextrin inclusion complex (NHC) was prepared to improve the solubility and bioavailability of NIC. X-ray diffraction (XRD) analysis of the NHC showed that the NHC was successfully prepared. The NIC standard curve was then established by UV spectrophotometry and the encapsulation rate of the NHC was examined and the encapsulation rate of NHC was 81.05%. The therapeutic effects of NIC and NHC on breast cancer were compared by in vivo and in vitro experiments. In the in vitro experiments, we performed MTT, apoptosis, and cell cycle assays, and the results showed that NHC was able to promote apoptosis and block the G2/M phase better than NIC. The tumour inhibition rate of NIC was 39.99% and that of NHC was 49.76%, which showed a significant reduction in tumors. There was also a reduction in lung metastasis after NHC inclusion treatment compared to NIC. Histopathological sections also showed significant improvement in symptoms after administration. In conclusion, the NHC is a potentially effective treatment for breast cancer compared to NIC.

Exploring the pharmacological mechanisms of icaritin against nasopharyngeal carcinoma via network pharmacology and experimental validation.

Background: Icaritin is a natural product with a wide range of anti-tumor effects. However, its anti-tumor mechanism has not been thoroughly studied. This study examined the inhibitory effect of icaritin on nasopharyngeal cancer and its underlying mechanism using network pharmacology along with in vivo and in vitro experiments. Methods: MTT and clone formation assays were used to detect the effects of icaritin on the viability and proliferation of nasopharyngeal carcinoma cells, followed by the construction of a HONE1 xenograft tumor model to evaluate the anti-tumor efficacy of icaritin in vivo. A public database was used to predict prospective targets, built a protein-protein interaction (PPI) network, and analyze gene enrichment and biological processes. Based on network pharmacological data, cell cycle-related proteins were identified using western blotting. Besides, cell cycle distribution, apoptosis, and intracellular reactive oxygen species (ROS) generation were identified using flow cytometry. In addition, SA-β-Gal staining was performed to detect cellular senescence, and western blotting was performed to detect the expression of P53, P21, and other proteins to verify key signaling pathways. Results: Icaritin effectively inhibited the viability and proliferation of nasopharyngeal carcinoma cell lines and showed good anti-tumor activity against HONE1 nasopharyngeal carcinoma cells in vivo. Key protein targets, including AKT1, HSP90AA1, CDK4, CCND1, and EGFR, were screened using PPI network topology analysis. GO and KEGG analysis revealed that the cell cycle, p53 signaling, and cell senescence pathways may be the main regulatory pathways. Flow cytometry and western blot experiments showed that icaritin caused S-phase arrest and promoted an increase in ROS. SA-β-Gal staining showed that icaritin significantly induced cellular senescence, and western blotting showed that the expression of senescence-related proteins p53 and P21 increased significantly. Moreover, inhibition of ROS levels by N-Acetylcysteine (NAC) enhanced cell viability, reversed cellular senescence and reduced cellular senescence-associated protein expression. Conclusion: The results of network pharmacological analysis and in vivo and in vitro experiments showed that icaritin effectively inhibited the growth of nasopharyngeal carcinoma cells, promoted ROS production, induced cellular senescence, and inhibited tumor cells, which are related to the regulation of P53/P21 signal pathway.

Phase 1 Safety and Dose Escalation of Purinostat Mesylate, a Uniquely Potent and Selective Inhibitor of HDAC I and IIb in Relapsed or Refractory Lymphoma and Multiple Myeloma

Introduction Current treatment options for patients with relapsed or refractory (RR) lymphoma and multiple myeloma (MM) are limited, highlighting the unmet need for effective therapies in these disease settings. Purinostat Mesylate (PM) is a small molecule that is designed to selectively inhibit histone deacetylase (HDAC) enzymes class I and IIb, which are members of common oncogenic pathways in hematologic malignancies. This study examined PM monotherapy in patients with RR lymphoma and MM. Methods This open-label, non-randomized, first-in-human, phase 1 two-center trial enrolled adult patients with lymphoma or MM who were refractory to or relapsed after ≥1 prior regimens. PM was administered by 30-minute intravenous infusion in a standard 3+3 dose escalation design. The trial was conducted in three stages sequentially as follows: the first stage as a single dose (Day 1), the second stage as multiple doses (Day 8,11, and 15), and the third stage as extended doses (Day1, 4, 8, 11 in 21-day cycles). The decision to proceed to the third stage is based on patient tolerability in the previous two stages, disease status, and continued benefit determined by investigators. Initially dosing started at 1.2 mg/m2, escalated to 2.4 mg/m2, 4.0 mg/m2, 6.0 mg/m2, 8.4 mg/m2, 11.2 mg/m2 and finally 15.0 mg/m2. Patients continued to receive PM until disease progression or other treatment discontinuation criteria were met. The primary objective was to determine the maximum-tolerated dose and recommended phase 2 dose (RP2D); secondary objectives were to assess the safety and tolerability, pharmacokinetic profiles, and preliminary anti-tumor activity. This ongoing trial is registered at Chinese Clinical Trial Registry, number ChiCTR20191121. Results A total of 11 heavily pretreated MM patients(11/27,41%) and 16 lymphoma patients(16/27,59%) were enrolled to receive PM up to a maximum of 15.0 mg/m2 in the dose escalation. Most adverse events (AEs) were grade 1 to 2 and recovered with observation or symptomatic management. The most common Grade ≥3 AEs were thrombocytopenia (n=48.1%), neutropenia (n=48.1%), and anemia (11.1%), which occurred primarily during the extended dosing stages. AEs led to dose reductions in 4 patients. Dose limiting toxicities (DLTs) have not been observed. Twenty-seven patients were evaluable for responses. Eleven patients with RR MM had a disease control rate (DCR) of 72.7%. Eight patients had stable disease (SD) in cycle 1 and entered the third stage with a maximum of 6 extended cycles, of which 1 patient achieved a minimal remission (MR) in cycle 2. Nine out of 16 patients with RR lymphoma achieved objective responses rates (ORR) of 56.2%. Among them, six of 10 patients with diffuse large B-cell lymphoma (DLBCL) achieved objective responses (3 complete remissions [CR], 2 partial remissions [PR], and 1 MR). CRs occurred in 2 patients with DLBCL in cycle 3 (8.4mg/m2, 11.2 mg/m2) and 1 patient in cycle 2 (11.2 mg/m2). PRs occurred in 4 patient in cycle 1 (2 in 8.4 mg/m2, 2 in 11.2 mg/m2 ) and another patient who relapsed after 2 lines of prior therapy including autologous stem cell transplantation(ASCT) in cycle 3 (11.2 mg/m2). One MR and 1 SD have been observed in patients with double-expression DLBCL in cycle 1(15.0 mg/m2, 8.4 mg/m2) . Thus, the ORR in patients with RR DLBCL was 60.0% (6/10) and DCR was 70.0% (7/10). Two out of 4 follicular lymphoma patients relapsed after 2~4 lines of prior therapy also achieved objective responses (1 MR in cycle 1 and 1 PR in cycle 4). Of note, one patient with peripheral T-cell lymphoma who relapsed after four lines of treatment, including ASCT and Chidamide combination treatment with R-CHOP, obtained PR in cycle 1. Up to date, eight active response patients are still being treated. On the basis of the confirmed objective response and tolerability profile, the RP2D of PM was determined to be 8.4mg/m2 and 11.2mg/m2. Conclusions PM has demonstrated tolerability and good anti-tumor activity across all dosing schedules studied, especially multiple objective responses and disease control in patients with DLBCL. These results support continued development of PM, alone or in combination with other therapies, for the treatment of RR DLBCL. An open-label, non-randomized, phase 2, multicenter trial will be soon conducted in China to evaluate the efficacy of PM monotherapy in RR DLBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal