Targeting the chromatin structural changes of antitumor immunity

Epigenomic imbalance drives abnormal transcriptional processes,promoting the onset and progression of cancer.Although defective gene regulation generally affects carcinogenesis and tumor suppression networks,tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes,which may have significant implications for the development and application of epigenetic therapy,cancer immunotherapy,and their combinations.Herein,we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes,DNA methylation,histone post-translational modification,and chromatin structure in tumor immunogenicity,and introduce these epigenetic research methods.We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immuno-therapy through the complex interaction between cancer epigenetics and cancer immunology.

Establishment of NaLuF_(4):15%Tb-based low dose X-PDT agent and its application on efficient antitumor therapy

X-ray excited photodynamic therapy(X-PDT)is the bravo answer of photodynamic therapy(PDT)for deep-seated tumors,as it employs X-ray as the irradiation source to overcome the limitation of light penetration depth.However,high X-ray irradiation dose caused organ lesions and side effects became the major barrier to X-PDT application.To address this issue,this work employed a classic-al co-precipitation reaction to synthesize NaLuF_(4):15%Tb^(3+)(NLF)with an average particle size of(23.48±0.91)nm,which was then coupled with the photosensitizer merocyanine 540(MC540)to form the X-PDT system NLF-MC540 with high production of singlet oxygen.The system could induce antitumor efficacy to about 24%in relative low dose X-ray irradiation range(0.1-0.3 Gy).In vivo,when NLF-MC540 irradiated by 0.1 Gy X-ray,the tumor inhibition percentage reached 89.5%±5.7%.The therapeutic mechanism of low dose X-PDT was found.A significant increase of neutrophils in serum was found on the third day after X-PDT.By immunohistochemical staining of tumor sections,the Ly6G^(+),CD8^(+),and CD11c^(+)cells infiltrated in the tumor microenvironment were studied.Utilizing the bilat-eral tumor model,the NLF-MC540 with 0.1 Gy X-ray irradiation could inhibit both the primary tumor and the distant tumor growth.De-tected by enzyme linked immunosorbent assay(ELISA),two cytokines IFN-γand TNF-αin serum were upregulated 7 and 6 times than negative control,respectively.Detected by enzyme linked immune spot assay(ELISPOT),the number of immune cells attributable to the IFN-γand TNF-αlevels in the group of low dose X-PDT were 14 and 6 times greater than that in the negative control group,respectively.Thus,it conclude that low dose X-PDT system could successfully upregulate the levels of immune cells,stimulate the secretion of cy-tokines(especially IFN-γand TNF-α),activate antitumor immunity,and finally inhibit colon tumor growth.

Receptor tyrosine kinase-like orphan receptor 1:A novel antitumor target in gastrointestinal cancers

Receptor tyrosine kinase-like orphan receptor 1(ROR1)is a member of the type I receptor tyrosine kinase family.ROR1 is pivotal in embryonic development and cancer,and serves as a biomarker and therapeutic target.It has soluble and membrane-bound subtypes,with the latter highly expressed in tumors.ROR1 is conserved throughout evolution and may play a role in the development of gastrointestinal cancer through multiple signaling pathways and molecular mechanisms.Studies suggest that overexpression of ROR1 may increase tumor invasiveness and metastasis.Additionally,ROR1 may regulate the cell cycle,stem cell characteristics,and interact with other signaling pathways to affect cancer progression.This review explores the structure,expression and role of ROR1 in the development of gastrointestinal cancers.It discusses current antitumor strategies,outlining challenges and prospects for treatment.

Structure elucidation,immunomodulatory activity,antitumor activity and its molecular mechanism of a novel polysaccharide from Boletus reticulatus Schaeff

A new water-soluble heteropolysaccharide with a molecular weight of 15 k Da was isolated from the fruiting bodies of Boletus reticulatus Schaeff.Structural characterization results revealed that B.reticulatus Schaeff polysaccharide(BRS-X)had a backbone of 1,6-linkedα-D-galactose and 1,2,6-linkedα-D-galactose which branches were mainly composed of a terminal 4-linkedβ-D-glucose and the ratio of D-galactose and D-glucose was 5:1.Bioactivity assays indicated that BRS-X displayed a strong proliferative activity in T cells and B cells and promoted the secretion of immunoglobulin G(Ig G),Ig E,Ig D and Ig M.In addition,BRS-X could facilitate the proliferation and phagocytosis of RAW264.7 cells and could significantly inhibit the growth of tumors in S180-bearing mice.The results of transcriptome sequencing analysis illustrated that total 46 genes enriched in MAPK and total 34 genes enriched in PI3 K/Akt signaling pathways in BRS-X group.The protein VEGF and VEGFR expression were significantly reduced under the treatment with BRS-X.These findings provide a scientific basis for the edible and medicinal value of BRS-X.

Artificial Macrophage with Hierarchical Nanostructure for Biomimetic Reconstruction of Antitumor Immunity

Artificial cells are constructed from synthetic materials to imitate the biological functions of natural cells.By virtue of nanoengineering techniques,artificial cells with designed biomimetic functions provide alternatives to natural cells,showing vast potential for biomedical applications.Especially in cancer treatment,the deficiency of immunoactive macrophages results in tumor progression and immune resistance.To overcome the limitation,a BaSO_(4)@ZIF-8/transferrin(TRF)nanomacrophage(NMΦ)is herein constructed as an alternative to immunoactive macrophages.Alike to natural immunoactive macrophages,NMΦis stably retained in tumors through the specific affinity of TRF to tumor cells.Zn^(2+)as an“artificial cytokine”is then released from the ZIF-8 layer of NMΦunder tumor microenvironment.Similar as proinflammatory cytokines,Zn^(2+)can trigger cell anoikis to expose tumor antigens,which are selectively captured by the BaSO_(4)cavities.Therefore,the hierarchical nanostructure of NMΦs allows them to mediate immunogenic death of tumor cells and subsequent antigen capture for T cell activation to fabricate long-term antitumor immunity.As a proof-of-concept,the NMΦmimics the biological functions of macrophage,including tumor residence,cytokine release,antigen capture and immune activation,which is hopeful to provide a paradigm for the design and biomedical applications of artificial cells.

A novel lectin from mushroom Phellodon melaleucus displays hemagglutination activity,and antitumor activity in a B16 melanoma mouse model

A novel lectin(termed PML)was purified from fruiting bodies of the edible mushroom Phellodon melaleucus(division Basidiomycota)by ion exchange,hydrophobic interaction,and gel filtration chromatographies,with overall titer recovery~60%and 20-fold purification.PML displayed hemagglutination activity 13319 units/mg toward rabbit erythrocytes.SDS-PAGE and gel filtration analyses revealed that PML is a homodimeric lectin with a molecular weight of 28.8 kDa.PML hemagglutination activity was not inhibited by various simple sugars or their derivatives,but was enhanced by cations Ca^(2+),Mg^(2+),Zn^(2+),and Cu^(2+).The activity was stable in pH range 6–9 and in the temperature range 20–60°C.Circular dichroism(CD)spectroscopic analysis showed that PML was composed primarily ofβ-sheets with lowα-helix content.In a B16 melanoma mouse model,PML treatment significantly inhibited tumor growth,and increased cytokine IL-10 content.Our findings suggest that PML is a potential anticancer therapeutic agent.

Mechanisms and applications of antitumor immunotherapy of responsive drug-loaded nanoparticles in breast cancer

During the chemotherapy of tumors,the cytotoxic effect of drugs is vital to kill tumor cells,and the delivery of a chemotherapeutic agent is of great importance for optimal therapeutic effects.The high in vivo clearance rate and low delivery efficiency of conventional chemotherapeutic agents affect the therapeutic effect.In recent years,the responsive drug delivery nanosystem has received increasing concern owing to its excellent biocompatibility,stable delivery performance,and controlled drug release strategies.To lucidly explain the cytocidal and immunotherapeutic effects of such responsive nanosystems in breast cancer,this review discusses the various stimuli and responses of drug-loaded liposomal nanosystems.The light/magnetic response of drug-loaded bionic membranes nanosystems and the heat/magnetic response of drug-loaded iron oxide nanosystems are also elaborated.Their cancer cell-killing efficacy and antitumor immunotherapeutic effects are also scrutinized.

Study on the chemical constituents and antitumor activity of galangal

Objective:The main chemical components of galangal(Alpinia officinarum Hance)are flavonoids and diarylheptanes.In the previous work,the total heptane and total flavonoid components of galangal were isolated.In this paper,the two components were separated.The monomeric compound was purified and its cytotoxic activity was determined.Methods:Silica gel column chromatography,ODS column chromatography,preparative thin layer chromatography,preparative and semi-preparative HPLC methods were used to separate and purify the total heptane components and total flavonoid components of galangal.Structures of compounds were identified by 1H-NMR,13C-NMR modern spectroscopic techniques combined with literature.The cytotoxic activity of the isolated compounds against MDA-MB-231(breast cancer),HepG-2(liver cancer)and MKN-45(gastric cancer)cells was tested by CCK-8 method.Results:Six compounds were isolated from the total heptane fractions of galangal,and three compounds were isolated from the total flavonoids of galangal.Their structures were identified as:5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-1-phenylheptan-3-one(1),(E)-7-(4-hydr-oxy-3-methoxyphenyl)-1-phenylhept-4-en-3-one(2),5-hydroxy-1,7-diphenylheptan-3-one(3)7-(4-hydroxyphenyl)-5-methoxy-1-phenylheptan-3-one(4),(E)-7-(4-hydroxyphenyl)-1-phenylhept-4-en-3-one(5),(E)-1,7-diphenylhept-4-en-3-one(6),pinocembrin(7),galangin(8),3-O-methylgalangin(9).Conclusion:Compounds 1-6 were isolated from the total heptane components of galangal,and compounds 7-9 were isolated from the total flavonoids of galangal.The results of CCK-8 showed that compounds 2,3,5,6,7 and 8 had weak antitumor activity.

Antitumor Effect and Molecular Mechanism of Ophiopogonin B

Ophiopogonin B is a kind of saponin active substance extracted and purified from Ophiopogon japonicus,and plays an antitumor role by inhibiting cancer cell adhesion,invasion and proliferation,and inducing tumor cell apoptosis and autophagy.This paper reviews recent studies on antitumor effects and molecular mechanisms of ophiopogonin B,in order to provide a theoretical basis for subsequent development and clinical application of ophiopogonin B.

Synthesis and Antitumor Activity of 3-[2-(4-Hydroxy-Phenyl)-Ethyl]-Benzo[d] Isoxazole-4,6-Diol

A new phloretin derivative 1 3-[2-(4-hydroxy-phenyl)-ethyl]-benzo[d] isoxazole-4,6-diol (yield 63%) was synthesized from phloretin by carbonyl nucleophilic addition condensation reaction. Its structure was characterized by 1H NMR, 13C NMR and HR-MS. The phloretin, compound 1, resveratrol and acetylated resveratrol were determined by comparing them with paclitaxel. Anti-tumor activity of alcohol on SPC-A1, EC109, A549, MCF-7 and MDA-MB-231 cell lines. Compound 1 showed better antitumor activity than docetaxel against A549 tumor cells.

Volatile Components and Antitumor Activity of Ganoderma lucidum Spore Oil and Its Molecular Distillation Components

[Objectives]To compare the effects of molecular distillation on the flavor and antitumor activity of Ganoderma lucidum spore oil.[Methods]G.lucidum spore oil was separated and purified by molecular distillation technology,and the volatile components of different components of molecular distillation were analyzed by gas chromatography-ion mobility spectrometry(GC-IMS)technology.Human liver carcinoma cells(HepG2),human breast cancer cells(MCF-7),and human cervical cancer cells(Hela)were selected as the tumor cell lines to be tested,and the cell viability was detected by the MTT assay.[Results]Molecular distillation effectively reduced small molecular substances produced by oil oxidation in G.lucidum spore oil,such as heptanal,octanal,linalool,hexanal,E-2-octanal,3-ethylpyridine,etc.Among the heavy components,the content of esters was relatively high,mainly including ethyl levulinate,ethyl crotonate,and amyl butyrate.The MTT cytotoxicity test indicated that G.lucidum spore oil and its molecular distillation components had certain inhibitory effects on the growth of three tumor cells,and G.lucidum spore oil crude oil had the most significant antitumor activity.G.lucidum spore oil crude oil,heavy component,and light component had the most significant antitumor activity on HepG2 cells,followed by MCF-7 cells,and the weakest antitumor activity on Hela cells.The quality of G.lucidum spore oil became higher after molecular distillation,and the rancid smell was reduced,and molecular distillation had little effect on the antitumor activity of G.lucidum spores.[Conclusions]Molecular distillation technology can be applied to the refining of G.lucidum spore oil to improve product quality.

Doxorubicin Stealth Liposomes Prepared with PEG-Distearoyl Phosphatidylethanolamine and Distribution as well as Antitumor Activity in Mice

目的：研制出能够逃避体内网状内皮细胞的阿霉素隐形脂质体，并考察其在生物体内的分布以及比较阿霉素隐形脂质体与阿霉素普通脂质体的抗肿瘤活性。方法：将聚乙二醇－二硬脂酰磷脂酰乙醇胺（PEG－DSPE）同磷脂酰胆碱和胆固醇材料加在一起，用硫酸铵梯度法制备阿霉素隐形脂质体，同法制备阿霉素普通脂质体（但脂膜中不含PEG－DSPE）；通过尾静脉注射给药，比较隐形脂质体阿霉素、普通脂质体阿霉素和游离型阿霉素（盐酸阿霉素注射液）给药后在小鼠各主要脏器组织和血液中的分布情况；采用动物移植性肿瘤实验法，用H22小鼠肝癌细胞接种于小鼠右侧腋皮下形成实体瘤，考察阿霉素隐形脂质体和普通脂质体给药后对实体瘤的瘤重抑制率。结果：通过硫酸铵梯度法制备出了包封率高达95％的阿霉素隐形脂质体；同游离型阿霉素和普通脂质体阿霉素相比，隐形脂质体阿霉素在血液中浓度显著提高，循环时间显著延长，在心脏中分布的浓度显著降低；按5mg·kg^-1剂量治疗，第二天给药和第七天给药治疗方案，阿霉素隐形脂质体给药组的瘤重抑制率均显著高于普通脂质体给药组的瘤重抑制率；按10mg·kg^-1剂量治疗，隐形脂质体给药组的瘤重抑制率比普通脂质体给药组的瘤重抑制率稍高。结论：用普通脂质体给药相比，隐形脂质体阿霉素给药后延长了其在小鼠血液中的循环时间，说明经过PEG－DSPE修饰后的脂质体有逃避网状内皮细胞吞噬的功能（隐形），并且隐形脂质体阿霉素的抗肿瘤活性显著地提高。

Antitumor Activity of the Ganoderma Lucidum Spore Alcohol Extract in Vitro

Several cancer cell lines(epithelioma cells or leukemia cells)from human being or mouse were first used to study the antitumor activity of the Ganoderma lucidum spore alcohol extract(GLSAE)in vitro by the MTT test A comparision was made between the sporodermbroken(SB)and sporoderm nonbroken(SN)GLSAE It was showed that both GLSAE SB and GLSAE SN could inhibit the proliferation of these cancer cells,but the activity of GLSAE SB was much higher than that of GLSAE SN These results suggested that Ganoderma lucidum spore could probably be used for tumor treatment

Synthesis of Aminoglucose Conjugates of 5-Fluorouracil-1-acetic Acid and 5-Fluorouracil-1-propanoic Acid and Their Antitumor Activities

Six aminoglucose conjugates were synthesized by the reaction of aminoglucose with 5-fluorou-racil-1-acetic acid or 5-fluorouracil-1-propanoic acid and confirmed by IR, 1H NMR and elemental analyses. Their antitumor activities against A2780 cells and PC-14 cells were also evaluated.

Preliminary screening of antimicrobial and antitumor activities from cultivated microalgaes

Hydrophilic and lipophilic extracts were prepared from 8 microalgal strains, and screened for antimicrobial and antitumor activities. Antimicrobial activity was determined by observing bacterial （ S. aureus, Bacillus subtilis and Escherichia coh~ and fungal（Aspergillus niger and Penicillium chrysogenum） growth inhibition. All the microalgae had different degrees of antimicrobial activity against one or more microbe - tested, and 56.47% of the extracts showing the anti-S.aureus activity exhibited the antibacterial activity against （MRSA）. Cytotoxic activities were measured in vitro against human cancer cell lines HeLa by the MTT assay. Most of these extracts showed potent activity against the growth of the tumor cells, especially the intracellular lipophilic extracts from Isochrysis galbana Parke 3011 and Isochrysis galbana Parke H29, which exhibited strong antitumor activity against HeLa cell lines. The overall results of this study indicate that the extracts from microalgae represent a potential sources of medicine for the treatment of infectious and cancer diseases.

Antitumor Actinity of Puqietinone,a Novel Alkaloid fromthe Bulbs of Fritillaria puqiensis

从蒲圻贝母中分得的一种新生物碱蒲贝酮碱，按一定剂量灌胃给药，显示了强的抗小鼠艾氏腹水癌（ＥＡＳ，实体型），宫颈癌（Ｕ＿（１４），实体型）及肝癌（ＨｅＰＡ，实体型）的活性。

Antitumor Alkaloids Isolated from Tylophora ovata

Four phenanthroindolizidine alkaloids, named tylophoridicine A (1), tylophorinine (2), O_methyl tylophorinidine (3) and tylophorinidine (4), were isolated from the roots of Tylophora ovata (Lindl.) Hook. ex Steud. Using modern NMR techniques including NOESY and 1H_NMR line broadening effect experiments, CD spectra and MS analysis as well as chemical methods, their structures were identified as (13aR)_6_hydroxy_3,7_dimethoxy_phenanthroindolizidine (1), (13aS,14R)_14_hydroxy_3,6,7_trimethoxy_phenanthro_indolizidine (2), (13aS,14S)_14_hydroxy_3,6,7_trimethoxy_phenanthroindolizidine (3), and (13aS,14S)_6,14_dihydroxy_3,7_dimethoxy_phenanthroindolizidine (4) respectively. Compound 1 is a new compound, compounds 2-4 are obtained from this plant for the first time. Compounds 1, 3 and 4 showed strong antitumor activities.

Improved Synthesis of Fructose-Derived 1, 3, 4-Oxadiazole as Novel Antitumor Agents

Aim To optimize the reaction condition for preparation of 3-spiro-1, 3, 4-oxadiazole substituted fructose and hydrolysis of its isopropylidenes stepwisely. Methods Cyclohexane was added to the reaction mixture every 8 h to remove acetic acid at 90 ℃. The isopropylidenes were hydrolyzed in 80% AcOH at 60 ℃ stepwisely in a reaction time- dependent manner. Results The yields of cyclization products 1b and 1c were improved from 53% and 51% to 74% and 79% respectively. The 1, 2-di-O-isopropylidene product 3 was obtained after 1 h and the total deprotected product 4 was obtained after 3 h in 80% AcOH at 60 ℃. Conclusion The yield of 1 is improved by cyclohexane-aided azeotropic removal of AcOH from the reaction mixture. Deprotection of 1 in 80% AcOH at 60 ℃ gives 3 or 4 after different time periods.

Synthesis and Antitumor Activity of Podophyllotoxin Analogues

Seven podophyllotoxin analogues were synthesized by condensation of 4′ demethyl epipodophyllotoxin 10 with 5 alkyl 4 amino 3 mercapto 1,2,4 triazoles 9(a g) in the presence of TFA(CF 3COOH). Their antitumor activities were screened in vitro against HL 60 and K 562 cells.

Berberine displays antitumor activity in esophageal cancer cells in vitro

To investigate the effects of berberine on esophageal cancer (EC) cells and its molecular mechanisms. METHODS Human esophageal squamous cell carcinoma cell line KYSE-70 and esophageal adenocarcinoma cell line SKGT4 were used. The effects of berberine on cell proliferation were evaluated using the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide (MTT) assay. For cell cycle progression, KYSE-70 cells were stained with propidium iodide (PI) staining buffer (10 mg/mL PI and 100 mg/mL RNase A) for 30 min and cell cycle was analyzed using a BD FACSCalibur flow cytometer. For apoptosis assay, cells were stained with an Annexin V-FITC/PI apoptosis detection kit. The rate of apoptotic cells was analyzed using a dual laser flow cytometer and estimated using BD ModFit software. Levels of proteins related to cell cycle and apoptosis were examined by western blotting. RESULTS Berberine treatment resulted in growth inhibition of KYSE-70 and SKGT4 cells in a dose-dependent and time-dependent manner. KYSE-70 cells were more susceptible to the inhibitory activities of berberine than SKGT4 cells were. In KYSE-70 cells treated with 50 mu mol/L berberine for 48 h, the number of cells in G2/M phase (25.94% +/- 5.01%) was significantly higher than that in the control group (9.77% +/- 1.28%, P < 0.01), and berberine treatment resulted in p21 upregulation in KYSE-70 cells. Flow cytometric analyses showed that berberine significantly augmented the KYSE-70 apoptotic population at 12 and 24 h post-treatment, when compared with control cells (0.83% vs 43.78% at 12 h, P < 0.05; 0.15% vs 81.86% at 24 h, P < 0.01), and berberine-induced apoptotic effect was stronger at 24 h compared with 12 h. Western blotting showed that berberine inhibited the phosphorylation of Akt, mammalian target of rapamycin and p70S6K, and enhanced AMP-activated protein kinase phosphorylation in a sustained manner. CONCLUSION Berberine is an inhibitor of human EC cell growth and could be considered as a potential drug for the treatment of EC patients.