Antitumor Ability Research Articles

Precise engineering of dual drug-loaded polymeric nanoparticles system to improve the treatment of glioma-specific targeting therapy

We have fabricated a novel method to achieve therapy- triggered changes in tumor cells by using promising effects concerning dual chemotherapeutic drugs. Dual-drug conveyance of Salinomycin (SAL) and Doxorubicin (DOX) exhibits a great anti-tumor ability, as SAL improves the impact of DOX management of glioma cells by supplying stability of the microenvironment. Nevertheless, encapsulations of SAL and DOX fanatical by (lactic-co-glycolic acid (PLGA) and polyethylene glycol (PEG)- based nanoparticles (NPs) is incompetents due to inappropriateness between the dual drug SAL and DOX polymeric framework. At the present, we show DOX and SAL can be formulated with dioleoylphosphatide acid (DOPA) through the hydrophobic covering of drug centers. In PEG-PLGA NPs, the DOPA- enclosed DOX can be co-incorporating in addition to SAL to encourage superior cancer activities. The DOX revealed seductively that the SAL encapsulations in PEG-PLGA NPs (SAL-DOX NPs) were improved. The transmission microscopy (TEM) studied the morphology of SAL NPs, DOX NPs, SAL-DOX NPs, and nanoparticle size. SAL-DOX NPs also induced major apoptosis in vitro human glioma cells such as LN229 and U251. Different biochemical trials such as AO-EB, Hoechst staining, and annexin V-FITC have confirmed morphological observations and apoptosis. The findings indicate that the SAL-DOX NPs is one of the promising caregivers of therapeutic candidates for human glioma cancer worth further study.

MicroRNA-138 Regulates T-Cell Function by Targeting PD-1 in Patients with Hepatitis B Virus-Related Liver Diseases.

T-cell exhaustion in hepatitis B virus (HBV) infection, which results from upregulation of programmed cell death-1 (PD-1), leads to persistent HBV infection and related disease progression. Therefore, agents targeting PD-1 may prove beneficial in the treatment of this condition. MicroRNA-138 (miR-138) possesses an anti-tumor ability in that it targets immune checkpoints, including PD-1. However, the function and underlying mechanisms of miR-138 in patients with HBV infection remains unclear. Specimens were collected from healthy volunteers (n = 43) and patients with chronic hepatitis B (CHB; n = 52), liver cirrhosis (LC; n = 26), and hepatocellular carcinoma (HCC; n = 31); carriers of HBV who were asymptomatic (n = 51); and patients with CHB receiving antivirus treatment (n = 11). These specimens were then used to study the expression and relationship among miR-138, PD-1, and HBV DNA viral load. To investigate the role of miR-138 in regulating PD-1 expression and determine the effect of miR-138 in regulating T-cell function, a luciferase assay and a transfection assay were each performed with primary CD3+ T cells. We found that PD-1 was upregulated and miR-138 was downregulated in patients with CHB, LC, and HCC. Correlations analysis revealed that PD-1 expression was positively correlated with HBV DNA viral load whereas miR-138 was negatively correlated. Luciferase assay results showed that miR-138 directly inhibited PD-1 expression by interacting with the 3'-untranslated region of PD-1. As a result of miR-138 overexpression in primary T cells, PD-1 in these T cells was downregulated and antivirus cytokines secreted by T cells were significantly upregulated. In addition, the expression levels of PD-1 and miR-138 were reversed in patients with CHB who received antivirus treatments. Results showed that miR-138 can promote T-cell responses within patients with HBV infection by inducing a PD-1 blockade. Such an effect suggests that miR-138 may serve as a new therapeutic target for the treatment of HBV infection.

Engineering NK Cells for CAR Therapy-Recent Advances in Gene Transfer Methodology.

The development of chimeric antigen receptor (CAR) T cell therapy has introduced a new and effective strategy to guide and promote the immune response against tumors in the clinic. More recently, in an attempt to enhance its utility, this method has been expanded to novel cell types. One of the more successful variants has proven to be the expression of CARs in Natural Killer (NK) cells (CAR-NK). Gene engineering NK cells to express an exogenous CAR receptor allows the innate anti-tumor ability of NK cells to be harnessed and directed against a target tumor antigen. In addition, the biology of NK cells allows the development of an allogeneic cell therapeutic product useable with most or all patient haplotypes. NK cells cause little or no graft versus host disease (GvHD) and are therefore suitable for development of an “off the shelf” therapeutic product. Initial trials have also shown that CAR-NK cells rarely cause cytokine release syndrome. However, despite their potential NK cells have proven to be difficult to engineer, with high sensitivity to apoptosis and low levels of gene expression. The creation of optimized methods to introduce genes into NK cells will promote the widespread application of CAR-NK in research laboratories and the clinics.

A Novel Blockade CD47 Antibody With Therapeutic Potential for Cancer.

Macrophages as components of the innate immune system play a critical role in antitumor responses. Strategies for targeting CD47 are becoming a hot spot for cancer therapy. The expression of CD47 is exercised by macrophages to make a distinction between “self” or “nonself.” Anti-CD47 antibodies block the interaction between macrophage signal regulatory protein-α (SIRPα) and tumor surface CD47. In this study, we report and assess a novel anti-CD47 blocking antibody named 2C8, which exhibits high affinity and tremendous anticancer effects. More concretely, 2C8 significantly induces macrophages, including protumorigenic subtype M2 macrophages killing tumor cells in vitro, and is revealed to be more effective than commercially available anti-CD47 mAb B6H12.2. In vivo, 2C8 controls tumor growth and extends survival of xenograft mice. The antitumor ability of 2C8 might be applicable to many other cancers. The generation of a novel CD47 antibody contributes to consolidating clinical interest in targeting macrophages for the treatment of malignancy and, moreover, as a supplement therapy when patients are resistant or refractory to other checkpoint therapies or relapse after such treatments.

Synthesis of Multi-Functional Carbon Quantum Dots for Targeted Antitumor Therapy.

Carbon dots are nano-sized photoluminescence materials which have good biocompatibility and low cytotoxicity, while the previously synthesized carbon dots lack tumor targeting capability and therapy function so that it cannot achieve the purpose of diagnosis and treatment. Herein, a new kind of multi-functional carbon dots (GFCDs) is promising to be applied in tumor cells imaging and clinical targeted therapy. Gallic acid (GA) was used as the carbon resource and antitumor active molecule, folic acid (FA) was used as the nitrogen resource and tumor targeting molecule, and citric acid monohydrate (CA) was used as the auxiliary carbon source. Multi-functional GACDs were synthesized by a simple one-step microwave-assisted procedure and analyzed with UV - vis spectrophotometer, fourier transform infrared spectrometer, transmission electron microscopy and X-ray photoelectron spectrometer. Results show that the diameter of GFCDs is about 3nm. And GFCDs are pale-yellow under natural light which turn blue under 360nm UV lamp. Besides ester bond is the connecting mode between functional molecules. In addition, the results of in vitro cell imaging experiments and in vivo antitumor experiments demonstrate the targeting imaging and antitumor abilities towards Hela cells. The synthesis route and properties of GFCDs.

Genetic engineering cellular vesicles expressing CD64 as checkpoint antibody carrier for cancer immunotherapy.

Immune checkpoint blockade therapies, especially those targeting the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) have achieved impressive clinical responses in multiple types of cancers. To optimize the therapeutic effect of the checkpoint antibodies, many strategies including targeting delivery, controlled release, and cellular synthesis have been developed. However, within these strategies, antibodies were attached to drug carriers by chemical bonding, which may affect the steric configuration and function of the antibodies. Herein, we prepared cluster of differentiation 64 (CD64), a natural catcher of the fragment crystalline (Fc) of monomeric immunoglobulin G (IgG), and over-expressed it on the cell membrane nanovesicles (NVs) as PD-L1 antibody delivery vehicle (CD64-NVs-aPD-L1), which was employed to disrupt the PD-1/PD-L1 immunosuppressive signal axis for boosting T cell dependent tumor elimination. Meanwhile, chemical immunomodulatory drug cyclophosphamide (CP) was also encapsulated in the vesicle (CD64-NVs-aPD-L1-CP), to simultaneously restrain the regulatory T cells (Tregs) and invigorate Ki67+CD8+ T cells, then further enhance their anti-tumor ability.Methods: The cell membrane NVs overexpressing CD64 were incubated with PD-L1 antibody and chemotherapeutic agent CP to prepare CD64-NVs-aPD-L1-CP.Results: The CD64-NVs-aPD-L1-CP could simultaneously interrupt the immunosuppressive effect of PD-L1 and decrease the inhibition of Tregs, leading to tumor growth suppression and survival time extension.Conclusion: CD64-NVs are charismatic carriers to achieve both checkpoint blockade and immunomodulatory drugs for combined cancer immunotherapy.

Tumor RNA-loaded nanoliposomes increases the anti-tumor immune response in colorectal cancer

Purpose Tumor RNA vaccines can activate dendritic cells to generate systemic anti-tumor immune response. However, due to easily degraded of RNA, direct RNA vaccine is less effective. In this study, we optimized the method for preparing PEGylated liposom-polycationic DNA complex (LPD) nanoliposomes, increased encapsulate amount of total RNA derived from CT-26 colorectal cancer cells. Tumor RNA LPD nanoliposomes vaccines improved anti-tumor immune response ability of tumor RNA and can effectively promote anti-tumor therapeutic effect of oxaliplatin. Methods Total tumor-derived RNA was extracted from colorectal cancer cells (CT-26 cells), and loaded to our optimized the LPD complex, resulting in the LPD nanoliposomes. We evaluated the characteristics (size, zeta potential, and stability), cytotoxicity, transfection ability, and tumor-growth inhibitory efficacy of LPD nanoliposomes. Results The improved LPD nanoliposomes exhibited a spherical shape, RNA loading efficiency of 9.07%, the average size of 120.37 ± 2.949 nm and zeta potential was 3.34 ± 0.056 mV. Also, the improved LPD nanoliposomes showed high stability at 4 °C, with a low toxicity and high cell transfection efficacy toward CT-26 colorectal cancer cells. Notably, the improved LPD nanoliposomes showed tumor growth inhibition by activating anti-tumor immune response in CT-26 colorectal cancer bearing mice, with mini side effects toward the normal organs of mice. Furthermore, the effect of the improved LPD nanoliposomes in combination with oxaliplatin can be better than that of oxaliplatin alone. Conclusion The improved LPD nanoliposomes may serve as an effective vaccine to induce antitumor immunity, presenting a new treatment option for colorectal cancer.

Interleukin-18 promotes the antitumor ability of natural killer cells in colorectal cancer via the miR-574-3p/TGF-β1 axis

ABSTRACT Interleukin (IL)-18 has a clear antitumor effect; however, its mechanisms of action are not understood in patients with colorectal cancer (CRC). Here, we investigated the potential mechanism of IL-18 in CRC. The results showed that IL-18 treatment alone had no effect on HCT116 cells apoptosis, whereas IL-18 in the presence of natural killer (NK) cells resulted in apoptosis and inhibition of cells proliferation in vitro. Profiling of miRNA expression following coculture with NK cells and treatment with IL-18 resulted in significant downregulation of miR-574-3p expression and upregulated expression of the target gene transforming growth factor beta 1 (TGF-β1). miR-574-3p binds to TGF-β1, and miR-574-3p overexpression increased the proliferation and decreased the apoptotic rate of HCT116 cells in NK cells coculture with IL-18 treatment; overexpression of TGF-β1 restored the effect of miR-574-3p overexpression. The miRNA profile of HCT116 undergoes significant alteration before and after coculturing with NK cells and treatment with IL-18. IL-18 alone did not affect HCT116 cells apoptosis but did promote the antitumor ability of NK cells in coculture with HCT116 cells via the miR-574-3p/TGF-β1 axis. Our study suggested that IL-18 can be a new potential target for cancer immunotherapy for CRC.

Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer

ABSTRACT Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4–1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and off-target toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3+CD8+ T cells and CD62L+CCR7+ central memory T cells (TCM) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the anti-tumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.

Design and evaluation of glutathione responsive glycosylated camptothecin nanosupramolecular prodrug

A novel tumor-targeted glutathione responsive Glycosylated-Camptothecin nanosupramolecular prodrug (CPT-GL NSp) was designed and fabricated via a disulfide bond. The effects of glycoligand with different polarities on solubility, self-assembly, stability, cellular uptake, and glutathione responsive cleaving were explored, and an optimal glycosylated ligand was selected for nanosupramolecular prodrug. It has been found that CPT-GL NSp exhibited higher drug loading than traditional nanoparticles. Among of which maltose modified NSp had the strongest anti-tumor effects than that of glucose and maltotriose. CPT-SS-Maltose had a similar anti-tumor ability to Irinotecan (IR), but the superior performance in solubility, hemolysis, and uptake of HepG2 cells.

Prodrug-based nano-delivery strategy to improve the antitumor ability of carboplatin in vivo and in vitro

Chemotherapy plays a major role in the treatment of cancer, but it still has great limitations in anti-tumor effect. Carboplatin (CAR) is the first-line drug in the treatment of non-small cell lung cancer, but the therapeutic effect is demonstrated weak. Therefore, we modified CAR with hexadecyl chain and polyethylene glycol, so as to realize its liposolubility and PEGylation. The synthesized amphiphilic CAR prodrugs could self-assemble into polymer micelles in water with an average particle size about 11.8 nm and low critical micelles concentration (0.0538 mg·mL–1). In vivo pharmacodynamics and cytotoxicity experiment evidenced that the polymer micelles were equipped with preferable anti-tumor effect, finally attained the aim of elevating anti-tumor effect and prolonging retention time in vivo. The self-assembled micelles skillfully solve the shortcomings of weak efficacy of CAR, which provides a powerful platform for the application of chemical drug in oncology.

Kaempferol-3-O-rutinoside, a flavone derived from Tetrastigma hemsleyanum, suppresses lung adenocarcinoma via the calcium signaling pathway.

Lung cancer has been threatening human health worldwide for a long time. However, the clinic therapies remain unsatisfactory. In this study, the anti-adenocarcinoma lung cancer A549 cell line abilities of Tetrastigma hemsleyanum tuber flavonoids (THTF) were evaluated in vivo, and isobaric tags for relative and absolute quantification (iTRAQ)-based proteomic analysis was conducted to detect the protein alterations in THTF-treated solid tumors. The differentially expressed proteins were related to the cytoskeleton and mostly accumulated in the calcium signaling pathway. The in vitro study illustrated that 80 μg mL-1 THTF significantly suppressed cellular viability to approximately 75% of the control. Further results suggested that kaempferol-3-O-rutinoside (K3R), the major component of THTF, effectively triggered cytoskeleton collapse, mitochondrial dysfunction and consequent calcium overload to achieve apoptosis, which remained consistent with proteomic results. This study uncovers a new mechanism for THTF anti-tumor ability, and suggests THTF and K3R as promising anti-cancer agents, providing new ideas and possible strategies for future anti-lung cancer prevention and therapy.

An Overview of Bioactive Natural Products-Based Nano-Drug Delivery Systems in Antitumor Chemotherapy

Many bioactive natural products are derived from traditional Chinese medicine. Some of them showed good treatment potential in tumor chemotherapy. However, limited by the poorly solubility and non-selective toxicity of most of bioactive natural products, their antitumor efficacy could not be further applied in clinicals. Nano-drug delivery systems provided good platforms for bioactive natural products in antitumor treatment, and many tumor microenvironment-responsive nano-delivery carriers facilitated them to achieve more accurate tumor targeting and less toxicity, and finally improved antitumor ability of bioactive natural products.

Using of brown algae Sargassum pallidum as raw materials for extraction of fucoxanthin

Fucoxanthin is a widespread carotenoid contained in tissues of brown algae, known by its antitumor activity and ability to suppress cancer cells growth. Its inclusion into diet prevents accumulation of the body fat and regulates level of glucose and insulin in the blood. Fucoxanthin can be considered as a promising nutritional supplement for suppressing obesity. Extraction of fucoxanthin from brown algae Sargassum pallidum is investigated under various conditions. The samples of algae were collected in different sites at Primorye coast in 2018–2019. Two types of the preparations were used ― frozen and dried. The frozen preparations were stored under temperature of –18 оC no more than 30 days. For the dried preparations, fresh algae were dried in a dark room by air fan under temperature of +18–+20 оC and then crushed to powder and stored in dark place under the same temperature no more than 6 months. Content of dry substance in the preparations was 16.4 ± 1.0 % for frozen algae and 93.6 ± 1.0 % for dried algae. Fucoxanthin was extracted from these preparations by method of alcohol extraction using the ethanol water solution in ratio of 1 : 10 during 24 hours in a dark place, then the solution was filtered or centrifuged. Concentration of fucoxanthin in the filtered solution was measured in spectrophotometer relative to a standard solution (ethanol 96 %) with wavelength of 350–800 nm. Yield of fucoxanthin was higher from the frozen preparations, but more ethanol was consumed for its extraction in comparison with extraction from the dried preparations. Besides, the dried preparations were processed during 1 day with the ethanol solution in concentration 96, 88, 84, 80, and 76 %, under various temperature. Yield of fucoxanthin decreased with temperature increasing: the optimal temperature was +7 оC, so the room temperature could not be recommended for extraction. The optimum concentration of ethanol for fucoxanthin extraction was 80 ± 2%.

Construction of PD1/CD28 Fusion Receptor Enhances Anti-Tumor Ability of c-Met CAR-T in Gastric Cancer

Background: Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problem was immunosuppression cased by PD-1. Methods: The expression of c-Met in GC was analyzed from TCGA datasets, GC tissues and cell lines. The c-Met CAR was a second generation CAR with 4-1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 fusion receptor. In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and off-target toxicity of different CAR-Ts. Findings: The expression of c-Met was increased in GC. CD3+CD8+ T cells and CD62L+CCR7+ central memory T cells (TCM) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T (blank control), the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts were increased, the killing ability to c-Met positive GC cells were enhanced. The PD1/CD28 fusion receptor could further enhance the killing ability especially the long-term anti-tumor effect of c-Met CAR-T and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Interpretation: The PD1/CD28 fusion receptor could further enhance the anti-tumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC. Funding Statement: This study was supported by National Natural Science Foundation of China (31770537), Key Research and Development Project of Gansu Science and Technology Plan (18YF1WA113), Special Research Project of Lanzhou University Serving the Economic and Social Development of Gansu Province (054000282) Declaration of Interests: The authors declared they have no conflict of interest. Ethics Approval Statement: Approval of the Ethics Committee of Lanzhou University Second Hospital and informed consent of patients. Animal experiments were approved by the Institutional Animal Care and Use Committee of Lanzhou University Second Hospital, comply with the animal welfare.

Anticancer potential of garlic and its bioactive constituents: A systematic and comprehensive review.

Vegetables of the Allium genus, such as garlic (Allium sativum L.), onions, shallots, leaks, and chives, have been used for many years for food consumption and for medicinal purposes. Historical medical texts have indicated the therapeutic applications of garlic as an antitumor, laxative, diuretic, antibacterial and antifungal agent. Specifically, garlic's antitumor abilities have been traced back 3500 years as a chemotherapeutic agent used in Egypt. Other beneficial effects of garlic consumption include lowering blood pressure, blood cholesterol, sugar and lipids. The processing and aging of garlic result in the production of non-toxic organosulfur by-products. These sulfur-containing compounds, such as allicin, diallyl sulfide, diallyl disulfide, diallyl trisulfide, alliin, S-allylcysteine, and S-allylmercaptocysteine, impact various stages of carcinogenesis. The anticancer mechanisms of action of these garlic-derived phytochemicals include altering mitochondrial permeability, inhibiting angiogenesis, enhancing antioxidative and proapoptotic properties, and regulating cell proliferation. All these effects of garlic's sulfur-compounds have been demonstrated in various human cancers. The intent of this literature research is to explore the potential of garlic-derived products and bioactive organosulfur compounds as cancer chemopreventive and chemotherapeutic agents. This investigation employs criteria for systematic review and critically analyzes published in vitro, in vivo and clinical studies. Concerns and limitations that have arisen in past studies regarding standards of measurement, bioavailability, and method of delivery are addressed. Overall, it is hoped that through this systematic and comprehensive review, future researchers can be acquainted with the updated data assembled on anticancer properties of garlic and its phytoconstituents.

Novel Scopoletin Derivatives Kill Cancer Cells by Inducing Mitochondrial Depolarization and Apoptosis.

Natural products and their molecular frameworks have been explored as invaluable sources of inspiration for drug design by means of structural modification, computer-aided drug design, and so on. Scopoletin extracting from multiple herbs exhibits potential anti-cancer activity in vitro and in vivo without toxicity towards normal cells. The study aims to obtain new scopoletin derivatives with enhanced anti-cancer activity. We performed chemical structure modification and researched the mechanism of anti-tumor activity. In this study, we considered scopoletin as a lead compound, designed and synthesized a series of scopoletin derivatives via introducing different heterocyclic fragments, and their chemical structures were characterized by NMR spectra (1H NMR and 13C NMR) and HRMS(ESI). The antiproliferative activity of target compounds in four cancer cell lines (MDA-MB-231, MCF-7, HepG2, and A549) was determined by the MTT assay. Compound 11b was treated with Ac-cys under different reaction conditions to explore the thiol addition activity of it. The Annexin V/PI and JC-1 staining assay were performed to investigate the anti-tumor mechanism of 11b. Novel compounds 8a-h and 11a-h derivatives of scopoletin were synthesized. Most of the target compounds exhibited enhanced antiproliferative activity against different cancer cells and reduced toxicity towards normal cells. In particular, 11b displayed the optimal antitumor ability against breast cancer MDA-MB- 231 cells with an IC50 value of 4.46 μM. Compound 11b also cannot react with Ac-cys under the experimental condition. When treated with 11b for 24 h, the total apoptotic cells increased from 10.8% to 79.3%. Besides, 11b induced the depolarization of mitochondrial membrane potential. Compound 11b was more active than other derivatives, indicating that the introduction of thiophene fragment was beneficial for the enhancement of antitumor effect, and it was also not an irreversible inhibitor based on the result that the α, β-unsaturated ketones of 11b cannot undergo Michael addition reactions with Accys. Furthermore, studies on the pharmacological mechanism showed that 11b induced mitochondrial depolarization and apoptosis, which indicated that 11b killed cancer cells via a mitochondrial apoptotic pathway. Therefore, in-depth research and structure optimization of this compound is warranted.

A Review on Anti-Tumor Mechanisms of Coumarins.

Coumarins are a class of compound with benzopyrone as their basic structure. Due to abundant sources, easy synthesis, and various pharmacological activities, coumarins have attracted extensive attention from researchers. In particular, coumarins have very significant anti-tumor abilities and a variety of anti-tumor mechanisms, including inhibition of carbonic anhydrase, targeting PI3K/Akt/mTOR signaling pathways, inducing cell apoptosis protein activation, inhibition of tumor multidrug resistance, inhibition of microtubule polymerization, regulating the reactive oxygen species, and inhibition of tumor angiogenesis, etc. This review focuses on the mechanisms and the research progress of coumarins against cancers in recent years.

In Vitro and In Vivo Antitumor Activity of Silver Nanoparticles on B16 Melanoma

Melanoma, one of the most malignant tumors, is difficult to treat due to its high drug resistance. Silver nanoparticles (AgNPs) are widely used as antimicrobial agents in biomedical fields. In this study, the spherical AgNPs with average sizes of 5[Formula: see text]nm were prepared using a dopamine reduction method. The in vitro study shows that AgNPs with the concentrations of 0.5[Formula: see text][Formula: see text]g/mL and 1[Formula: see text][Formula: see text]g/mL exhibit good biocompatibility to 3T3L1 fibroblast cells. AgNPs with the same concentrations significantly inhibited the growth of B16 melanoma cells. In culture with B16 cells, AgNPs induced intracellular oxidative stress by generating the reactive oxygen species and reducing the superoxide dismutase, which further reduces the mitochondrial membrane potential. Moreover, the damage in mitochondria could activate mitochondrion-mediated cell apoptosis. The B16 cells apoptosis was analyzed by FITC-Annexin V/propidium iodide double staining assay, which confirms that AgNPs caused the abundance of apoptotic cells in different stages. Thus, AgNPs displayed the antitumor activity in vitro. Then, the therapeutic efficacy in vivo was evaluated in mice-bearing B16 melanoma tumors. The obtained results show the antitumor ability of AgNPs and provide a potential strategy for cancer treatment.

The Target Differences of Anti-Tumorigenesis Potential of Curcumin and its Analogues Against HER-2 Positive and Triple-Negative Breast Cancer Cells.

Purpose: The current study aims to evaluate the in vitro cytotoxic and cell migration effects of synthetic curcumin and its analogues on HER2 and nuclear factor kappa B (NFκB) pathways, as well as the in vivo inhibitory effect on cancer growth of metastatic breast cancer. Methods: Cell viability, protein expression, and protein localization were determined in vitro using MTT assay, western blotting, and immunofluorescence, respectively. Meanwhile, scratch wound healing assay and gelatin zymography were conducted to investigate the metastasis inhibitory effect. The in vivo anti-tumor ability was evaluated in xenograft mouse model using triple-negative breast cancer (TNBC) cells. Results: Curcumin, PGV-0, and PGV-1 exhibited cytotoxic effect against HER2-overexpressing breast cancer cells. Although PGV-1 showed the best activity in the single cytotoxic assay, curcumin showed the strongest synergism with doxorubicin. Curcumin and PGV-0 inhibited membrane localization of HER2. In contrast, PGV-1 neither inhibited localization nor decreased the expression of HER2, nonetheless showed the most potent inhibition against nuclear localization of p65 indicating the different mechanisms of curcumin, PGV-0, and PGV-1. Regarding cancer metastasis, curcumin and PGV-1 showed inhibitory activities against cell migration and inhibited MMP-2 and MMP-9 protein expression. Lastly, PGV-1 was more potent compared to curcumin to suppress the tumor formation of metastatic breast cancer xenograft model in nude mice. Conclusion: Overall, our study strengthens the potency of curcumin analogue, PGV-1, for treating several types of cancer, including metastatic breast cancer.