Significant Anti-tumour Effect Research Articles

Delivery of SiRNA-PD-L1 by attenuated Salmonella in combination with oxaliplatin in a hepatocellular carcinoma mouse model

Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.

Ethnozoological importance of Eisenia fetida and experimental validation of its anticancer activity in ascites Dalton’s lymphoma (DL) bearing mice

Eisenia fetida, commonly known as the red earthworm, holds significant ethnozoological importance due to its traditional use in various cultures as a medicinal agent. This study aims to explore the potential anticancer effects of Eisenia fetida paste (EFP) and evaluate its therapeutic efficacy in mice with ascites Dalton's lymphoma (DL). The EFP extract demonstrated a significant antitumour effect, possibly by initiating programmed cell death and mitochondrial changes in the tumour cells. The viability of tumour cells exhibited a reduction over time due to EFP treatment. Comparative analysis with the reference drug cisplatin revealed that EFP exhibited fewer or no adverse effects on mutagenicity, hepatotoxicity, and nephrotoxicity in tumour-bearing hosts. EFP treatment was found to show progressive increase in the quantity of apoptotic DL cells over time suggesting a time-dependent impact on the induction of apoptosis in the treated groups. These results imply that EFP might serve as a safer substitute for cancer treatment and hold promise for developing new and improved therapeutic strategies against cancer. The main implication of the study is that EFP might serve as a safer substitute for cancer treatment. It suggests a promising avenue for developing new and improved therapeutic strategies against cancer, with the potential to enhance treatment outcomes while minimising adverse effects.Graphical abstract

Pirfenidone inhibits TGF-β1-induced metabolic reprogramming during epithelial-mesenchymal transition in non-small cell lung cancer.

Metastasis is an important contributor to increased mortality rates in non-small cell lung cancer (NSCLC). The TGF-β signalling pathway plays a crucial role in facilitating tumour metastasis through epithelial-mesenchymal transition (EMT). Glycolysis, a key metabolic process, is strongly correlated with NSCLC metastasis. Pirfenidone (PFD) has been shown to safely and effectively inhibit TGF-β1 in patients with lung diseases. Furthermore, TGF-β1 and glycolysis demonstrate an interdependent relationship within the tumour microenvironment. Our previous study demonstrated that PFD effectively inhibited glycolysis in NSCLC cells, prompting further investigation into its potential antitumour effects in this context. Therefore, the present study aims to investigate the potential antitumour effect of PFD in NSCLC and explore the relationship among TGF-β1, glycolysis and EMT through further experimentation. The antitumour effects of PFD were evaluated using five different NSCLC cell lines and a xenograft tumour model. Notably, PFD demonstrated a significant antitumour effect specifically in highly glycolytic H1299 cells. To elucidate the underlying mechanism, we compared the efficacy of PFD after pretreatment with either TGF-β1 or a TGF-β receptor inhibitor (LY2109761). The energy metabolomics analysis of tumour tissue demonstrated that PFD, a chemosensitizing agent, reduced lactate and ATP production, thereby inhibiting glycolysis and exerting synergistic antineoplastic effects. Additionally, PFD combined with cisplatin targeted TGF-β1 to inhibit glycolysis during EMT and enhanced the chemosensitization of A549 and H1299 cells. The magnitude of the anticancer effect exhibited by PFD was intricately linked to its metabolic properties.

Enhanced antitumour response of gold nanostar-mediated photothermal therapy in combination with immunotherapy in a mouse model of colon carcinoma.

This study investigated the potential of combining PTT with dendritic cell (DC)-based immunotherapy and anti-PD-L1 immune checkpoint blockade (ICB) therapy against colorectal cancer and elucidated the underlying mechanisms. The CT26 tumour-bearing mice were divided into seven treatment groups: control, atezolizumab (A), dendritic cells (DC), pAuNSs-mediated PTT (PTT), PTT combined with atezolizumab (PTT + A), PTT combined with dendritic cells (PTT + DC), and PTT combined with dendritic cells and atezolizumab (PTT + DC + A). Therapeutic efficacy was monitored. PTT upregulated most immune cell membrane receptor genes, including PD-L1, and downregulated genes associated with antigen presentation and T cell activation. Although the PTT + A and PTT + DC treatments showed partial tumour growth retardation, the combination of PTT with DCs and atezolizumab (PTT + DC + A) exhibited the most significant antitumour effect, with a complete remission rate of 50% and prolonged survival. On day 14, tumour samples from non-responsive mice revealed insufficient recruitment of T cells as the reason for uncured tumours. Notably, mice cured with PTT + DC and PTT + DC + A treatments showed no detectable lung nodules. This study demonstrated that the combination of PTT with DC-based immunotherapy and atezolizumab effectively overcomes the non-sensitive nature of CT26 tumours. These findings highlight the potential of this combination approach for colorectal cancer treatment.

New Dipyrroloquinones from a Plant-Derived Endophytic Fungus Talaromyces sp.

Two new dipyrroloquinones, namely talaroterreusinones A (1) and B (2), together with four known secondary metabolites, terreusinone A (3), penicillixanthone A (4), isorhodoptilometrin (5), and chrysomutanin (6), were isolated from the solid culture of the endophytic fungus Talaromyces sp. by integrating mass spectrometry-based metabolic profiling and a bioassay-guided method. Their planar structures and stereochemistry were elucidated by comprehensive spectroscopic analysis including NMR and MS. The absolute configuration at C-1″ of terreusinone A (1) was established by applying the modified Mosher’s method. Compounds 1–6 were evaluated for anti-inflammatory activity and cytotoxicity. As a result, 1–3 inhibited the LPS-stimulated NO production in macrophage RAW264.7 cells, with IC50 values of 20.3, 30.7, and 20.6 µM, respectively. Penicillixanthone A (4) exhibited potent cytotoxic activity against Hep G2 and A549 cell lines, with IC50 values of 117 nM and 212 nM, respectively, and displayed significant antitumour effects in A549 cells by inhibiting the PI3K-Akt-mTOR signalling pathway.

CAR-T cells targeting CD38 and LMP1 exhibit robust antitumour activity against NK/T cell lymphoma

BackgroundNatural killer/T cell lymphoma (NKTCL) is an aggressive lymphoma with a poor prognosis. Chimeric antigen receptor-transduced T (CAR-T) cell therapy has become a promising immunotherapeutic strategy against haematologic malignancies.MethodsIn this study, four CAR-T cell lines (CD38-CAR, LMP1-CAR, CD38-LMP1 tandem CAR 1 and CD38-LMP1 tandem CAR 2) were generated. The effect of CAR-T cells against NKTCL cells was evaluated both in vitro and in vivo. Expression of T cell activation markers and cytokines produced by CAR-T cells were detected by flow cytometry.ResultsThe four CAR-T cell lines could effectively eliminate malignant NKTCL cells. They could be activated and produce inflammatory cytokines in a target-dependent manner. In vivo tests showed that the CAR-T cells exhibited significant antitumour effects in a xenotransplanted NKTCL mouse model.ConclusionsIn summary, four CAR-T cell lines exhibited significant cytotoxicity against NKTCL cells both in vitro and in vivo. These results indicated the effective therapeutic promise of CD38 and LMP1 CAR-T cells in NKTCL.

Discovery of potent heat shock protein 90 (Hsp90) inhibitors: structure-based virtual screening, molecular dynamics simulation, and biological evaluation

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1–4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC50 = 17.64 ± 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs.

Identification of berberine as a potential therapeutic strategy for kidney clear cell carcinoma and COVID-19 based on analysis of large-scale datasets.

Regarding the global coronavirus disease 2019 (COVID)-19 pandemic, kidney clear cell carcinoma (KIRC) has acquired a higher infection probability and may induce fatal complications and death following COVID-19 infection. However, effective treatment strategies remain unavailable. Berberine exhibits significant antiviral and antitumour effects. Thus, this study aimed to provide a promising and reliable therapeutic strategy for clinical decision-making by exploring the therapeutic mechanism of berberine against KIRC/COVID-19. Based on large-scale data analysis, the target genes, clinical risk, and immune and pharmacological mechanisms of berberine against KIRC/COVID-19 were systematically investigated. In total, 1,038 and 12,992 differentially expressed genes (DEGs) of COVID-19 and KIRC, respectively, were verified from Gene Expression Omnibus and The Cancer Genome Atlas databases, respectively, and 489 berberine target genes were obtained from official websites. After intersecting, 26 genes were considered potential berberine therapeutic targets for KIRC/COVID-19. Berberine mechanism of action against KIRC/COVID-19 was revealed by protein-protein interaction, gene ontology, and Kyoto Encyclopedia of Genes and Genomes with terms including protein interaction, cell proliferation, viral carcinogenesis, and the PI3K/Akt signalling pathway. In COVID-19 patients, ACOX1, LRRK2, MMP8, SLC1A3, CPT1A, H2AC11, H4C8, and SLC1A3 were closely related to disease severity, and the general survival of KIRC patients was closely related to ACOX1, APP, CPT1A, PLK1, and TYMS. Additionally, the risk signature accurately and sensitively depicted the overall survival and patient survival status for KIRC. Numerous neutrophils were enriched in the immune system of COVID-19 patients, and the lives of KIRC patients were endangered due to significant immune cell infiltration. Molecular docking studies indicated that berberine binds strongly to target proteins. This study demonstrated berberine as a potential treatment option in pharmacological, immunological, and clinical practice. Moreover, its therapeutic effects may provide potential and reliable treatment options for patients with KIRC/COVID-19.

Synergistic binding of actinomycin D and echinomycin to DNA mismatch sites and their combined anti-tumour effects.

Combination cancer chemotherapy is one of the most useful treatment methods to achieve a synergistic effect and reduce the toxicity of dosing with a single drug. Here, we use a combination of two well-established anticancer DNA intercalators, actinomycin D (ActD) and echinomycin (Echi), to screen their binding capabilities with DNA duplexes containing different mismatches embedded within Watson-Crick base-pairs. We have found that combining ActD and Echi preferentially stabilised thymine-related T:T mismatches. The enhanced stability of the DNA duplex-drug complexes is mainly due to the cooperative binding of the two drugs to the mismatch duplex, with many stacking interactions between the two different drug molecules. Since the repair of thymine-related mismatches is less efficient in mismatch repair (MMR)-deficient cancer cells, we have also demonstrated that the combination of ActD and Echi exhibits enhanced synergistic effects against MMR-deficient HCT116 cells and synergy is maintained in a MMR-related MLH1 gene knockdown in SW620 cells. We further accessed the clinical potential of the two-drug combination approach with a xenograft mouse model of a colorectal MMR-deficient cancer, which has resulted in a significant synergistic anti-tumour effect. The current study provides a novel approach for the development of combination chemotherapy for the treatment of cancers related to DNA-mismatches.

α‑hederin overcomes hypoxia‑mediated drug resistance in colorectal cancer by inhibiting the AKT/Bcl2 pathway.

Currently, chemoresistance is a major challenge that directly affects the prognosis of patients with colorectal cancer (CRC). In addition, hypoxia is associated with poor prognosis and therapeutic resistance in patients with cancer. Accumulating evidence has shown that α‑hederin has significant antitumour effects and that α‑hederin can inhibit hypoxia‑mediated drug resistance in CRC; however, the underlying mechanism remains unclear. In the present study, viability and proliferation assays were used to evaluate the effect of α‑hederin on the drug resistance of CRC cells under hypoxia. Sequencing analysis and apoptosis assays were used to determine the effect of α‑hederin on apoptosis under hypoxia. Western blot analysis and reverse transcription‑quantitative PCR were used to measure apoptosis‑related protein and mRNA expression levels. Furthermore, different mouse models were established to study the effect of α‑hederin on hypoxia‑mediated CRC drug resistance invivo. In the present study, the high expression of Bcl2 in hypoxic CRC cells was revealed to be a key factor in their drug resistance, whereas α‑hederin inhibited the expression of Bcl2 by reducing AKT phosphorylation invitro and invivo, and promoted the apoptosis of CRC cells under hypoxia. By contrast, overexpression of AKT reversed the effect of α‑hederin on CRC cell apoptosis under hypoxia. Taken together, these results suggested that α‑hederin may overcome hypoxia‑mediated drug resistance in CRC by inhibiting the AKT/Bcl2 pathway. In the future, α‑hederin may be used as a novel adjuvant for reversing drug resistance in CRC.

Pirfenidone suppressed triple-negative breast cancer metastasis by inhibiting the activity of the TGF-β/SMAD pathway.

Among breast cancer patients, metastases are the leading cause of death. Despite decades of effort, little progress has been made to improve the treatment of breast cancer metastases, especially triple-negative breast cancer (TNBC). The extracellular matrix plays an important role in tumour growth and metastasis by causing its deposition, remodelling, and signalling. As we know, the process of fibrosis results in excessive amounts of extracellular matrix being deposited within the cells. So, it will be interesting to study if the use of anti-fibrotic drugs in combination with conventional chemotherapy drugs can produce synergistic antitumor effects. In this study, we assessed the efficacy of Pirfenidone (PFD), an FDA-approved medication for the treatment of idiopathic pulmonary fibrosis, on TNBC cells as well as its anti-tumour effects in xenograft tumour model. PFD inhibited in a dose-dependent manner breast cancer cell proliferation, migration, and invasion, while promoted their apoptosis in vitro. PFD also suppressed TGF-β-induced activation of Smad signalling pathway and expression level of EMT-inducing transcription factors (e.g. SNAI2, TWIST1, ZEB1) as well as the mesenchymal genes such as VIMENTIN and N-Cadherin. On the contrary, the expression level of epithelial marker gene E-Cadherin was up-regulated in the presence of PFD. In vivo, PFD alone exerted a milder but significant anti-tumour effect than the chemotherapy drug nanoparticle albumin-bound paclitaxel (nab-PTX) did in the breast cancer xenograft mouse model. Interestingly, PFD synergistically boosted the cancer-killing effect of nab-PTX. Furthermore, Our data suggest that PFD suppressed breast cancer metastasis by inhibiting the activity of the TGFβ/SMAD pathway.

An Overview of Antitumour Activity of Polysaccharides.

Cancer incidence and mortality are rapidly increasing worldwide; therefore, effective therapies are required in the current scenario of increasing cancer cases. Polysaccharides are a family of natural polymers that hold unique physicochemical and biological properties, and they have become the focus of current antitumour drug research owing to their significant antitumour effects. In addition to the direct antitumour activity of some natural polysaccharides, their structures offer versatility in synthesizing multifunctional nanocomposites, which could be chemically modified to achieve high stability and bioavailability for delivering therapeutics into tumor tissues. This review aims to highlight recent advances in natural polysaccharides and polysaccharide-based nanomedicines for cancer therapy.

90Y-CA/SPIONs for dual magnetic hyperthermia-radionuclide nanobrachytherapy of solid tumours

Radiolabelled superparamagnetic iron oxide nanoparticles (SPIONs) are a promising nanomaterial for the development of dual radiation/hyperthermia cancer therapy. To that purpose, flower-shaped SPIONs with an exceptional heating capability were synthesised and coated with citrate, dextran or (3-aminopropyl)triethoxysilane. Both non-coated and coated SPIONs were nontoxic to CT-26 mouse colon cancer cells up to 1.0 mg ml−1 in vitro. In an oscillating magnetic field, citrate-coated SPIONs (CA/SPIONs) displayed the highest heating rate (SAR ∼ 253 W g−1) and the strongest hyperthermia effects against CT-26 cells. Labelling of the CA/SPIONs by the 90Y radionuclide, emitting β− radiation with an average/maximum energy of 0.94/2.23 MeV, and deep tissue penetration generated 90Y-CA/SPIONs intended for the therapy of solid tumours. However, intravenous injection of 90Y-CA/SPIONs in CT-26 xenograft-bearing mice resulted in low tumour accumulation. On the contrary, intratumoural injection resulted in long-term retention at the injection site. A single intratumoural injection of 0.25 mg CA/SPIONs followed by 30-min courses of magnetic hyperthermia for four consecutive days caused a moderate antitumour effect against CT-26 and 4T1 mouse tumour xenografts. Intratumoural application of 1.85 MBq/0.25 mg 90Y-CA/SPIONs, alone or combined with hyperthermia, caused a significant (P ≤ 0.01) antitumour effect without signs of systemic toxicity. The results confirm the suitability of 90Y-CA/SPIONs for monotherapy or dual magnetic hyperthermia-radionuclide nanobrachytherapy (NBT) of solid tumours.

Antitumour effects of apatinib in progressive, metastatic differentiated thyroid cancer (DTC)

PurposeManagement of progressive, metastatic radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC) has been a great challenge due to its poor prognosis and limited treatment options. Recently, apatinib, an orally anti-angiogenic tyrosine kinase inhibitor (TKI) is reported to be useful for treatment of progressive RAIR-DIC. The aim of this study was to evaluate the antitumour effect of apatinib and the combination therapy with radioactive iodine (RAI) in patients with progressive metastatic DTC.MethodsFive patients (all female, mean age 62 ± 8 years, ranged from 51 to 69 years) with distant metastatic DTC (dmDTC) after total thyroidectomy (TTE) and neck lymph node dissection were treated with apatinib at a dose 500 mg per day after 18F-Fluorodeoxyglucose (18F-FDG) PET/CT. The effects of apatinib on DTC were evaluated at 4 ± 1 months after treatment with apatinib. RAI therapy was then initiated. The response to apatinib and the combination therapy with RAI treatment was evaluated by Response Evaluation Criteria in Solid Tumours (RECIST, version 1.1) and metabolic activity using serum thyroglobulin (Tg) and 18F-FDG PET/CT.ResultsPositive 18F-FDG PET/CT results were found in all patients before apatinib therapy. The immunohistochemical analysis of primary tumour tissues showed high expression of vascular endothelial growth factor receptor-2 (VEGFR-2). Four patients with follicular thyroid carcinoma (FTC) showed partial response (PR) with significant decrease in tumour size and maximum standardized uptake value (SUVmax) after 4 ± 1 month’s treatment with apatinib. Further significant reduction of tumour size and SUVmax were observed in three patients after combination therapy with apatinib and RAI. Only one patient with both FTC and papillary thyroid cancer (PTC) demonstrated progressive disease (PD) after treatment with apatinib alone, however, a decrease in tumour size and SUVmax as well as serum Tg levels was achieved after the combination with RAI therapy and apatinib.ConclusionsApatinib had significant antitumour effects on progressive distant metastatic DTC. Moreover, beneficial synergistic and complementary effects were shown when apatinib combined with RAI therapy.Clinical Trial RegistrationNCT 04180007, Registered November 26, 2019.

The mesoionic compound MI-D changes energy metabolism and induces apoptosis in T98G glioma cells

The mesoionic compound 4-phenyl-5-(4-nitro-cinnamoyl)-1,3,4-thiadiazolium-2-phenylamine chloride (MI-D) impairs mitochondrial oxidative phosphorylation and has a significant antitumour effect against hepatocarcinoma and melanoma. This study evaluated the cytotoxic effect of MI-D on T98G glioblastoma cells and investigated whether the impairment of oxidative phosphorylation promoted by MI-D is relevant to its cytotoxic effect. The effects of MI-D on T98G cells cultured in high glucose Dulbecco's modified Eagle's medium (DMEM) HG (glycolysis-dependent) and galactose plus glutamine-supplemented Dulbecco's modified Eagle's medium (DMEM) GAL (oxidative phosphorylation-dependent) were compared. T98G cells grown in DMEM GAL medium exhibited higher respiration rates and citrate synthase activity and lower lactate levels, confirming the metabolic shift to oxidative phosphorylation in these cells. MI-D significantly decreased the cell viability in a dose-dependent manner in both media; however, T98G cells cultured in DMEM GAL medium were more susceptible. The mesoionic significantly inhibited mitochondrial oxidative phosphorylation of glioma cells in both media. At the same time, lactate levels were not altered, indicating an absence of compensatory glycolysis activation. Additionally, MI-D increased the citrate synthase activity of cells in both media, which in DMEM HG-cultivated cells was followed by citrate accumulation. Apoptosis dependent on caspase-3 mediated the toxicity of MI-D on T98G cells. The higher susceptibility of glioma cells cultured in DMEM GAL medium to MI-D indicates that the impairment of mitochondrial functions is involved in mesoionic cytotoxicity. The results of this study indicate the potential use of MI-D for glioblastoma treatment.

Nanoreactor activated in situ for starvation-chemodynamic therapy of breast cancer

The nano-drug delivery system activated by the tumour microenvironment (TME) can effectively treat tumours with low toxicity. Based on a high level of reductive GSH in TME and the different coordination properties of Fe ions, this project intended to prepare a GSH-activated cascade catalytic nanoreactor for breast cancer treatment using Fe3+/Fe2+ as the molecular switch. In this study, the glucose oxidase (GOx) loaded iron alginate nano hydrogel (FeAlg/GOx) was prepared by the simple one-step titration method. Results showed that FeAlg/GOx could remain stable during in vivo circulation to avoid hypoglycaemia. When it reached the targeted tumour site, reductive GSH can reduce Fe3+ to Fe2+. Thereafter, FeAlg/GOx nanogel was broken and GOx was released to consume the essential nutrient glucose (Glu) to achieve tumour starvation therapy. Next, the substrate H2O2 generated by the reaction between GOx and Glu can be catalysed by Fe2+ to produce highly cytotoxic •OH in situ, which could further kill tumour cells. The in vivo pharmacodynamics results demonstrated that compared with the control group (V/V0 = 8.36 ± 1.73), FeAlg/GOx group showed the most significant anti-tumour effect with V/V0 of 3.08 ± 1.06. In conclusion, this "inactivated" FeAlg/GOx nanogel can be converted into "activated" therapeutic substances in situ to achieve starvation-chemodynamic combined treatment for breast cancer.

Monoclonal antibody Daratumumab promotes macrophage-mediated anti-myeloma phagocytic activity via engaging FC gamma receptor and activation of macrophages.

Daratumumab (DAR) is novel human anti-CD38 IgG1, high-affinity human monoclonal antibody having broad-spectrum killing activity. The antibody is recommended to treat multiple myeloma. Recently Antibody-dependent cellular phagocytosis (ADCP) have been identified as the potential mechanism of DAR in addition to complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). In the present study we evaluated the effect of Daratumumab on other effector cells of multiple myeloma. Luciferase+ MM.1R GFP cells were selected for the study. For immune-compromised multiple myeloma tumour xenograft mouse model we used severe combined immunodeficient beige (SCID-beige), NOD SCID gamma (NSG) and C57Bl/6j mice. Bioluminescence imaging was carried by injecting luciferin, and in vivo confocal microscopy was done for tracing bone marrow niches. Spleen and tumours were submitted to immunophenotypic analysis. MTT assay was done for cell proliferation studies. We established tumour xenograft mouse model. It was found that DAR showed significant anti-tumour effect in tumour xenograft multiple myeloma mice. We found that DAR showed anti-tumour activity via Fc-FcγR interaction with macrophages. DAR induced phenotypic activation of macrophages in mice and resulted in ADCP of cancerous cells via interacting Fc-FcγR in vitro. The study suggested that DAR exerted anti-tumour activity in multiple myeloma by interacting with Fc-FcγR.

Combination of the 6-thioguanine and disulfiram/Cu synergistically inhibits proliferation of triple-negative breast cancer cells by enhancing DNA damage and disrupting DNA damage checkpoint

Because of the lack of specific molecular targeted therapies, triple-negative breast cancer (TNBC) has high tumour recurrence and metastasis rates. It is urgent to develop novel chemotherapeutic strategies to improve patient survival. DNA damaging agents have been shown to sensitize cancer to genotoxic chemotherapies. We first found that 6-thioguanine (6-TG) can activate the NF-кB signalling pathway. Our results showed that NF-кB signalling was reduced when cells were treated with 6-TG/disulfiram (DSF)/Cu. DSF/Cu enhanced the 6-TG-mediated inhibition of proliferation. 6-TG/DSF/Cu inhibited cell cycle progression, causing cell cycle arrest in the S phase and G2/M phase. Moreover, the combined effect of 6-TG and DSF/Cu induced apoptosis, and either agent alone was able to induce apoptosis. The accumulation of γH2A indicated that DSF/Cu increased the DNA damage induced by 6-TG. Combined treatment with 6-TG and DSF/Cu synergistically reduced the levels of both phosphorylated and total ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR), suggesting that DSF/Cu promoted 6-TG-induced DNA damage by suppressing ATR protein kinases, therefore enhancing cell apoptosis. In conclusion, we demonstrate that the combination of 6-TG and DSF/Cu exerted a significant synergistic antitumour effect on human TNBC in vitro and in vivo by enhancing DNA damage and disrupting DNA damage checkpoints. We propose that this combination therapy could be a novel strategy for the treatment of TNBC.

SC66 inhibits the proliferation and induces apoptosis of human bladder cancer cells by targeting the AKT/β-catenin pathway.

Bladder cancer (BC) is a major disease of the genitourinary tract, and chemotherapy is one of the main treatments commonly used at present. SC66 is a new type of allosteric AKT inhibitor that is reported to play an effective inhibitory role in the progression of many other types of tumours, but there is no reported research on its role in BC. In this study, we found that SC66 significantly inhibited the proliferation and EMT‐mediated migration and invasion of T24 and 5637 cells. In addition, experiments confirmed that SC66 achieved its antitumour effect by inducing cell apoptosis and affecting the cell cycle. Luciferase assays confirmed that SC66 exerted an antitumour effect through the AKT/β‐catenin signalling pathway, and this inhibitory effect was reversed after the addition of the β‐catenin signalling pathway activator, CHIR‐99021. In addition, animal studies have shown that, compared with the control group, the experimental group with SC66 intraperitoneal injection showed significantly reduced the tumour weight and volume in nude mice with T24 tumours and that SC66 combined with cisplatin achieved better inhibition on tumours. Western blot analysis and immunohistochemistry staining confirmed that SC66 inhibited the EMT process in vivo and induced apoptosis through the AKT/β‐catenin signalling pathway. In conclusion, our study demonstrated that SC66 exerts a significant antitumour effect through the AKT/β‐catenin signalling pathway, thereby providing a new potential treatment for BC.

Anti-tumour effect of neo-antigen-reactive T cells induced by RNA mutanome vaccine in mouse lung cancer

PurposeMutation-specific T-cell response to epithelial cancers and T-cell-based immunotherapy has been successfully used to treat several human solid cancers. We aimed to investigate the anti-tumour effect of neo-antigen-reactive T(NRT) cells induced by RNA mutanome vaccine, which may serve as a feasible and effective therapeutic approach for lung cancer.MethodsWe predicted candidate neo-antigens according to the mutant gene analysis by sequencing the mouse Lewis cells and C57BL/6 mouse tail tissue. RNA vaccine was prepared with the neo-antigens as the template. We assessed antitumor efficacy, cytokine secretion and pathological changes after adoptive transfer of NRT cells in vitro and vivo experiments.ResultsWe identified 10 non-synonymous somatic mutations and successfully generated NRT cells. The percentage of T-cell activation proportion was increased from 0.072% in conventional T cells to 9.96% in NRT cells. Interferon-γ secretion augmented from 17.8 to 24.2% as well. As an in vivo model, adoptive NRT cell infusion could promote active T-cell infiltration into the tumour tissue and could delay tumour progression.ConclusionNRT cells induced by RNA mutanome vaccine exert a significant anti-tumour effect in mouse lung cancer, and adoptive NRT cell therapy might be considered a feasible, effective therapeutic approach for lung cancer.