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Background: Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite advancements in therapeutic methodologies, it still causes a high rate of patient mortality. CD8+ tissue-resident memory T (TRM) cells are strategically positioned to mediate effective anti-tumor responses. However, the characteristic surface molecules and functions of CD8+ TRM cells exhibit significant heterogeneity. Methods: The roles and anti-tumor biological functions of different CD8+ TRM subsets in CRC were determined by clinical CRC samples, bioinformatics analysis, and in vitro experiments including co-culture experiments and transwell migration assays. The signaling pathways that synergistically regulate the differentiation of CD8+ TRM cells were identified by in vitro CD8+ T cell activation and inhibition assays, and the functioning transcription factors were predicted using the UCSC and JASPAR databases. Results: We found that different CD8+ TRM subsets existed in CRC tumor tissues, which were identified as CD69−CD103−CD8+ TRM, CD69+CD103−CD8+ TRM (SP CD8+ TRM), and CD69+CD103+CD8+ TRM (DP CD8+ TRM) subsets. Compared with SP CD8+ TRM cells, increased infiltration of DP CD8+ TRM cells predicted better prognosis and played a protective role mainly in tumor invasion and lymph node metastasis of CRC. DP CD8+ TRM cells expressed higher levels of effector molecules and exerted stronger anti-tumor effects in a FAS/FASL pathway-dependent manner. Additionally, DP CD8+ TRM cells secreted higher levels of CXCL13 and recruited B cells into tumor tissues through the CXCL13/CXCR5 signaling axis to form tertiary lymphoid structures, participating in anti-tumor immune responses. Notch and TGF-β signaling pathways synergistically regulate the differentiation of DP CD8+ TRM cells. Conclusions: We clarified the roles and mechanisms of different CD8+ TRM subsets in CRC and identified that DP CD8+ TRM cells exert stronger anti-tumor effects and predict better prognosis, which provides ideas for developing new clinically available therapeutic targets. [ABSTRACT FROM AUTHOR]

Despite the promise of cold atmospheric plasma (CAP) for cancer treatment, the challenges associated with the treatment of solid tumors and penetration depth limitations remain, restricting its clinical application. Here, biological evidence is provided that the killing effect of CAP treatment is confined to less than 500 µm subcutaneously and the actual biological dose decreased gradually with depth for the first time, indicating that the limited penetration depth has become an urgent problem that demands immediate solutions. Significantly, it is showed that different from high‐dose treatments, CAP decreased the doses to the low‐dose range but still exhibited anti‐tumor effects via mitotic catastrophe. Unlike radiotherapy or chemotherapy, low‐dose CAP treatment induces mitochondrial structural damage and dysfunction, disrupts energy metabolism and redox balance, and results in mitotic catastrophe. Collectively, these findings suggest that better understanding and taking full advantage of the dose‐response gradient effect of CAP is a potential strategy to prompt its clinical application beyond improving CAP penetration. [ABSTRACT FROM AUTHOR]

Objective: To prepare and characterize transferrin (Tf)-modified liposomes (Lipo) encapsulating the photosensitizing agent neoindocyanine green (IR820), and to investigate their effects on breast cancer 4T1 cells as well as in a breast cancer mouse model. Methods: Photosensitive liposomes, IR820@Lipo and Tf-IR820@Lipo, were synthesized using thin film dispersion, with encapsulation efficiency assessed via UV detection. The physicochemical properties were analyzed using transmission electron microscopy (TEM) and particle size analysis. Uptake by breast cancer 4T1 cells was evaluated through confocal laser scanning microscopy and flow cytometry, while cell proliferation inhibition was measured using the CCK8 assay. Differences in intracellular fluorescence intensity were utilized to assess drug aggregation in vivo through small animal imaging techniques. The anticancer efficacy and potential side effects of the formulations were examined through pharmacodynamic studies conducted in vivo. Results: The mean particle sizes of IR820@Lipo and Tf-IR820@Lipo were found to be 84.30 ± 15.66 nm and 116.20 ± 14.68 nm respectively, with zeta potentials of −8.21 ± 2.06 mV for IR820@Lipo and −5.23 ± 1.19 mV for Tf-IR820@Lipo; TEM revealed that the liposomes exhibited a spheroid morphology with uniform distribution across samples; encapsulation efficiencies reached 86.38 ± 0.99% for IR820@Lipo and an impressive 93.81 ± 1.06% for Tf-IR820@Lipo; notably, Tf-IR820@Lipo significantly inhibited proliferation while promoting apoptosis of the 4T1 cells upon laser irradiation; reactive oxygen species (ROS) detection indicated enhanced fluorescence intensity within the treated cells under light exposure when utilizing both formulations; in vivo experiments demonstrated tumor accumulation of both IR820@Lipo and Tf-IR820@Lipo, indicating effective tumor targeting within a breast cancer mouse model; pharmacodynamic assessments revealed that Tf-IR820@Lipo exhibited superior inhibitory effects against breast cancer without causing liver or kidney dysfunctions in mice nor presenting significant toxic side effects overall. Conclusion: Given its high targeting capability, potent efficacy, and low toxicity profile, Tf-IR820@Lipo holds promise as a novel therapeutic agent for breast cancer treatment when combined with photodynamic therapy (PDT), potentially offering new avenues for patient management. [ABSTRACT FROM AUTHOR]

Abstract Objective To prepare and characterize transferrin (Tf)-modified liposomes (Lipo) encapsulating the photosensitizing agent neoindocyanine green (IR820), and to investigate their effects on breast cancer 4T1 cells as well as in a breast cancer mouse model. Methods Photosensitive liposomes, IR820@Lipo and Tf-IR820@Lipo, were synthesized using thin film dispersion, with encapsulation efficiency assessed via UV detection. The physicochemical properties were analyzed using transmission electron microscopy (TEM) and particle size analysis. Uptake by breast cancer 4T1 cells was evaluated through confocal laser scanning microscopy and flow cytometry, while cell proliferation inhibition was measured using the CCK8 assay. Differences in intracellular fluorescence intensity were utilized to assess drug aggregation in vivo through small animal imaging techniques. The anticancer efficacy and potential side effects of the formulations were examined through pharmacodynamic studies conducted in vivo. Results The mean particle sizes of IR820@Lipo and Tf-IR820@Lipo were found to be 84.30 ± 15.66 nm and 116.20 ± 14.68 nm respectively, with zeta potentials of −8.21 ± 2.06 mV for IR820@Lipo and −5.23 ± 1.19 mV for Tf-IR820@Lipo; TEM revealed that the liposomes exhibited a spheroid morphology with uniform distribution across samples; encapsulation efficiencies reached 86.38 ± 0.99% for IR820@Lipo and an impressive 93.81 ± 1.06% for Tf-IR820@Lipo; notably, Tf-IR820@Lipo significantly inhibited proliferation while promoting apoptosis of the 4T1 cells upon laser irradiation; reactive oxygen species (ROS) detection indicated enhanced fluorescence intensity within the treated cells under light exposure when utilizing both formulations; in vivo experiments demonstrated tumor accumulation of both IR820@Lipo and Tf-IR820@Lipo, indicating effective tumor targeting within a breast cancer mouse model; pharmacodynamic assessments revealed that Tf-IR820@Lipo exhibited superior inhibitory effects against breast cancer without causing liver or kidney dysfunctions in mice nor presenting significant toxic side effects overall. Conclusion Given its high targeting capability, potent efficacy, and low toxicity profile, Tf-IR820@Lipo holds promise as a novel therapeutic agent for breast cancer treatment when combined with photodynamic therapy (PDT), potentially offering new avenues for patient management.

Polysaccharides derived Grifola frondosa (GFP) possess diverse biological activities. In this study, a GFP fraction (coded as GFP1) purified from the crude GFP prepared by an H2O2/Vc-assisted extraction method was investigated for its inhibitory effects on lung cancer cells (H1975) and immunomodulatory activities in RAW264.7 macrophages. It was found that GFP1 significantly inhibited the proliferation, induced the cell apoptosis, and suppressed the migration and invasion of H1975 cells. Additionally, GFP1 increased the intracellular reactive oxygen species (ROS) levels, reduced mitochondrial membrane potential, and upregulated the expressions of caspase-3, caspase-8, and caspase-9. RT-qPCR analysis indicated that GFP1 downregulated the mRNA expression levels of PI3K, ERK2, ERK1, FAK, and RAF. GFP1 was also found to upregulate the mRNA expressions of nitric oxide synthase (iNOS), IL-1β, IL-6, and TNF-α, thereby promoting the release of nitric oxide and secretion of the corresponding cytokines. Western blot experiments indicated that GFP1 activated the NF-κB signaling pathway through the promotion of p65 phosphorylation, exerting immunomodulatory effects. Therefore, GFP1 exerted anti-tumor effect by both direct cytotoxic effects on tumor cells and modulating the body's immune function. These findings provide new insights for the development of functional foods and effective and safe anti-tumor drugs. [ABSTRACT FROM AUTHOR]

Abstract Despite the promise of cold atmospheric plasma (CAP) for cancer treatment, the challenges associated with the treatment of solid tumors and penetration depth limitations remain, restricting its clinical application. Here, biological evidence is provided that the killing effect of CAP treatment is confined to less than 500 µm subcutaneously and the actual biological dose decreased gradually with depth for the first time, indicating that the limited penetration depth has become an urgent problem that demands immediate solutions. Significantly, it is showed that different from high‐dose treatments, CAP decreased the doses to the low‐dose range but still exhibited anti‐tumor effects via mitotic catastrophe. Unlike radiotherapy or chemotherapy, low‐dose CAP treatment induces mitochondrial structural damage and dysfunction, disrupts energy metabolism and redox balance, and results in mitotic catastrophe. Collectively, these findings suggest that better understanding and taking full advantage of the dose‐response gradient effect of CAP is a potential strategy to prompt its clinical application beyond improving CAP penetration.

Objective To evaluate the stability, safety and immune enhancement and anti-tumor effects of Wilms' tumor gene 1 (WT1) peptide combined with AddaVaxTM emulsion vaccine for acute myeloid leukemia. Methods The stability of WT1 peptide in the adjuvant vaccine was evaluated using MALDI-TOF-MS time-of-flight mass spectrometry. Female C57BL/6 mice were randomly divided into PBS group, WT1 peptide group, and WT1 peptide+AddaVaxTM emulsion adjuvant vaccine group. The immunization was performed at a dose of 50 μg/mouse for antigen and 50 μg/mouse for adjuvant, with intramuscular injection on days 0, 14, and 28. HE staining was used to assess the toxicity of intramuscular vaccination on mouse organ tissues. Cytokine levels were detected by ELISA, and the number of IFN-γ-secreting splenocytes was measured by ELISpot. Flow cytometry was employed to detect the maturation of bone marrow-derived dendritic cells (BMDCs) promoted by the vaccine in vitro and the promotion for lymphocyte activation, and H-2Db WT1 tetramer was utilized to detect the proportion of specific CD8+ T cells. After establishing a mouse leukemia tumor model using the C1498-mWT1 stable cell line, the anti-tumor effects of the vaccine for prevention and treatment were evaluated. Results The WT1 peptide stably existed in the vaccine without causing significant organ tissue changes in mice after intramuscular injection. Compared to the mice immunized with WT1 aqueous solution, the mice after intramuscular injection of the WT1 peptide emulsion adjuvant vaccine showed stronger immune responses of Th1 cells, including IFN-γ and TNF-α, as well as Th17 cells of IL-17A (P

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models.

In this study, glucanase and mannanase were selected to hydrolysis DOP to obtain low molecular weight DOP (LMWDOP), namely glucanase-hydrolysis Dendrobium officinale polysaccharides (GDOP) and mannanase-hydrolysis Dendrobium officinale polysaccharides (MDOP). The antitumor activity of LMWDOPs and its effect on tumor immune microenvironment were investigated. The growth of transplantable S180 sarcoma in mice was significantly inhibited by GDOP, and MDOP in a dose-dependent manner compared with the model group (P

Simple Summary: Our in vitro and in vivo experiments demonstrated that bladder tumor growth can be attenuated even with the intravesical administration of lidocaine as a single agent, and that the mechanism involves autophagy influx. These findings support the potential of intravesical lidocaine injection for clinical application. Further successful validation using human-derived bladder cancer cell lines and confirmation of the effectiveness of intravesical lidocaine administration in patients in clinical trials could help establish lidocaine as a novel adjuvant treatment for bladder cancer. Lidocaine exerts potential anti-tumor effects on various cancer cell lines, and its intravesical instillation is considered safer than intravenous administration for bladder cancer. However, the mechanisms underlying its anti-tumor effects have not been fully elucidated. Here, we aimed to elucidate the anti-tumor molecular mechanisms of lidocaine in bladder cancer cells and a xenograft model to substantiate the efficacy of its intravesical administration. We investigated the anti-proliferative and autophagyinducing activities of lidocaine in Nara Bladder Tumor No. 2 (NBT-II) rat bladder carcinoma cells using cell viability, flow cytometry, a wound healing assay, and western blotting. We also established a xenograft mouse model of bladder cancer, and cancer growth was examined using in vivo bioluminescence imaging. Lidocaine decreased cell viability, induced G0/G1 phase cell cycle arrest, and inhibited cell migration partially via glycogen synthase kinase (GSK) 3β phosphorylation. Moreover, a combination of lidocaine and SB216763 (a GSK3β inhibitor) suppressed autophagy-related protein expression. Bafilomycin-A1 with lidocaine significantly enhanced microtubule-associated protein 1A/1B-light chain (LC3B) expression; however, it decreased LC3B expression in combination with 3-methyladenine compared to lidocaine alone. In the xenograft mouse model, the bladder cancer volume was reduced by lidocaine. Overall, lidocaine exerts anti-proliferative effects on bladder cancer via an autophagy-inducing mechanism. [ABSTRACT FROM AUTHOR]

Malignant melanoma is a high-grade aggressive skin tumor with an increasing incidence and mortality rates worldwide. Chemotherapeutic drugs such as doxorubicin have limited efficacy against melanoma due to their poor sensitivity, severe side effects, and drug resistance. Recent studies have shown that combinations of immunotherapy and chemotherapy have a synergistic effect in enhancing the anti-tumor effect. Here, we have developed liposomes co-loaded with chlorogenic acid (CA) and doxorubicin (DOX), modified with sialic acid-octadecylamine conjugate (SA-ODA), designated CA-DOX-SAL, that facilitate drug delivery by recognizing Siglec-1 receptor on TAMs. The physicochemical studies revealed the particle size and zeta potential of CA-DOX-SAL as 128.3 ± 0.8 nm and − 4.33 ± 0.50 mV, respectively. In vitro, CA-DOX-SAL demonstrated robust cellular uptake through SA receptor-mediated tumor-associated macrophages (TAM) targeting and exerted greater cytotoxicity on tumor cells. In vivo, targeted liposomes were found to accumulate in the tumor area, leading to an improvement in anti-tumor efficacy. In addition, CA-DOX-SAL effectively inhibited B16F10 melanoma tumor growth by stimulating the transition from tumor-promoting M2-type to anti-tumor M1-type and directly killing tumor cells. Overall, the co-delivery of immunomodulatory CA and chemotherapeutic DOX presents a promising therapeutic strategy to enhance clinical outcomes in the treatment of melanoma. [ABSTRACT FROM AUTHOR]

Reversine, or 2-(4-morpholinoanilino)-6-cyclohexylaminopurine, is a 2,6-disubstituted purine derivative. This small molecule shows anti-tumor potential by playing a central role in the inhibition of several kinases related to cell cycle regulation and cytokinesis. In this study, systematic review demonstrated the feasibility and pharmacological mechanism of anti-tumor effect of reversine. Firstly, we grafted MNNG/HOS, U-2 OS, MG-63 osteosarcoma cell aggregates onto chicken embryonic chorioallantoic membrane (CAM) to examine the tumor volume of these grafts after reversine treatment. Following culture, reversine inhibited the growth of osteosarcoma cell aggregates on CAM significantly. In vitro experiment, reversine suppressed osteosarcoma cell viability, colony formation, proliferation, and induced apoptosis and cell cycle arrest at G0-G1 phase. Scratch wound assay demonstrated that reversine restrained cell migration. Reversine increased the protein expression of E-cadherin. The mRNA expression of Rac1, RhoA, CDC42, PTK2, PXN, N-cadherin, Vimentin in MNNG/HOS, U-2 OS and MG-63 cells were suppressed and PTEN increased after reversine treatment. Network pharmacology prediction, molecular docking and systematic review revealed MEK1 can be used as an effective target for reversine to inhibit osteosarcoma. Western blot results show the regulation of MEK1 and ERK1/2 by reversine was not consistent in different osteosarcoma cell lines, but we found that reversine significantly inhibited the protein expression of MEK1 in MNNG/HOS, U-2 OS and MG-63. All these suggested that reversine can exert its anti-tumor effect by targeting the expression of MEK1.

Abstract Background Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML. Methods The up‐regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used. Results Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small‐molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS‐5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS‐5584 induced apoptosis and cycle arrest of AML cells in a dose‐ and time‐dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS‐5584 treatment, with 287 proteins being down‐regulated and 71 proteins being up‐regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS‐5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS‐5584 caused a significant reduction in the half‐maximal inhibitory concentration (IC50) of VS‐5584 on AML cells. In vivo, experiments suggested that VS‐5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein. Conclusions Taken together, the PI3K/mTOR inhibitor VS‐5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML.

Wide resection is the main treatment for sarcomas; however, when they are located near major nerves, their sacrifices might affect limb function. The efficacy of ethanol adjuvant therapy for sarcomas has not been established. In this study, the anti-tumor effect of ethanol, as well as its neurotoxicity, were assessed. In vitro anti-tumor effect of ethanol as evaluated using MTT, wound healing, and invasion assays on a synovial sarcoma cell line (HS-SY-II). In vivo, an assessment was conducted in nude mice (implanted with subcutaneous HS-SY-II) treated with different ethanol concentrations after surgery with a close margin. Sciatic nerve neurotoxicity was assessed with electrophysiological and histological examination. In vitro, ethanol concentrations at 30% and higher showed cytotoxic effects in MTT assay and markedly reduced migration and invasive ability of HS-SY-II. In vivo, both 30% and 99.5% ethanol concentrations, compared to 0% concentration, significantly reduced the local recurrence. However, in the group treated with 99.5% ethanol, nerve conduction tests showed prolonged latency and decreased amplitude, and morphological changes suggestive of nerve degeneration were observed in the sciatic nerve, while the 30% ethanol did not cause neurological damage. In conclusion, 30% is the optimal concentration for ethanol adjuvant therapy after close-margin surgery for sarcoma.

Secreted phospholipases A2 are snake-venom proteins with many biological activities, notably anti-tumor activity. Phospholipases from the same snake type but different geographical locations have shown similar biochemical and biological activities with minor differences in protein sequences. Thus, the discovery of a new phospholipase A2 with unique characteristics identified in a previously studied venom could suggest the origins of these differences. Here, a new Group II secreted phospholipase A2 (Cc-PLA2-II) from the snake venom of Saudi Cerastes cerastes gasperetti was isolated and characterized. The purified enzyme had a molecular weight of 13.945 kDa and showed high specific activity on emulsified phosphatidylcholine of 1560 U/mg at pH 9.5 and 50 °C with strict calcium dependence. Interestingly, stability in extreme pH and high temperatures was observed after enzyme incubation at several pH levels and temperatures. Moreover, a significant dose-dependent cytotoxic anti-tumor effect against six human cancer cell lines was observed with concentrations of Cc-PLA2 ranging from 2.5 to 8 µM. No cytotoxic effect on normal human umbilical-vein endothelial cells was noted. These results suggest that Cc-PLA2-II potentially has angiogenic activity of besides cytotoxicity as part of its anti-tumor mechanism. This study justifies the inclusion of this enzyme in many applications for anticancer drug development. [ABSTRACT FROM AUTHOR]

[Display omitted] Herein, ultra dispersed and stably suspended nanodiamonds (NDs) were demonstrated to have a high load capacity, sustained release, and ability to serve as a biocompatible vehicle for delivery anticancer drugs. NDs with size of 50–100 nm exhibited good biocompatibility in normal human liver (L-02) cells. In particular, 50 nm ND not only promoted the noticeable proliferation of the L-02 cells but also can effectively inhibited the migration of human liver carcinoma (HepG2) cells. The gambogic acid-loaded nanodiamond (ND/GA) complex assembled by π–π stacking exhibits ultrasensitive and apparent suppression efficiency on the proliferation of HepG2 cells through high internalization and less efflux compared to free GA. More importantly, the ND/GA system can significantly increase the intracellular reactive oxygen species (ROS) levels in HepG2 cells and thus induce the cell apoptosis. The increase in intracellular ROS levels causes damage to the mitochondrial membrane potential (MMP) and activates cysteinyl aspartate specific proteinase 3 (Caspase-3) and cysteinyl aspartate specific proteinase 9 (Caspase-9), which leads to the occurrence of apoptosis. In vivo experiments also confirmed that the ND/GA complex has a much higher anti-tumor capability than free GA. Thus, the current ND/GA system is promising for cancer therapy. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a highly aggressive form of cancer that is frequently diagnosed in adults and small molecule inhibitors have gained significant attention as a potential treatment option for AML. Methods: The up‐regulated genes in AML were identified through bioinformatics analysis. Potential candidate agents were selected through pharmacogenomics analysis. Proteomic experiments were conducted to determine the molecular mechanism after inhibitor treatment. To evaluate drug synergy, both cellular functional experiments and an AML mouse model were used. Results: Through bioinformatics analysis, we conducted a screening for genes that are highly expressed in AML, which led to the identification of nine small‐molecule inhibitors. Among these inhibitors, the PI3K/mTOR inhibitor VS‐5584 demonstrated significant effectiveness in inhibiting AML cell proliferation at low concentrations. Further testing revealed that VS‐5584 induced apoptosis and cycle arrest of AML cells in a dose‐ and time‐dependent manner. Proteomics analysis showed significant changes in protein expression profiles of AML cells after VS‐5584 treatment, with 287 proteins being down‐regulated and 71 proteins being up‐regulated. The proteins that exhibited differential expression were primarily involved in regulating the cell cycle and apoptosis, as determined by GO analysis. Additionally, KEGG analysis indicated that the administration of VS‐5584 predominantly affected the P53 and SIRT2 signaling pathways. The use of SIRT2 inhibitor SirReal2 alongside VS‐5584 caused a significant reduction in the half‐maximal inhibitory concentration (IC50) of VS‐5584 on AML cells. In vivo, experiments suggested that VS‐5584 combined with SirReal2 suppressed tumor growth in the subcutaneous model and extended the survival rate of mice injected with tumor cells via tail vein. Conclusions: Taken together, the PI3K/mTOR inhibitor VS‐5584 was effective in suppressing AML cell proliferation. PI3K/mTOR inhibitor combined with SIRT2 inhibitor exhibited a synergistic inhibitory effect on AML cells. Our findings offer promising therapeutic strategies and drug candidates for the treatment of AML. [ABSTRACT FROM AUTHOR]

Objective: To investigate the influences of astragalus polysacharide(APS) on anti-tumor effect and immune function of esophageal carcinoma(EPC) rats through phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt) signal pathway. Methods: 50 healthy 6-week-old SPF grade SD rats were randomly divided into model group(group M), cisplatin group(group S), APS low dosage group(group APSL), APS middle dosage group(group APSM) and APS high dosage group(group APSH), with 10 rats in each group. EPC model rats were established by transplantation of Eca109 cells, and 3mg/kg cisplatin and 100, 200, 400 mg/kg APS were given to each rat. Tumor volume and tumor mass were detected, tumor growth inhibition rate, thymus index and spleen index were calculated, histomorphology was observed by HE staining, CD3+, CD4+, CD8+T lymphocyte population were detected by flow cytometer, the relative expressions of PI3K and Akt protein were detected by Western blot. Results: After intervention, tumor volume and tumor mass of group S and group APS were all lower than group M(P＜0.05); the tumor volume and tumor mass of group S and group APSH were all lower than group APSM and group APSL(P＜0.05); the tumor growth inhibition rate of each APS group were 45.59%, 32.35% and 17.65%. The thymus index and spleen index of group S were lower than group M(P＜0.05); the thymus index and spleen index of each APS group were all higher than group S(P＜0.05); while group APSH and APSM were higher than group M(P＜0.05). The CD3+, CD4+ and CD4+/CD8+ of each APS group were higher than group S and group M, while the CD8+ was lower(P＜0.05); group APSH, APSM and APSL also had statistical differences(P＜0.05). The relative expressions of PI3K/Akt signal pathway protein of group S and each APS group were lower than group M(P＜0.05); group APSH, APSM and APSL also had statistical differences(P＜0.05). Conclusion: APS exerts inhibition effect on EPC via regulation of PI3K/Akt signal pathway and immune function, which can provide new thought and theoretical basis for clinical treatment of EPC. [ABSTRACT FROM AUTHOR]

Ginkgo biloba (GB) has enormous bioactives with anti‐bacterial, anti‐oxidant, anti‐cancer, and immune‐stimulating properties, with global sales exceeding $10 billion. The terpene trilactones (ginkgolides A, B, and C) and flavonoids (mostly quercetin, isorhamnetin, and kaempferol) have received the most significant focus in GB research to date, whereas other bioactive compounds such as ginkgols and bilobols with various bioactivities such as anti‐viral, anti‐oxidant, and anti‐tumor actions have received less attention. Therefore, for the first time, this review focused on GB ginkgols, bilobols extraction, and bioactivities. This review showed that petroleum ether and acetone extraction had successfully extracted ginkgols and bilobols. Furthermore, bioactivities such as anti‐tumor activity and so on have been demonstrated for ginkgols, and bilobols, providing theoretical justification for ginkgols and bilobol as raw material for nutraceuticals, functional foods, pharmaceuticals, and cosmeceuticals. Future research could look into other biological applications (such as anti‐oxidant, antitoxins, anti‐radiation, anti‐microbial, and antiparasite) and their applications in the pharmaceutical, cosmetic, and nutraceutical industries. Besides, the primary research should be on developing green and effective methods for preparing ginkgols and bilobols and fully utilizing their pharmacological activity. This will also provide a new avenue for efficiently utilizing these bioactive compounds. [ABSTRACT FROM AUTHOR]

Abstract Purpose Wasabi is a traditional plant seasoning with an anti-septic function. Recent studies revealed several functions of Wasabi, such as anti-inflammation; however, the anti-tumor effect against endometrial carcinoma (EMC) cells has not been examined. In the present study, we investigated the anti-tumor effect of 6-(methylsulfinyl) hexyl isothiocyanate (6-MITC), a major chemical compound of Wasabi, against various EMC cell lines in vitro and in vivo. Methods The effect of 6-MITC on cell viability was measured by the WST-1 assay in EMC and HUVEC cells. The impact of 6-MITC oral administration in nude mice was measured to assess the growth of the EMC xenograft and natural killer (NK) cell activity in the spleen. Results The addition of 6-MITC suppressed the proliferation of EMC cells (Ishikawa, HEC265, HEC108, KLE, and HEC1B) dose-dependently, but not HUVEC cells. 6-MITC (5 µM) enhanced the cisplatin sensitivity of EMC cells. 6-MITC induced apoptosis in a dose-dependent fashion in EMC cells other than HEC1B cells and was associated with increased expression of cleaved-caspase3 and decreased expression of BCL2. Oral administration of 6-MITC (2 and 4 µmol/kg) to Ishikawa and HEC1B xenografting mice resulted in a reduced tumor volume compared with the control (P

Macrophages are the primary immune cells in the tumor microenvironment, where they exhibit the immunosuppressive M2 phenotype to support tumor development. Reshaping M2 tumor-associated macrophages (TAMs) into the antitumor M1 phenotype is a promising approach in tumor immunotherapy. We had previously demonstrated that a high-purity homogeneous Sambucus adnata wall polysaccharide SPS-1 isolated from S. adnata exerted a good immunoregulatory effect. In the present study, we explored whether SPS-1 can remodel TAMs and inhibit the development of lung cancer. In the tumor mouse model transplanted with Lewis lung cancer, SPS-1 promoted the apoptosis of tumor cells and inhibited angiogenesis in tumor tissues by remodeling M2 macrophages in the tumor microenvironment into M1 macrophages, which exerted effective antitumor effects. Therefore, SPS-1 may be used as a novel immunostimulator in tumor immunotherapy, and our study also provides a novel pathway and material for reshaping immune defense to prevent and treat tumors. [ABSTRACT FROM AUTHOR]

Wide resection is the main treatment for sarcomas; however, when they are located near major nerves, their sacrifices might affect limb function. The efficacy of ethanol adjuvant therapy for sarcomas has not been established. In this study, the anti-tumor effect of ethanol, as well as its neurotoxicity, were assessed. In vitro anti-tumor effect of ethanol as evaluated using MTT, wound healing, and invasion assays on a synovial sarcoma cell line (HS-SY-II). In vivo, an assessment was conducted in nude mice (implanted with subcutaneous HS-SY-II) treated with different ethanol concentrations after surgery with a close margin. Sciatic nerve neurotoxicity was assessed with electrophysiological and histological examination. In vitro, ethanol concentrations at 30% and higher showed cytotoxic effects in MTT assay and markedly reduced migration and invasive ability of HS-SY-II. In vivo, both 30% and 99.5% ethanol concentrations, compared to 0% concentration, significantly reduced the local recurrence. However, in the group treated with 99.5% ethanol, nerve conduction tests showed prolonged latency and decreased amplitude, and morphological changes suggestive of nerve degeneration were observed in the sciatic nerve, while the 30% ethanol did not cause neurological damage. In conclusion, 30% is the optimal concentration for ethanol adjuvant therapy after close-margin surgery for sarcoma. [ABSTRACT FROM AUTHOR]

Chemokines are a group of cytokines involved in the mobilization of leukocytes, which play a role in host defense and a variety of pathological conditions, including cancer. Interferon (IFN)-inducible chemokines C-X-C motif ligand 9 (CXCL), CXCL10, and CXCL11 are anti-tumor chemokines; however, the differential anti-tumor effects of IFN-inducible chemokines are not completely understood. In this study, we investigated the anti-tumor effects of IFN-inducible chemokines by transferring chemokine expression vectors into a mouse squamous cell carcinoma cell line, SCCVII, to generate a cell line stably expressing chemokines and transplanted it into nude mice. The results showed that CXCL9- and CXCL11-expressing cells markedly inhibited tumor growth, whereas CXCL10-expressing cells did not inhibit growth. The NH2-terminal amino acid sequence of mouse CXCL10 contains a cleavage sequence by dipeptidyl peptidase 4 (DPP4), an enzyme that cleaves the peptide chain of chemokines. IHC staining indicated DPP4 expression in the stromal tissue, suggesting CXCL10 inactivation. These results suggest that the anti-tumor effects of IFN-inducible chemokines are affected by the expression of chemokine-cleaving enzymes in tumor tissues. [ABSTRACT FROM AUTHOR]

Osteosarcoma, the most common primary malignant bone tumor, is characterized by malignant cells producing osteoid or immature bone tissue. Most osteosarcoma patients require reconstructive surgery to restore the functional and structural integrity of the injured bone. Metal orthopedic implants are commonly used to restore the limb integrity in postoperative patients. However, conventional metal implants with a bioinert surface cannot inhibit the growth of any remaining cancer cells, resulting in a higher risk of cancer recurrence. Herein, we fabricate a selenium-doped TiO2 nanotube array (Se-doped TNA) film to modify the surface of medical pure titanium substrate, and evaluate the anti-tumor effect and biocompatibility of Se-doped TNA film. Moreover, we further explore the anti-tumor potential mechanism of Se-doped TNA film by studying the behaviors of human osteosarcoma cells in vitro. We provide a new pathway for achieving the anti-tumor function of orthopedic implants while keeping the biocompatibility, aiming to suppress the recurrence of osteosarcoma.

Abstract Background Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies. Several chemotherapies employing fluorouracil (5-FU) and gemcitabine were attempted, but the survival rate was extremely low. Resveratrol (RVT), known as a polyphenol compound and phytoalexin, was demonstrated to induce intrinsic apoptosis in cancer cells. However, its low delivery performance and efficiency at tumor sites remain an obstacle to exploit RVT as a drug. To address these problems, we bio-conjugated resveratrol with gold nanoparticles (GNPs) via polyvinylpyrrolidone as a cross-linker (RVT@PVP-GNPs) and investigated whether the fabrications could enhance the delivery performance and anti-tumor efficacy of RVT. Results The fabrication of gold nanoparticles (GNPs) and bio-conjugated with resveratrol (RVT@PVP-GNPs) was conducted firstly. TEM image, spectrophotometry and zeta-potential revealed that the GNPs and RVT@PVP-GNPs having a size of approximately 40 nm were successfully synthesized and exhibited moderate stability. GNPs alone represented no damage in PANC-1 cells and moreover diminished the cytotoxicity of RVT in Raw264.7 murine macrophage cells, demonstrating the superiority of gold nanoparticles as a drug carrier. Evaluation using dialysis showed a burst release rate of RVT within 96 h at pH 5.0, demonstrating the possibility of enhanced efficiency of RVT delivery through blood vessels to the tumor. The RVT@PVP-GNPs induced increased rates of S-phase cell cycle arrest and apoptosis compared with free RVT. Notably, RVT@PVP-GNPs diminished the proportion of necrotic cells, whereas free RVT increased it. We also demonstrated that the RVT@PVP-GNPs may induce an apoptosis via intrinsic mitochondria with higher degree compared with free RVT, indicating the possibility of enhanced anti-tumor agents. In animal studies, RVT@PVP-GNPs conjugated with AS1411 aptamer induced efficient tumor volume suppression without accumulation in or damage to the kidneys in vivo. Conclusions The results demonstrate that RVT@PVP-GNPs enhance the anti-tumor efficacy of free RVT by activating the intrinsic apoptotic pathway and could be considered as potential anti-tumor drug candidates against pancreatic cancer cells.

Objective To investigate the photodynamic antitumor activity and chemical characteristics of pheophorbide A (PPBa)in vitro. Methods Breast cancer cells (MCF-7), lung cancer cells (A549), cervical cancer cells (HeLa), and three kinds of hepatoma cells (HepG2, hep3B and sk-Hep1) were planted in 96-well plates.The effects of light and dark toxicity, light intensity, and drug concentration on the phototoxicity of PPBa were investigated by MTT, and the uptake of PPBa was observed by Hoechst staining under a confocal microscope.The production of singlet oxygen was observed by flow cytometry and confocal microscopy with the reactive oxygen species detection kit.The photobleaching of PPBa was investigated by measuring the absorbance by a microplate reader according to the luminescence characteristics of PPBa. Results PPBa showed strong phototoxicity and low dark toxicity to six kinds of cancer cells, and IC50 values to cancer cells were as follows: MCF-7:1.033 μmol/L, A549:1.911 μmol/L, HeLa: 2.319 μmol/L, HepG2:2.015 μmol/L, Hep3B: 2.089 μmol/L, sk-Hep1:2.467 μmol/L.The main uptake site of PPBa was the cytoplasm.The production of singlet oxygen was strongly dependent on the administration concentration, and photobleaching was very low. Conclusion For the six kinds of cancer cells, PPBa has the highest phototoxicity to breast cancer cells (MCF-7), with excellent properties and ideal photosensitizer characteristics.

Activating transcription factors, ATFs, are a group of bZIP transcription factors that act as homodimers or heterodimers with a range of other bZIP factors. In general, ATFs respond to extracellular signals, indicating their important roles in maintaining homeostasis. The ATF family includes ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7. Consistent with the diversity of cellular processes reported to be regulated by ATFs, the functions of ATFs are also diverse. ATFs play an important role in cell proliferation, apoptosis, differentiation and inflammation-related pathological processes. The expression and phosphorylation status of ATFs are also related to neurodegenerative diseases and polycystic kidney disease. Various miRNAs target ATFs to regulate cancer proliferation, apoptosis, autophagy, sensitivity and resistance to radiotherapy and chemotherapy. Moreover, ATFs are necessary to maintain cell redox homeostasis. Therefore, deepening our understanding of the regulation and function of ATFs will provide insights into the basic regulatory mechanisms that influence how cells integrate extracellular and intracellular signals into genomic responses through transcription factors. Under pathological conditions, especially in cancer biology and response to treatment, the characterization of ATF dysfunction is important for understanding how to therapeutically utilize ATF2 or other pathways controlled by transcription factors. In this review, we will demonstrate how ATF1, ATF2, ATF3, ATF4, ATF5, ATF6, and ATF7 function in promoting or suppressing cancer development and identify their roles in tumour immunotherapy.

Patients receiving chemotherapy by intravenous (i.v.) or oral administration of anticancer drugs often experience side effects. In this study, an electro-osmotic flow (EO) pump was used for the direct administration of an anticancer drug with minimum side effects. Doxorubicin hydrochloride (DXR) was used as an anticancer drug, and its antitumor effect and toxicity were evaluated in comparison with i.v. administration. Balb/c female mice were subcutaneously transplanted with a breast cancer cell line (4T1/Luc) stably expressing luciferase, and 20 μL of DXR solution (1.0 mg/mL) was administered intratumorally (i.t.) at a slow rate (0.6 µL/min) using an EO pump or rapidly using a syringe. For comparison, 100 μL of DXR solution was injected through the tail vein at the same dose and a 5-times higher dose. A tumor growth inhibitory effect without significant weight loss was observed with direct i.t. administration of DXR using an EO pump. On the other hand, no suppressive tumor growth effect was observed with i.v. administration of DXR at the same dose. Although there was no significant difference in the suppression effect on tumor growth between i.t. administration with EO pump and syringe, the peripheral skin concentration of DXR were decreased after slow administration with EO pump compared with that after rapidly administration with a syringe. These results indicated that direct i.t. administration of DXR with lower dosing using an EO pump at slower administration rate may be useful for exhibiting antitumor effects and suppressing systemic side effects. In addition, the blood concentration and the peripheral skin concentration of DXR after administration at lower rate with EO pump were decreased compared with those after the rapidly administration with a syringe.

The venom of honeybees is composed of numerous peptides and proteins and has been used for decades as an anti-inflammatory and anti-cancer agent in traditional medicine. However, the bioactivity of specific biomolecular components has been evaluated for the predominant constituent, melittin. So far, only a few melittin-like peptides from solitary bee species have been investigated, and the molecular mechanisms of bee venoms as therapeutic agents remain largely unknown. Here, the preclinical pharmacological activities of known and proteo-transcriptomically discovered new melittin variants from the honeybee and more ancestral variants from phylogenetically older solitary bees were explored in the context of cancer and inflammation. We studied the effects of melittin peptides on cytotoxicity, second messenger release, and inflammatory markers using primary human cells, non-cancer, and cancerous cell lines. Melittin and some of its variants showed cytotoxic effects, induced Ca2+ signaling and inhibited cAMP production, and prevented LPS-induced NO synthesis but did not affect the IP3 signaling and pro-inflammatory activation of endothelial cells. Compared to the originally-described melittin, some phylogenetically more ancestral variants from solitary bees offer potential therapeutic modalities in modulating the in vitro inflammatory processes, and hindering cancer cell viability/proliferation, including aggressive breast cancers, and are worth further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Therapies with monoclonal antibodies (mAbs) targeting tumor-associated antigens (TAAs) or immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment. Nevertheless, the inevitable development of resistance and the failure to respond are among this approach's disadvantages, limiting the duration of disease- or progression-free and overall survival. As an alternative to therapeutically efficacious monoclonal antibodies, the concept of active immunization with vaccines has been repeatedly discussed. In particular, mimotopes, representing the B cell epitope of therapeutic mAbs, have been shown to induce immunological memory and effectively produce antibodies with similar functionality to the respective mAbs/ICIs. This review focuses on a new frontier of vaccinations directed against two cancer-relevant targets, addresses concerns about the safety of active immunization targeting PD-1 and discusses limitations and outlooks. The application of monoclonal antibodies (mAbs), targeting tumor-associated (TAAs) or tumor-specific antigens or immune checkpoints (ICs), has shown tremendous success in cancer therapy. However, the application of mAbs suffers from a series of limitations, including the necessity of frequent administration, the limited duration of clinical response and the emergence of frequently pronounced immune-related adverse events. However, the introduction of mAbs has also resulted in a multitude of novel developments for the treatment of cancers, including vaccinations against various tumor cell-associated epitopes. Here, we reviewed recent clinical trials involving combination therapies with mAbs targeting the PD-1/PD-L1 axis and Her-2/neu, which was chosen as a paradigm for a clinically highly relevant TAA. Our recent findings from murine immunizations against the PD-1 pathway and Her-2/neu with peptides representing the mimotopes/B cell peptides of therapeutic antibodies targeting these molecules are an important focus of the present review. Moreover, concerns regarding the safety of vaccination approaches targeting PD-1, in the context of the continuing immune response, as a result of induced immunological memory, are also addressed. Hence, we describe a new frontier of cancer treatment by active immunization using combined mimotopes/B cell peptides aimed at various targets relevant to cancer biology. [ABSTRACT FROM AUTHOR]

Epidermal growth factor receptor (EGFR) is a starring target for the treatment of non-small cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been used to treat NSCLC patients with EGFR-activating mutations. However, most patients invariably develop resistance to these agents due to the occurrence of novel mutations at the EGFR kinase domain. There is an urgent need to develop more effective therapy strategies to provide more selection for patients with NSCLC. Coccinic acid was reported to exerts potential anti-tumor effects, but its mechanism has not been elucidated and warrants investigation. In this study, coccinic acid was shown to inhibit cell proliferation on cells harboring L858R/T790M mutant EGFR by suppressing p-EGFR and p-STAT3. It was also shown that coccinic acid promoted cell cycle distribution and showed a potent apoptosis-inducing efficacy. Further results in vivo assays demonstrated that coccinic acid reduced tumor growth of NCI-H1975 xenograft in nude mice via the EGFR/STAT3 signaling. Moreover, these effects are involving in the binding of coccinic acid to the EGFR extracellular domain. In conclusion, our finding demonstrated that coccinic acid may be utilized as a potential novel candidate for NSCLC with EGFR L858R/T790M mutation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The term ‘magic bullet’ is a scientific concept proposed by the German Nobel laureate Paul Ehrlich in 1907, describing a medicine that could specifically and efficiently target a disease without harming the body. Oncologists have been looking for a magic bullet for cancer therapy ever since. However, the current therapies for cancers—including chemotherapy, radiation therapy, hormone therapy, and targeted therapy—pose either pan-cytotoxicity or only single-target efficacy, precluding their ability to function as a magic bullet. Intriguingly, niclosamide, an FDA-approved drug for treating tapeworm infections with an excellent safety profile, displays broad anti-cancer activity in a variety of contexts. In particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK. Moreover, niclosamide potentially improves immunotherapy by modulating pathways such as PD-1/PDL-1. We recently discovered that niclosamide ethanolamine (NEN) reprograms cellular metabolism through its uncoupler function, consequently remodeling the cellular epigenetic landscape to promote differentiation. Inspired by the promising results from the pre-clinical studies, several clinical trials are ongoing to assess the therapeutic effect of niclosamide in cancer patients. This current review summarizes the functions, mechanism of action, and potential applications of niclosamide in cancer therapy as a magic bullet.

Secreted phospholipases A2 are snake-venom proteins with many biological activities, notably anti-tumor activity. Phospholipases from the same snake type but different geographical locations have shown similar biochemical and biological activities with minor differences in protein sequences. Thus, the discovery of a new phospholipase A2 with unique characteristics identified in a previously studied venom could suggest the origins of these differences. Here, a new Group II secreted phospholipase A2 (Cc-PLA2-II) from the snake venom of Saudi Cerastes cerastes gasperetti was isolated and characterized. The purified enzyme had a molecular weight of 13.945 kDa and showed high specific activity on emulsified phosphatidylcholine of 1560 U/mg at pH 9.5 and 50 °C with strict calcium dependence. Interestingly, stability in extreme pH and high temperatures was observed after enzyme incubation at several pH levels and temperatures. Moreover, a significant dose-dependent cytotoxic anti-tumor effect against six human cancer cell lines was observed with concentrations of Cc-PLA2 ranging from 2.5 to 8 µM. No cytotoxic effect on normal human umbilical-vein endothelial cells was noted. These results suggest that Cc-PLA2-II potentially has angiogenic activity of besides cytotoxicity as part of its anti-tumor mechanism. This study justifies the inclusion of this enzyme in many applications for anticancer drug development.

Background: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most fatal malignancies. Several chemotherapies employing fluorouracil (5-FU) and gemcitabine were attempted, but the survival rate was extremely low. Resveratrol (RVT), known as a polyphenol compound and phytoalexin, was demonstrated to induce intrinsic apoptosis in cancer cells. However, its low delivery performance and efficiency at tumor sites remain an obstacle to exploit RVT as a drug. To address these problems, we bio-conjugated resveratrol with gold nanoparticles (GNPs) via polyvinylpyrrolidone as a cross-linker (RVT@PVP-GNPs) and investigated whether the fabrications could enhance the delivery performance and anti-tumor efficacy of RVT. Results: The fabrication of gold nanoparticles (GNPs) and bio-conjugated with resveratrol (RVT@PVP-GNPs) was conducted firstly. TEM image, spectrophotometry and zeta-potential revealed that the GNPs and RVT@PVP-GNPs having a size of approximately 40 nm were successfully synthesized and exhibited moderate stability. GNPs alone represented no damage in PANC-1 cells and moreover diminished the cytotoxicity of RVT in Raw264.7 murine macrophage cells, demonstrating the superiority of gold nanoparticles as a drug carrier. Evaluation using dialysis showed a burst release rate of RVT within 96 h at pH 5.0, demonstrating the possibility of enhanced efficiency of RVT delivery through blood vessels to the tumor. The RVT@PVP-GNPs induced increased rates of S-phase cell cycle arrest and apoptosis compared with free RVT. Notably, RVT@PVP-GNPs diminished the proportion of necrotic cells, whereas free RVT increased it. We also demonstrated that the RVT@PVP-GNPs may induce an apoptosis via intrinsic mitochondria with higher degree compared with free RVT, indicating the possibility of enhanced anti-tumor agents. In animal studies, RVT@PVP-GNPs conjugated with AS1411 aptamer induced efficient tumor volume suppression without accumulation in or damage to the kidneys in vivo. Conclusions: The results demonstrate that RVT@PVP-GNPs enhance the anti-tumor efficacy of free RVT by activating the intrinsic apoptotic pathway and could be considered as potential anti-tumor drug candidates against pancreatic cancer cells. [ABSTRACT FROM AUTHOR]

Berberine (BBR) is a plant derived quaternary benzylisoquinoline alkaloid, which has been widely used in traditional medicines for a long term. It possesses broad pharmacological effects and is widely applied in clinical. In recent years, the anti-tumor effects of BBR have attracted more and more attention of the researchers. The canonical right-handed double-stranded helical deoxyribonucleic acid (B-DNA) and its polymorphs occur under various environmental conditions and are involved in a plethora of genetic instability-related diseases especially tumor. BBR showed differential binding effects towards various polymorphic DNA structures. But its poor lipophilicity and fast metabolism limited its clinical utility. Structural modification of BBR is an effective approach to improve its DNA binding activity and bioavailability in vivo. A large number of studies dedicated to improving the binding affinities of BBR towards different DNA structures have been carried out and achieved tremendous advancements. In this article, the main achievements of BBR derivatives in polymorphic DNA structures binding researches in recent 20 years were reviewed. The structural modification strategy of BBR, the DNA binding effects of its derivatives, and the structure activity relationship (SAR) analysis have also been discussed. [ABSTRACT FROM AUTHOR]

Objective To investigate the photodynamic antitumor activity and chemical characteristics of pheophorbide A (PPBa) in vitro. Methods Breast cancer cells (MCF-7), lung cancer cells (A549), cervical cancer cells (HeLa), and three kinds of hepatoma cells (HepG2, hep3B and sk-Hep1) were planted in 96-well plates. The effects of light and dark toxicity, light intensity, and drug concentration on the phototoxicity of PPBa were investigated by MTT, and the uptake of PPBa was observed by Hoechst staining under a confocal microscope. The production of singlet oxygen was observed by flow cytometry and confocal microscopy with the reactive oxygen species detection kit. The photobleaching of PPBa was investigated by measuring the absorbance by a microplate reader according to the luminescence characteristics of PPBa. Results PPBa showed strong phototoxicity and low dark toxicity to six kinds of cancer cells, and IC50 values to cancer cells were as follows: MCF-7: 1.033 μmol/L, A549: 1.911 μmol/L, HeLa: 2.319 μmol/L, HepG2: 2.015 μmol/L, Hep3B: 2.089 μmol/L, sk-Hep1: 2.467 μmol/L. The main uptake site of PPBa was the cytoplasm. The production of singlet oxygen was strongly dependent on the administration concentration, and photobleaching was very low. Conclusion For the six kinds of cancer cells, PPBa has the highest phototoxicity to breast cancer cells (MCF-7), with excellent properties and ideal photosensitizer characteristics. [ABSTRACT FROM AUTHOR]

Background: Lung cancer is the second most common cancer worldwide. Eucalyptus plant extract has been shown to have anti-neoplastic effects. We investigated the antitumor effect of ethanolic and aqueous extracts of Eucalyptus camaldulensis collected at different altitudes on A549. In addition, we evaluated the additive effect of its combination with low-dose cisplatin (CDDP). Methods: Qualitative and quantitative analyses of secondary metabolites present in the plants were carried out. The antioxidant and cytotoxic activities of the different extracts on A549 were evaluated using the 2.2-diphenyl-1-picrylhydrazyl radical scavenging activity and neutral red assay, respectively. The cytotoxic effect of the combination of certain extract concentrations with low-dose CDDP on A549 cells was studied. Results: In the Ethanoic extract, a higher number of active substances and antioxidant activities were observed. The four E. camaldulensis extracts showed cytotoxic activity on A549 cells, with a higher cytotoxicity for the Ethanoic extract and the sea-level altitude species. Moreover, the dual exposure of cells to both E. camaldulensis extracts and a low dose of Cisplatin showed an additional cytotoxic effect on A549 cells in certain concentrations. Conclusions: This study opens novel therapeutic options in combinational therapies of Eucalyptus camaldulensis with low-dose CDDP for the treatment of adenocarcinoma cells of human lungs. [ABSTRACT FROM AUTHOR]

High Mobility Group Chromosomal Protein N2 (HMGN2) can recognize tumor cells and enhance the anti-tumor effect of immune cells. This study aimed to establish a lentiviral vector of recombinant HMGN2 gene, establish recombinant T cells (HMGN2-T cells), and observe their anti-tumor effects. Total RNA was isolated from peripheral blood mononuclear cells. HMGN2, cluster of differentiation (CD) 8 A, CD28, CD137, and CD3ζ genes were amplified and connected. Jurkat cells were transfected with the recombinant lentivirus vector. The viability, apoptosis, and cell cycle of HMGN2-T cells were detected using Cell Counting Kit-8 assay and flow cytometry. The co-culture was performed by adding HMGN2-T cells to tumor cells with different effect-to-target (E:T) ratios. The cytotoxic activity was measured by lactate dehydrogenase (LDH) releasing assay. The sequences of HMGN2, CD8A, CD28, CD137, and CD3ζ gene plasmids were confirmed using gene sequencing. After the lentiviral transfection for 72 h, green fluorescence cells (HMGN2-T cells) could be seen. Cell viability and apoptosis were increased in HMGN2-T cells. The cytokine levels of interleukin 2 (IL-2) and tumor necrosis factor α (TNF-α) increased in cell supernatants of HMGN2-T cells. The percentage of G0/G1 phase cells was lower, the rate of S phase cells was higher in HMGN2-T cells than control cells. The co-culture of HMGN2-T cells and tumor cells could promote the cytokines' release. The LDH level was increased with the elevation of E:T ratios. In conclusion, the HMGN2-T cells were well-established and have the effect of secreting cytokines and killing tumor cells. [ABSTRACT FROM AUTHOR]

Abstract Background and aims Several oncolytic viruses applications have been approved in the clinic or in different phases of clinical trials. However, these methods have some rudimentary problems. Therefore, to enhance the delivery and quality of treatment, considering the advantage of cell carrier-based methods such as Mesenchymal Stem Cells (MSC) have been proposed. This study was designed to evaluate the performance and quality of cancer treatment based on MSCs loaded by oncolytic reovirus in the cancerous C57BL/6 mouse model. Also, we evaluated MSCs migration potency in vitro and in vivo following the oncolytic reovirus infection. Methods C57BL/6 mice were inoculated with TC-1 cell lines and tumors were established in the right flank. Mice were systemically treated with reovirus, MSCs-loaded with reovirus, MSCs, and PBS as a control in separated groups. Effects of infected AD-MSCs with reovirus on tumor growth and penetration in the tumor site were monitored. All groups of mice were monitored for two months in order to therapeutic and anticancer potential. After treatments, tumor size alteration and apoptosis rate, as well as cytokine release pattern was assessed. Results The results of the current study indicated that the effect of reovirus infection on AD-MSCs is not devastating the migration capacity especially in MOI 1 and 5 while intact cells remain. On the other hand, MSCs play an efficient role as a carrier to deliver oncolytic virus into the tumor site in comparison with systemic administration of reovirus alone. Apoptosis intensity relies on viral titration and passing time. Followed by systemic administration, treatment with oncolytic reovirus-infected AD-MSCs and MSCs alone had shown significant inhibition in tumor growth. Also, treatment by reovirus causes an increase in IFN-γ secretion. Conclusion The results of in vitro and in vivo study confirmed the tumor-homing properties of infected AD-MSCs and the significant antitumor activity of this platform. Hence, our results showed that the cell carrier strategy using oncolytic reovirus-loaded AD-MSCs enhanced virus delivery, infiltration, and antitumor activity can be effectively applied in most cancers.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the alimentary tract. The prognosis depends on the primary site, and small intestinal GISTs have a worse prognosis than gastric GISTs. Molecularly targeted drugs to inhibit tyrosine kinase activity of KIT were used for unresectable or recurrent GISTs. However, secondary resistance to the drugs is often acquired, and treatments based on other mechanisms are needed. Previously, we reported that cell adhesion molecule 1 (CADM1) was highly expressed in most of small intestinal GISTs but not in most of gastric GISTs. In the present study, we examined whether the antibody-drug conjugate (ADC) with anti-CADM1 antibody and monomethyl auristatin E (anti-CAD-ADC) shows anti-tumor effect on CADM1-expressing human GIST cells. The ADC adhibited in this study was previously used for CADM1-expressing human mesothelioma cells and showed anti-tumor effect for them in vitro. GIST-T1 cell line of gastric origin which scarcely expresses CADM1 and GIST-T1 cells transfected with CADM1 cDNA (GIST-T1-CAD cells) which highly expresses CADM1 and represents small intestinal GIST were used. In vitro, anti-CAD-ADC showed remarkable cytotoxic activity on GIST-T1-CAD cells, but control ADC did not. Both anti-CAD-ADC and control ADC did not show anti-tumor effect on original GIST-T1 cells. When GIST-T1-CAD cells were subcutaneously injected to the nude mice, intravenous administration of anti-CAD-ADC showed inhibitory effect for tumor enlargement. Tumor of GIST-T1 cells grew even after anti-CAD-ADC injection. When GIST-T1-CAD cells were injected into peritoneal cavity of the SCID mice, intraperitoneal administration of anti-CAD-ADC showed reduction of the peritoneal tumor. On the other hand, peritoneal tumor grew after control ADC administration. Tissue and organ damage due to administration of anti-CAD-ADC was not apparent by macroscopic and histological examinations in mice. These results indicate that anti-CAD-ADC could have apparent anti-tumor effect on CADM1-expressing human GIST cells both in in vitro and in vivo mouse models. [ABSTRACT FROM AUTHOR]

[Display omitted] • LMWDOP obtained from the hydrolysis of mannanase have good anti-tumor activity. • MDOP reconstructs the immune microenvironment. • (→6-α-D-Glcp- (1 → 4)-β-D-Manp-(1→) may be the structural basis for MDOP to exert anti-tumor effects. In this study, glucanase and mannanase were selected to hydrolysis DOP to obtain low molecular weight DOP (LMWDOP), namely glucanase - hydrolysis Dendro bium officinale polysaccharides (GDOP) and mannanase - hydrolysis Dendro bium officinale polysaccharides (MDOP). The antitumor activity of LMWDOPs and its effect on tumor immune microenvironment were investigated. The growth of transplantable S180 sarcoma in mice was significantly inhibited by GDOP, and MDOP in a dose-dependent manner compared with the model group (P < 0.05, P < 0.01). This indicated that mannanase-hydrolysis Dendrobium officinale polysaccharides have stronger anti-tumor activity. The structure of MDOP was systematically characterized to explore the structure–activity relationship. The average molecular weight of MDOP was 3494 Da. MDOP had a linear chain structure consisting mainly of →6)-α- d -Glcp-(1→ and →4)-β- d -Manp-(1 → residues. O-acetyl group linked to C2 of →4)-β- d -Manp-(1 → residue. In conclusion, it has been determined that the small molecule dendrobium polysaccharides obtained from the hydrolysis of mannanase have good anti-tumor activity and can reconstruct the immune microenvironment. "→ 6-α- d -Glcp- (1 → 4)-β- d -Manp-(1→) may be the structural basis for Dendrobium officinale polysaccharides to exert anti-tumor effects. [ABSTRACT FROM AUTHOR]

Based on glucose (G) transporters (GLUTs), structuring nanoparticles with G as a target are an effective strategy to enhance oral bioavailability and anti-tumor effects of drugs. A novel drug delivery system using G-modified zein (GZ) nanoparticles loaded with docetaxel (DTX) (DTX-GNPs) was prepared and characterized in vitro and in vivo via assessment of cellular uptake, absorption site, pharmacokinetics, ex vivo distribution, and anti-tumor effects. The DTX-GNPs were approximately 120 nm in size. Compared with DTX-NPs, G modification significantly enhanced cellular uptake of DTX-GNPs by 1.22 times in CaCo-2 cells, which was related to GLUT mediation and the enhancement of endocytosis pathways via clathrin, micropinocytosis, and caveolin. Compared to DTX-NPs, G modification significantly enhanced DTX-NP absorption in the jejunum and ileum, delayed plasma concentration peak time, prolonged the average residence time in vivo, and increased oral bioavailability (from 43.82% to 96.04%). Cellular uptake and oral bioavailability of DTX were significantly affected by the G modification ratio. Compared with DTX-NPs, G modification significantly reduced drug distribution in the liver, lungs, and kidneys and increased tumor distribution and tumor growth inhibition rate without obvious systemic toxicity. This study demonstrated the potential of GZ-NPs as nanocarriers for DTX to enhance oral bioavailability and anti-tumor effects. [ABSTRACT FROM AUTHOR]

Background and Objective: Curcumin is a polyphenolic compound derived from Curcumin longa L. There is growing body of data showing the antitumor effect of curcumin in different cancers; however, its efficacy is limited by its low absorption rate. Here, we investigated the antitumor activity of turmeric oleoresin alone or in combination with paclitaxel in MCF-7 cells in monolayer cell cultures and spheroids models. Methods: The antiproliferative activities of 3 different form, curcumin, phospholipidated curcumin, and turmeric oleoresin were assessed by MTT assay. The migratory behaviors of the cells were determined by migration assay before and after treatment with curcumin. The expression levels of CyclinD1, P65, Nf-kB, and E-cadherin were studied. Findings: Curcumin suppressed cell growth in MCF-7 cells via modulation of CyclinD1 and NF-KB, which was more pronounced with turmeric oleoresin. Curcumin was able to reduce the invasiveness of MCF-7, compared to control cells through perturbation of E-cadherin. Conclusion: We demonstrated the antitumor activity of curcumin and curcumin oleoresin in breast cancer cells, supporting further investigations on the therapeutic potential of this novel anticancer agent in in vivo models. [ABSTRACT FROM AUTHOR]

Clathrin-mediated endocytosis plays a critical role for hydroxyapatite nanoparticles (HANPs) to enter tumor cells, induce mitochondrial apoptosis, and inhibit tumor growth. This study was aimed to investigate how the morphology of HANPs impacts the endocytosis of the particles in melanoma cells, and their anti-tumor effect by using in vitro cell experiments and in vivo tumor animal model. Three shapes of HANPs, including granular HANPs (G-HANPs), rod-like HANPs (R-HANPs), and needle-like HANPs (N-HANPs), were successfully prepared by wet chemical method. All the three HANPs could be internalized into A375 melanoma cells as indicated by cellular transmission electron microscopy images. Among these HANPs, only G-HANPs induced morphological change of mitochondria and loss of mitochondrial membrane potential (Δψm), and exhibited the greatest intracellular internalization efficiency in the tumor cells. Furthermore, the results of immunofluorescence staining and western blotting indicated that the level of adaptin-2 (AP2) protein was up-regulated by all the HANPs, and highest in G-HANPs treated A375 cells. Moreover, in the tumor-bearing mouse model, we found that tumor growth was delayed by all the three HANPs, of which, G-HANPs delayed tumor growth most efficiently and presented a highest expression level of AP2 protein in tumor tissues. Therefore, this study suggested that the morphology of HANPs regulated their endocytosis efficiency and their effect to inhibit tumor growth. This work facilitates to direct the rational design of nano-materials for tumor therapy. [ABSTRACT FROM AUTHOR]