Significant Antitumor Effect Research Articles

Discovery of novel and highly potent dual-targeting PKMYT1/HDAC2 inhibitors for hepatocellular carcinoma through structure-based virtual screening and biological evaluation

Simultaneous inhibition of two or more pathways is playing a crucial role in the treatment of hepatocellular carcinoma with complex and diverse pathogenesis. However, there have been no reports of dual-targeting inhibitors for protein kinase membrane-associated tyrosine/threonine 1 (PKMYT1) and histone deacetylase 2 (HDAC2), which are critical targets for hepatocellular carcinoma treatment. Here, an integrated strategy of virtual screening was utilized to identify dual-targeting inhibitors for PKMYT1 and HDAC2. Notably, PKHD-5 has been identified as a potent inhibitor that selectively targets both PKMYT1 and HDAC2 with nanomolar affinity. Molecular dynamics have confirmed the strong binding stability of PKHD-5 with PKMYT1 and HDAC2. Importantly, it displayed a notably lower IC50 against the HepG2/MDR cell line, underscoring its potential to surmount drug resistance, while exhibiting minimal toxicity towards the normal liver cell line L02. Additionally, PKHD-5 has demonstrated significant antitumor proliferation effects without significant toxicity. In summary, the results suggest that PKHD-5 is a promising candidate for further preclinical studies of hepatocellular carcinoma therapy.

In Situ Tumor-Infiltrating Lymphocyte Therapy by Local Delivery of an mRNA Encoding Membrane-Anchored Anti-CD3 Single-Chain Variable Fragment.

Tumor-infiltrating lymphocyte (TIL) therapy has shown promising responses in clinical trials for highly aggressive cancers such as advanced melanoma and metastatic colorectal cancer. However, TIL therapy is still limited in clinical practice due to the complex ex vivo cell preparation process. Here, we report an "in situ TIL therapy" for the treatment of solid tumors. We utilized lipid nanoparticles for the delivery of an mRNA encoding membrane-anchored anti-CD3 single-chain variable fragment (scFv) (MA-aCD3), efficiently engineering both tumor-associated macrophages (TAMs) and tumor cells following intratumoral delivery. Expression of MA-aCD3 resulted in enhanced TIL activation, proliferation, and tumor cell engagement directly within the tumor microenvironment. In B16F10 and MC38 tumor models, concurrent expression of MA-aCD3 on TAMs and tumor cells mediated by mRNA delivery resulted in significant antitumor effects via in situ polyclonal CD8+ TIL expansion and directed cytotoxic effector functions. In addition, combinatorial treatment of MA-aCD3-encoding mRNA and antiprogrammed cell death 1 (anti-PD-1) antibodies exhibited synergistic antitumor effects on anti-PD-1 refractory B16F10 tumors. Together, our findings suggest that in situ TIL therapy is a practical and effective mRNA-based therapeutic modality for the treatment of solid tumors.

Discovery of anti-tumor agent targeted MetAP-2 using a special turn-on fluorescent probe

Methionine aminopeptidase 2 (MetAP-2) catalyzes the removal of methionine from the amino-terminus of proteins or peptides and is a known target for anti-tumor therapy. In this study, we developed an enzyme-activated fluorescent probe, DDAO-BMT, specifically for the real-time detection of endogenous MetAP-2. This probe enables the determination of extracellular MetAP-2 activity and visual monitoring of intracellular MetAP-2. Additionally, Sappan Lignum was identified as an active herbal medicine against MetAP-2, with brazilin identified as its key active constituent. Brazilin also exhibited a significant anti-tumor effect, including the inhibition on proliferation, migration, and invasion of tumor cells, and the preliminary mechanism of its activity against cancer has been elucidated. The use of this probe facilitates the monitoring of endogenous MetAP-2 in complex biological system, aiding in the discovery of novel active compounds for cancer treatment.

Progress in the study of anti-tumor effects and mechanisms of vitexin.

Vitexin (apigenin-8-C-beta-D-glucopyranoside) is a natural flavonoid derivative with anti-cancer, antioxidant, anti-inflammatory, antihypertensive, anti-asthma, anti-epilepsy, and other therapeutic effects. It is extracted from pearl millet, hawthorn, pigeon bean, mung bean, and other medicinal plants. Vitexin has received widespread attention because of its significant anti-tumor effect. It induces apoptosis and anti-tumor angiogenesis, inhibits tumor cell migration and invasion, regulates tumor cell autophagy and immunity, and increases patient sensitivity to radiotherapy and chemotherapy. It has a significant anti-tumor effect on breast, prostate, liver, cervical, and colon cancers, gliomas, and other malignant tumors. This review demonstrates the latest research progress on the anti-tumor effects and potential mechanisms of vitexin. It summarizes its anti-tumor mechanism to provide new theoretical support and reference for cancer treatment.

Trastuzumab-Mediated Antibody-Dependent Cell-Mediated Cytotoxicity (ADCC) Enhances Natural Killer Cell Cytotoxicity in HER2-Overexpressing Ovarian Cancer.

Ovarian cancer is the deadliest gynecologic cancer. Although human epidermal growth factor receptor-2 (HER2) overexpression, a poor prognostic molecular marker in ovarian cancer, is found in almost 30% of ovarian cancer cases, there are no established therapies for HER2-overexpressing ovarian cancer. In this study, we investigated the efficacy of combined samfenet, a biosimilar compound of trastuzumab, and natural killer (NK) cells in preclinical model of HER2-overexpressing ovarian cancer. Firstly, we screened the HER2 expression in three ovarian cancer cell lines and eight ovarian cancer patient-derived tumor xenograft (PDTX) samples. Then, immunohistochemistry and silver in situ hybridization (SISH) were performed following clinical criteria. HER2-overexpressing cells exhibited the highest sensitivity to samfenet compared with low-HER2-expressing cells. In addition, the combination of samfenet with natural killer (NK) cells resulted in significantly enhanced sensitivity to HER2-overexpressing cells and showed a significant antitumor effect on PDTX mice compared with monotherapy. It is known that anti-HER2-humanized IgG1 monoclonal antibodies, including trastuzumab, induce antibody-dependent cellular cytotoxicity (ADCC). Consequently, the combination of samfenet with NK cells demonstrated NK cell-mediated ADCC, as confirmed using an in vitro NK cytotoxicity assay and in vivo antitumor efficacy. A transferase dUTP nick end labeling (TUNEL) assay using xenografted tumors further supported the ADCC effects based on the increase in the number of apoptotic cells in the combination group. Furthermore, high HER2 expression was associated with shorter progression-free survival and overall survival based on public mRNA expression data. In this study, we demonstrated that the combination of samfenet and NK cell therapy could be a promising treatment strategy for patients with HER2-overexpressing ovarian cancer, through ADCC effects. Therefore, this study supports a rationale for further clinical studies of the combination of samfenet and NK cells as a therapy for patients with HER2-overexpressing ovarian cancer.

The Influence of Physical Training on Breast Cancer: The Role of Exercise-Induced Myokines in Regulating Breast Cancer Cell Growth and Survival.

The beneficial impact of physical training in lowering cancer risk is well known. However, the precise mechanisms linking physical training and cancer are not fully understood. Skeletal muscle releases various myokines that seem to possess a direct anti-tumor effect. Although breast cancer (BC) is the prevalent form of cancer among women on a global scale, only limited data are available about the secretion of myokines following exercise in patients with BC. To study the effects of exercise on BC, the blood samples of patients with varied stages of BC were analyzed after 12 weeks of resistance training with whole-body electromyostimulation (WB-EMS). Following the training period, we observed that resistance training helps these patients to improve their physical characteristics and performance function by increasing skeletal muscle mass and strengthening their hand grip. Notably, the patient's serum was found to inhibit the growth and promote the apoptosis of BC cells in vitro. Moreover, the conditioned medium collected from in vitro stimulated human myotubes using electric pulse stimulation (EPS), an in vitro simulation of WB-EMS training, induced the cell death of BC cells. These results highlighted the direct cancer-protective effects of activated skeletal muscle. In line with our observed effects of serum from exercise-trained pancreatic and prostate cancer patients, the growth of BC cells was notably inhibited when supplemented directly with recombinant myokines C-X-C motif ligand 1 (CXCL1), Interleukin 10 (IL10), and C-C motif chemokine ligand 4 (CCL4). Notably, treatment with these myokines also increased the expression of caspase 3/7 (Casp3/7), resulting in enhanced BC cell death. Our data strongly suggest that physical exercise has a positive impact on skeletal muscle mass and hand grip strength in BC patients, along with a significant anti-tumor effect in BC cells. This shows promising potential for considering sports and physical training as supportive therapies for achieving more impactful cancer treatment.

Synergistic effects of anlotinib and DDP on breast cancer: targeting the VEGF/JAK2/STAT3 axis.

Anlotinib, a highly selective inhibitor of VEGFR2, has demonstrated significant anti-tumor effects in various cancers. However, its potential synergistic effects with DDP (cisplatin) in breast cancer (BRCA) remain to be fully elucidated. This study aims to discover the therapeutic efficacy of anlotinib on BRCA, specifically the synergistic effects with DDP, and to elucidate the underlying molecular mechanisms. BRCA cells were treated with anlotinib and/or DDP. The proliferation, migration and invasion capabilities of BRCA cells were evaluated using CCK-8 assays, cell cycle distribution, clone formation assays, wound healing assays and transwell assays. Cell apoptosis was detected by flow cytometry technique and Hoechst33342 fluorescence staining. The potential mechanism of anlotinib in the development of BRCA was predicted through bioinformatics analysis, and the mRNA or protein levels were subsequently quantified using qPCR, immunofuorescence and western blot. The anti-breast cancer efficacy of anlotinib was evaluated in vivo using a xenograft tumor model. Our findings reveal that increased VEGFA expression in BRCA patients is associated with poorer prognosis, underscoring the need for targeted therapeutic strategies. We also demonstrate that both anlotinib and DDP independently inhibit BRCA cell growth, migration, and invasion, while their combination exhibits a synergistic effect, significantly enhancing the inhibition of these oncogenic processes. This synergy is further evident through the induction of apoptosis and autophagy in BRCA cells. Mechanistically, anlotinib's effectiveness is linked to its inhibition of the JAK2/STAT3 pathway, a critical axis in BRCA progression. In vivo study further support these results, showing that anlotinib markedly inhibits tumor growth in xenografted mice. This study confirms the efficacy of anlotinib or in combination with DDP and elucidates the mechanism behind anlotinib's effectiveness, highlighting its role in inhibiting the JAK2/STAT3 pathway.

Co-delivery of polyphyllin II and IR780 PLGA nanoparticles induced pyroptosis combined with photothermal to enhance hepatocellular carcinoma immunotherapy.

The clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) is significantly limited by the low immunogenicity of the tumor. Recent studies have revealed that both pyroptosis and photothermal therapy can effectively induce tumor immunogenic cell death (ICD) in liver cancer cells. Polyphyllin II (PPII), the major active component of Rhizoma Paridis, has been demonstrated for the first time to induce pyroptosis in tumor cells, while IR780 is activated by 808nm laser to transform light energy into heat energy, effectively eliminating tumor cells. However, both PPII and IR780 are afflicted with challenges such as low solubility and poor targeting, significantly limiting their utilization. To address these problems, the pyroptosis inducer PPII and photosensitizer IR780 were co-loaded in PLGA nanoparticles by precipitation method, and the aptamer AS1411 was modified on the surface of nanoparticles to construct the targeting nanoparticles (Apt/PPII/IR780-NPs). The nanoparticles exhibit a pH/NIR dual-response intelligent release feature, which realizes the targeted and controlled release of drugs in tumor site. Furthermore, it can rapidly release PPII to induce cell pyroptosis under laser irradiation, combining with IR780-based photothermal therapy exert a significant synergistic anti-tumor effect in vitro and in vivo. This process not only promotes maturation of DCs and activates effector T cells, thereby initiating adaptive immunity, but also generates enduring and effective immune memory. In addition, Apt/PPII/IR780-NPs significantly improved the Anti-PD-1 efficacy. In summary, chemo-photothermal therapy based on Apt/PPII/IR780-NPs can significantly enhance tumor ICD, which provides a promising new strategy for HCC immunotherapy.

Harnessing Lactobacillus reuteri-Derived Extracellular Vesicles for Multifaceted Cancer Treatment.

Extracellular vesicles (EVs) have emerged as valuable biological materials for treating intractable diseases. Extensive studies are conducted on EVs derived from various cellular sources. In this study, EVs derived from Lactobacillus reuteri (L. reuteri), a probiotic, exhibit remarkable cancer therapeutic efficacy when administered orally is reported. These L. reuteri-derived EVs (REVs) demonstrate stability in the gastrointestinal tract and exert significant anti-tumor effects. Using A549 cells and murine models, we confirmed that REVs mediate their therapeutic effects by modulating apoptotic signaling pathways. Furthermore, the combination of REV with drugs enhances tumor ablation and induces immunogenic cell death. In a mouse model, oral administration of REVs encapsulating indocyanine green followed by photothermal therapy led to complete tumor elimination within 32days. REVs represent a promising biological therapeutic platform for cancer treatment, either independently or in combination with other therapies, depending on the treatment objectives.

Targeting the Galectin-1/Ras Interaction for Treating Malignant Peripheral Nerve Sheath Tumors.

Background: Neurofibromatosis type 1 (NF1) is a common inherited neurological disorder that can lead to the development of malignant peripheral nerve sheath tumors (MPNSTs), a highly aggressive form of sarcoma. Current treatment options for MPNSTs are limited, with poor prognosis and high recurrence rates. This study aims to explore the potential of targeting the Galectin-1 (Gal-1) and Ras interaction as a novel therapeutic strategy for MPNSTs. Methods: Molecular docking simulations were conducted to identify specific residues involved in the Gal-1 and H-Ras(G12V) interaction. LLS30, a compound designed to target the Ras binding pocket on Gal-1, was developed and tested. The efficacy of LLS30 was evaluated through in vitro assays, including cell viability, apoptosis, and co-immunoprecipitation studies, as well as in vivo assays using orthotopic MPNST xenograft and experimental lung metastasis models. Transcriptome sequencing was performed to analyze the impact of LLS30 on gene expression and signaling pathways. Results: Molecular docking revealed key residues involved in the Gal-1/Ras interaction, and LLS30 was shown to bind to these residues, disrupting the interaction. LLS30 treatment resulted in Ras delocalization from the plasma membrane and suppression of the Ras/Erk signaling pathway. In vitro, LLS30 significantly reduced MPNST cell proliferation and induced apoptosis. In vivo, LLS30 demonstrated potent anti-tumor activity, reducing tumor burden and metastasis while improving survival in animal models. Transcriptome analysis showed that LLS30 downregulates critical pathways, including KRAS signaling and epithelial-mesenchymal transition (EMT). Conclusions: Interference with the Gal-1/Ras interaction could lead to suppression of the Ras signaling pathway. LLS30 effectively disrupts the Gal-1/Ras interaction, resulting in significant anti-tumor and anti-metastatic effects in MPNST models. These findings indicated that targeting Gal-1 with LLS30 offers a promising therapeutic approach for treating MPNSTs and may also be applicable to other malignancies where Gal-1 and Ras are key oncogenic drivers.

A Self-Assembled Transdermal Nanomedicines Incorporating Pendant Disulfides for Non-Invasive, Synergistic Treatment of Melanoma.

Transdermal drug delivery system (TDDS) offers lower systemic toxicity and good patient compliance, making it a promising treatment option for skin-related cancers. However, physiological barriers in the skin frequently impede the therapeutic efficiency of TDDS. To address this, a unique self-assembled TDDS that incorporates disulfide pendant groups (termed Sup-TDDS) is presented. It is formulated with dithiolane-containing lipoic acid (LA), photosensitizers Ce6, and chemotherapeutic agents trametinib. Pendant disulfide moieties on Sup-TDDS facilitate thiol-disulfide exchange reactions with exofacial thiols on cell surfaces, thus enhancing stratum corneum penetration. In contrast to intravenous injection, topical administration of Sup-TDDS can penetrate deeper into the skin (> 500 µm) and promote drug accumulation in subcutaneous tumors. In a B16F10-bearing mouse model, Sup-TDDS treatment demonstrates significant anti-tumor effects in primary and recurrent melanoma, benefiting from the synergistic effects of Ce6 and trametinib. These results underscore that Sup-TDDS's transdermal properties allow non-invasive melanoma therapy, implying the potential of nanodrugs containing pendant disulfides for transdermal treatment of skin illnesses.

Improved antitumor effectiveness of oncolytic HSV-1 viruses engineered with IL-15/IL-15Rα complex combined with oncolytic HSV-1-aPD1 targets colon cancer

Oncolytic virotherapy is emerging as a promising therapeutic avenue for cancer treatment, harnessing both innate and tumor-specific immune responses for targeted tumor elimination. In this study, we present a novel oncolytic virus (oHSV1-IL15B) derived from herpes simplex virus-1 (HSV-1), armed with IL-15/IL-15Rα complex, with a focus on treating colon cancer combined with oncolytic HSV-1 expressing anti-PD-1 antibody (oHSV1-aPD1). Results from our study reveal that recombinant oHSV-1 virus equipped with IL-15/IL-15Rα complex exhibited significant anti-tumor effects in a murine CT26 colon adenocarcinoma model. Notably, oHSV1-IL15B combined with oHSV-1-aPD1 demonstrates superior tumor inhibition and prolonged overall survival compared to oHSV1-mock and monotherapy groups. Further exploration highlights the impact of oHSV1-IL15B, oHSV-1-aPD1 and combined group on antitumor capacity, revealing a substantial increase in CD8+ T and CD4+ T cell proportions of CT26-bearing BALB/c mice and promoting apoptosis in tumor tissue. The study emphasizes the pivotal role of cytotoxic CD8+T cells in oncolytic virotherapy, demonstrating that recombinant oHSV1-IL15B combined with oncolytic HSV-1-aPD1 induces a robust tumor-specific T cell response. RNA sequence analysis highlighted oHSV1-IL15B combined with oHSV1-aPD1 improved tumors immune microenvironment on immune response, antiviral response-related genes and apoptosis-related genes, which contributed to anti-tumor immunotherapy. The findings underscore the promising antitumor activity achieved through the combination of IL-15/IL-15Rα complex and anti-PD-1 antibody with oHSV-1. This research opens avenues for diverse therapeutic strategies, suggesting the potential of synergistically utilizing cytokines and anti-PD-1 antibody with oncolytic viruses to enhance immunotherapy for cancer management.

Antitumor effects of intracranial injection of B7-H3-targeted Car-T and Car-Nk cells in a patient-derived glioblastoma xenograft model

BackgroundGlioblastoma multiforme (GBM) is the most lethal primary brain tumor for which novel therapies are needed. Recently, chimeric antigen receptor (CAR) T cell therapy has been shown to be effective against GBM, but it is a personalized medicine and requires high cost and long time for the cell production. CAR-transduced natural killer (NK) cells can be used for "off-the-shelf" cellular immunotherapy because they do not induce graft-versus-host disease. Therefore, we aimed to analyze the anti-GBM effect of CAR-T or NK cells targeting B7-H3, which is known to be highly expressed in GBM.MethodsCAR-T cells targeting B7-H3 were generated using previously reported anti-B7-H3 scFv sequences. Cord blood (CB)-derived NK cells transduced with the B7-H3 CAR were also generated. Their anti-GBM effect was analyzed in vitro. The antitumor effect of intracranial injection of the B7-H3 CAR-T or NK cells was investigated in an in vivo xenograft model with patient-derived GBM cells.ResultsBoth B7-H3 CAR-T cells and CAR-NK cells exhibited marked cytotoxicity against patient-derived GBM cells in vitro. Furthermore, intracranial injection of CAR-T cells and CAR-NK cells targeting B7-H3 resulted in a significant antitumor effect against patient-derived GBM xenografts.ConclusionNot only CAR-T cells but also CB-derived CAR-NK cells targeting B7-H3 may have the potential to eliminate GBM cells.

Eugenol-loaded nanoemulsions: Antiproliferative activity against breast cancer cells and hemocompatibility

Breast cancer poses a substantial global health challenge, lacking specific and less toxic treatment options. Eugenol, a phenolic compound, has demonstrated potential in vitro, but its susceptibility to degradation, volatility, and limited water solubility hampers its practical application. This study aimed to enhance eugenol's efficacy and stability by formulating nanoemulsions, offering a novel therapeutic strategy for breast cancer. Eugenol-loaded nanoemulsions were developed using high-energy (NE-Et) and low-energy (NE-Er) methods. Eugenol-nanoemulsions exhibited favorable nanometric characteristics, with sizes ranging from 110 to 120 nm, polydispersity index below 0.3, negative zeta potential, and an acidic pH. The eugenol content approached theoretical values, reaching approximately 100 % for NE-Et and 50 % for NE-Er. Moreover, these nanoformulations exhibited excellent physicochemical stability throughout a 90-day period. With a high antioxidant potential (190 μMol TE/μL), concentrations of 50–150 μg/mL free and nanoemulsified eugenol were considered non-toxic to blood cells. Finally, demonstrated a significant antitumor effect of eugenol-loaded nanoemulsions (150, 300, and 600 μg/mL) against breast cancer cells (MCF-7), with a notable enhancement of this activity attributed to the process of nanoemulsification. This research underscores nanotechnology's promise in advancing bioactive compound formulations for cancer therapy and clinical translation.

SHR6390 Combined with Cabozantinib Inhibits Tumor Progression in the Hepatocellular Carcinoma Mouse Model.

A novel CDK4/6 inhibitor SHR6390 has shown significant anti-tumor effects. However, its role in hepatocellular carcinoma (HCC) remains unknown. To explore the inhibitory effect of combination treatment with SHR6390 and cabozantinib in HCC, and its antitumor mechanism, so as to provide a more effective therapeutic strategy for HCC patients. We investigated SHR6390, monotherapy or combined with cabozantinib, by CCK8, wound healing, transwell, western blotting, immunohistochemistry and mouse model of a subcutaneous tumor. Our results show that SHR6390 exhibited potent anti-proliferative activity against HCC in a dose-dependent manner. SHR6390 combined with cabozantinib exhibited more potent inhibition of cell viability, migration and invasion. In terms of potential mechanisms, we found that cabozantinib could lead to phosphorylation of Rb, which was reduced in SHR6390 and combined groups. SHR6390 monotherapy inhibited the growth of subcutaneous HCC tumors, besides, the combination treatment with SHR6390 and cabozantinib exerted synergistic anti-tumor activity in vivo Conclusion: SHR6390 is effective against HCC, monotherapy or combined with cabozantinib.

Magnolol Induces Apoptosis and Suppresses Immune Evasion in Non-small Cell Lung Cancer Xenograft Models.

Non-small cell lung cancer is known for its rapid growth and immune evasion, demanding effective therapies targeting both tumor cells and the microenvironment. Magnolol has shown promising anti-tumor effects in various cancers. CL1-5-F4-bearing mice were divided into control, 40 mg/kg, and 60 mg/kg magnolol groups, once tumors reached 100 mm3 Tumor growth and body weight were monitored biweekly, and after 13 days, mice were euthanized for tumor and organ collection for subsequent staining. Histopathology and serum biochemistry assessed organ toxicity. Magnolol dose-dependently suppressed NSCLC progression, with no pathology alterations observed in normal organs. Magnolol-induced apoptosis and cell cycle arrest, evidenced by increased cleaved caspase-3 and decreased cyclin D1/CDK4 levels. It also down-regulated VEGF, FOXP3, and IDO-1 in tumors, implicating tumor microenvironment modulation. Magnolol exhibits significant antitumor effects in NSCLC by inducing apoptosis, inhibiting proliferation, and modulating the tumor microenvironment. These results support further investigation of magnolol as a therapeutic adjuvant to enhance NSCLC treatment outcomes.

Bojungikki-Tang Augments Pembrolizumab Efficacy in Human PBMC-Injected H460 Tumor-Bearing Mice

Bojungikki-Tang (BJIKT) is traditionally used to enhance digestive function and immunity. It has gained attention as a supplement to chemotherapy or targeted therapy owing to its immune-boosting properties. This study aimed to evaluate the synergistic anti-tumor effects of BJIKT in combination with pembrolizumab in a preclinical model. MHC I/II double knockout NSG mice were humanized with peripheral blood mononuclear cells (PBMCs) and injected subcutaneously with H460 lung tumor cells to establish a humanized tumor model. Both agents were administered to evaluate their impact on tumor growth and immune cell behavior. Immunohistochemistry showed decreased exhaustion markers in CD8(+) and CD4(+) T cells within the tumor, indicating enhanced T cell activity. Additionally, RNA sequencing, transcriptome analysis, and quantitative PCR analysis were performed on tumor tissues to investigate the molecular mechanisms underlying the observed effects. The results confirmed that BJIKT improved T cell function and tumor necrosis factor signaling while suppressing transforming growth factor-β signaling. This modulation led to cell cycle arrest and apoptosis. These findings demonstrate that BJIKT, when combined with pembrolizumab, produces significant anti-tumor effects by altering immune pathways and enhancing the anti-tumor immune response. This study provides valuable insights into the role of BJIKT in the tumor microenvironment and its potential to improve therapeutic outcomes.

Unveiling the antitumor synergy between pazopanib and metformin on lung cancer through suppressing p-Akt/ NF-κB/ STAT3/ PD-L1 signal pathway

Pazopanib, an inhibitor of the VEGF receptor tyrosine kinase, has demonstrated significant antitumor effects in lung cancer. However, its application as a standard treatment for this type of cancer is limited by its drug resistance and toxicity. Metformin has the potential to combat lung cancer by modifying the tumor’s immune microenvironment.In this study, we investigated the potential antitumor effects and the associated underlying molecular mechanisms of the combination of pazopanib and metformin in lung cancer. In vitro studies were conducted using the A549 and H460 lung cancer cell lines, whereas urethane-induced lung cancer-bearing mice were used for in vivo assessments. The urethane-induced mice received oral administration of pazopanib (50 mg/kg) and/or metformin (250 mg/kg) for a duration of 21 days.The results indicated that the MTT assay demonstrated a combined cytotoxic effect of the pazopanib/metformin combination in H460 and A549 cells, as evidenced by CI and DRI analyses. The observed increase in annexin V levels and the corresponding increase in Caspase-3 activity strongly suggest that this combination induced apoptosis.Furthermore, the pazopanib/metformin combination significantly inhibited the p-Akt/NF-κB/IL-6/STAT3, HIF1α/VEGF, and TLR2/TGF-β/PD-L1 pathways while also increasing CD8 expression in vivo. Immunohistochemical analysis revealed that these antitumor mechanisms were manifested by the suppression of the proliferation marker Ki67. In conclusion, these findings revealed that metformin augments the antitumor efficacy of pazopanib in lung cancer by simultaneously targeting proliferative, angiogenic, and immunogenic signaling pathways, metformin enhances the antitumor effectiveness of pazopanib in lung cancer, making it a promising therapeutic option for lung cancer.

Rationally designed catalytic nanoplatform for enhanced chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment

Chemodynamic therapy represents a novel tumor therapeutic modality via triggering catalytic reactions in tumors to yield highly toxic reactive oxygen species (ROS). Nevertheless, low efficiency catalytic ability, potential systemic toxicity and inefficient tumor targeting, have hindered the efficacy of chemodynamic therapy. Herein, a rationally designed catalytic nanoplatform, composed of folate acid conjugated liposomes loaded with copper peroxide (CP) and chloroquine (CQ; a clinical drug) (denoted as CC@LPF), could power maximal tumor cytotoxicity, mechanistically via maneuvering endogenous and exogenous copper for a highly efficient catalytic reaction. Despite a massive autophagosome accumulation elicited by CP-powered autophagic initiation and CQ-induced autolysosomal blockage, the robust ROS, but not aberrant autophagy, underlies the synergistic tumor inhibition. Otherwise, this combined mode also elicits an early onset, above all, long-term high-level existence of immunogenic cell death markers, associated with ROS and aberrant autophagy -triggered endoplasmic reticulum stress. Besides, CC@LPF, with tumor targeting capability and selective tumor cytotoxicity, could elicit intratumor dendritic cells (mainly attributed to CQ) and tumor infiltrating CD8+ T cells, upon combining with PD-L1 therapeutic antibody, further induce significant anti-tumor effect. Collectively, the rationally designed nanoplatform, CC@LPF, could enhance tumor chemoimmunotherapy via deploying endogenous plus exogenous copper and remodeling tumor microenvironment.Graphical abstract

In Vitro Cytotoxic Potential and In Vivo Antitumor Effects of NOS/PDK-Inhibitor T1084.

Previously, we showed the antitumor activity of the new NOS/PDK inhibitor T1084 (1-isobutanoyl-2-isopropylisothiourea dichloroacetate). The present study included an assessment of in vitro cytotoxicity against human malignant and normal cells according to the MTT-test and in vivo antitumor effects in solid tumor models in comparison with precursor compounds T1023 (NOS inhibitor; 1-isobutanoyl-2-isopropylisothiourea hydrobromide) and Na-DCA (PDK inhibitor; sodium dichloroacetate), using morphological, histological, and immunohistochemical methods. The effects of T1084 and T1023 on the in vitro survival of normal (MRC-5) and most malignant cells (A375, MFC-7, K562, OAW42, and PC-3) were similar and quantitatively equal. At the same time, melanoma A375 cells showed 2-2.5 times higher sensitivity (IC50: 0.39-0.41 mM) to the cytotoxicity of T1023 and T1084 than other cells. And only HeLa cells showed significantly higher sensitivity to the cytotoxicity of T1084 compared to T1023 (IC50: 0.54 ± 0.03 and 0.81 ± 0.02 mM). Comparative studies of the in vivo antitumor effects of Na-DCA, T1023, and T1084 on CC-5 cervical cancer and B-16 melanoma in mice were conducted with subchronic daily i.p. administration of these agents at an equimolar dose of 0.22 mmol/kg (33.6, 60.0, and 70.7 mg/kg, respectively). Cervical cancer CC-5 fairly quickly evaded the effects of both Na-DCA and T1023. So, from the end of the first week of Na-DCA or T1023 treatment, the tumor growth inhibition (TGI) began to decrease from 40% to an insignificant level by the end of the observation. In contrast, in two independent experiments, CC-5 showed consistently high sensitivity to the action of T1084: a significant antitumor effect with high TGI (43-58%) was registered throughout the observation, without any signs of neoplasia adaptation. The effect of precursor compounds on melanoma B-16 was either minimal (for Na-DCA) or moderate (for T1023) with TGI only 33%, which subsequently decreased by the end of the experiment. In contrast, the effect of T1084 on B-16 was qualitatively more pronounced and steadily increasing; it was accompanied by a 3-fold expansion of necrosis and dystrophy areas, a decrease in proliferation, and increased apoptosis of tumor cells. Morphologically, the T1084 effect was 2-fold superior to the effects of T1023-the TGI index reached 59-62%. This study suggests that the antitumor effects of T1084 develop through the interaction of NOS-dependent and PDK-dependent pathophysiological effects of this NOS/PDK inhibitor. The NOS inhibitory activity of T1084 exerts an anti-angiogenic effect on neoplasia. At the same time, the PDK inhibitory activity of T1084 enhances the cytotoxicity of induced intratumoral hypoxia and suppresses the development of neoplasia adaptation to anti-angiogenic stress. Such properties allow T1084 to overcome tumor resistance and realize a stable synergistic antitumor effect.