Recent patents on anti-cancer drug discovery最新文献

Background: The precise function of Tolloid Like 2 (TLL2) remains uncertain within the context of Lung Adenocarcinoma (LUAD).

Objectives: The primary objective of this investigation was to conduct a thorough analysis.

Methods: To assess its diagnostic utility, data from The Cancer Genome Atlas (TCGA) database were used to assess TLL2 expression in pan-cancer and LUAD. The study has also investigated the correlation between TLL2 expression levels and LUAD symptoms and prognosis. Furthermore, the study has explored possible regulatory networks involving TLL2, including its association with immune infiltration, tumor stemness index (mRNAsi), and drug sensitivity in LUAD. We have explored TLL2 expression in single-cell sequencing of LUAD and the genomic variation and clinical significance of TLL2 in LUAD. The expression of TLL2 has been validated in GSE87340 and cell lines by quantitative Real-time PCR (qRT-PCR).

Results: An abnormal expression of TLL2 has been found in pan-cancer and LUAD. In LUAD patients, elevated levels of TLL2 were significantly related to the T stage (p = 0.046) and the pathological stage (p = 0.016). The expression of TLL2 in patients with LUAD was significantly associated with poorer Overall Survival (OS) (p < 0.001). The expression of TLL2 was determined to be an independent predictor of poorer OS (p = 0.042). TLL2 was associated with ribosome, neuroactive ligand-receptor interaction, allograft rejection, ECM receptor interaction, asthma, porphyrin and chlorophyll metabolism, focal adhesion, pentose and glucuronate inter-conversions, and ascorbate and aldarate metabolism. The expression of TLL2 in LUAD was correlated with immune infiltration and mRNAsi. The expression of TLL2 was significantly and negatively correlated with TAK-715, XMD13-2, STF-62247, OSI-930, and EHT-1864 in LUAD. The TLL2 gene was up- -regulated in multiple individual LUAD cells. LUAD patients with altered TLL2 had a shorter PFS as opposed to those with unaltered TLL2. The expression of TLL2 was significantly increased in LUAD cells.

Conclusion: For patients with LUAD, TLL2 may serve as an immunotherapeutic target and a useful prognosis biomarker.

Background: Triple-negative breast cancer (TNBC) has a poor prognosis with current treatment options. Novel therapeutic strategies are urgently needed to enhance treatment outcomes for TNBC.

Objective: This study evaluated the efficacy of a three-agent regimen compared to existing treatment regimens in a TNBC mouse model, and elucidated its potential mechanisms of action.

Methods: The TNBC xenograft tumor mouse model was established using a 4T1 cell line in female BALB/c mice. Mice were treated with the three-agent regimen and other comparative treatments. Tumor volume was monitored to assess the anti-tumor effects. Biochemical and pathological evaluations were conducted to examine the impact of the regimen on anti-tumor immunity, anti- tumor angiogenesis, and tumor cell apoptosis.

Results: The three-agent regimen consisting of SIN+BEV+PAB demonstrated significant anti-tumor efficacy compared to controls, PAB alone, SIN+PAB, and BEV+PAB groups from day 9 of drug administration. The superior anti-tumor effect of SIN+BEV+PAB was primarily attributed to enhanced anti-tumor immunity, evidenced by increased percentages of CD4+ and CD8+ T cells, elevated IFN-γ levels, and decreased percentages of Tregs, reduced levels of TGF-β, IL-6, and IL-10. Additionally, the regimen showed potent anti-angiogenic effects by reducing VEGF expression and micro vessel density (MVD). Furthermore, it promoted tumor cell apoptosis through upregulation of BAX and cleaved caspase3, while downregulating Bcl2.

Conclusion: These findings suggest that the novel three-agent combination of SIN+BEV+PAB may prove beneficial in improving treatment outcomes for patients with TNBC. The development of this regimen, which may be eligible for patent protection, could facilitate its introduction as a new therapeutic option for advanced TNBC in clinical practice.

Background: Colorectal cancer is a significant global public health challenge, contributing substantially to cancer-related mortality worldwide. Vitexin has been shown to promote the polarization of macrophages towards the M1 phenotype, a process dependent on the Vitamin D receptor. This polarization is crucial in the tumor microenvironment, as it helps mitigate the progression from chronic colitis to colorectal cancer. Despite its potential, the mechanisms of vitexin's action and its impact on colon cancer remain unclear.

Objective: This study aims to evaluate the inhibitory effects of vitexin on cell proliferation and apoptosis in the Caco-2 colon cancer cell line, with a specific focus on its modulation of antioxidant enzyme activities, pro-apoptotic factors, and key signaling pathways involved in cell survival and proliferation.

Methods: The IC₅₀ of vitexin against Caco-2 cells was determined. Cell viability and necrosis rates were assessed after 48 hours of incubation with vitexin at concentrations of 19.01, 38.01, and 76.02 μg/mL. Additionally, levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), P53, Bax, TSC2, Sestrin 2, and PUMA, as well as the expression of AMPK, PI3K, Akt, and mTOR genes and proteins, were measured using q-PCR and Western blotting techniques in Caco-2 cells post-incubation.

Results: Vitexin exhibited an IC₅₀ of 38.01 ± 0.64 μg/mL against Caco-2 cells. Treatment with vitexin at the specified concentrations for 48 hours resulted in a significant decrease in cell viability by 28.40%, with inhibitory rates reaching 71.6%. Apoptosis rates increased to 93.81%, 171.41%, and 294.12%, respectively, with a corresponding rise in necrosis rates by 194.19%, 400.22%, and 811.44%. Pharmacological analysis revealed that vitexin significantly inhibited SOD and CAT activities while enhancing MDA production. Furthermore, vitexin treatment upregulated the expression of key apoptotic markers (P53, Bax, TSC2, Sestrin 2, and PUMA) and the expression of AMPK, PI3K, and Akt, while downregulating mTOR genes and proteins, implicating various signaling pathways.

Conclusion: This study demonstrates that vitexin induces apoptosis in Caco-2 colon cancer cells through multiple mechanisms, including modulation of antioxidant enzymes, upregulation of pro-apoptotic factors, and regulation of key signaling pathways involved in cell survival and proliferation. These findings suggest that vitexin's mechanisms of action involve complex interactions with various cellular pathways, making it a promising candidate for further research and potential therapeutic applications in colorectal cancer.

Objective: Current cisplatin (CDDP) resistance remains a major challenge in the treatment of advanced gastric cancer. To address the issue of drug resistance, we explored the regulatory functions of PDZ and LIM structural domain protein 1 (PDLIM1) in CDDP chemotherapy for gastric cancer.

Methods: In this study, we analyzed PDLIM1 expression and prognosis using bioinformatics on publicly available data. PDLIM1 expression in a gastric mucosal epithelial cell line (GSE-1), CDDP- sensitive (SGC7901, BGC823) and CDDP-resistant gastric cancer cells was detected by RTqPCR and Western blotting. Cell proliferative capacity was assessed by knockdown of PDLIM1 and overexpression of PDLIM1 in cells administered in combination with cisplatin, and apoptotic levels were measured by CCK-8 and colony formation assay and by flow cytometry. Expression of breast cancer susceptibility gene 1 (BRCA1) and γH2AX was determined by Western blotting or immunofluorescence staining.

Results: Downregulation of PDLIM1 was found in tumor tissues and cells, which was associated with poor clinical outcomes. Knockdown of PDLIM1 enhanced proliferation and attenuated apoptosis in gastric cancer cells. In addition, the therapeutic effects of CDDP on proliferation, apoptosis, and DNA damage repair were attenuated by PDLIM1 deletion.PDLIM1 expression was downregulated in CDDP-resistant tumor cells. Overexpression of PDLIM1 overcomes CDDP resistance in tumor cells as BRCA1 expression decreases and γH2AX expression increases.

Conclusion: Our findings demonstrate that PDLIM1 enables to alleviate gastric cancer progression and resistance to cisplatin via impeding DNA damage repair.

Background: Chromosomal rearrangements involving the Mixed lineage leukemia (MLL) gene are observed in acute leukemia (AL) patients, which have poor prognosis, especially in infants. Hence, there is still a challenge to develop other effective agents to treat AL with MLL rearrangements (MLLr). MLL has been shown to rearrange with partner genes, of which the most frequently observed are AF4 and AF9. Moreover, AL is characterized by a differentiation blockage resulting in the accumulation of immature cells. An ent-kaurene diterpenoid compound, Jiyuan Oridonin A (JOA), has been shown to reduce the viability of AML cells by differentiation.

Methods: We aimed to evaluate the effect of JOA on the growth and differentiation of AL cells (SEM, JURKAT and MV4-11) including cells with MLLr-AF4 by cell proliferation assay, colony formation assay, cell cycle analysis, cell apoptosis analysis, measurement of cell surface antigens and cell morphology, mRNA-sequencing analysis, quantitative Real-time PCR and Western blotting analysis.

Results: Our findings demonstrated that the proliferation of AL cells including cells with MLLr-AF4 was significantly suppressed by JOA, which induced cell differentiation followed by G0/G1 cell cycle withdrawal. Moreover, JOA-mediated cell differentiation was likely due to activation of G-CSFR in MV4-11 cells.

Conclusion: Our results suggest that JOA may be considered a promising anti-leukemia compound to develop to surmount the differentiation block in AL patients.

Background: Curcumin has been reported to have anti-hepatocellular carcinoma (HCC) effects, but the underlying mechanism is not well known.

Objectives: To investigate whether membrane-associated RING-CH 1 (MARCH1) is involved in the curcumin-induced growth suppression in HCC and its underlying molecular mechanism. A few recent patents for curcumin for cancer are also reviewed in this article.

Methods: The effect of curcumin on growth inhibition of HCC cells was analyzed through in vitro and in vivo experiments, and the expression levels of MARCH1, Bcl-2, VEGF, cyclin B1, cyclin D1, and JAK2/STAT3 signaling molecules were measured in HCC cells and the xenograft tumors in nude mice. Cell transfection with MARCH1 siRNAs or expression plasmid was used to explore the role of MARCH1 in the curcumin-induced growth inhibition of HCC cells.

Results: Curcumin inhibited cell proliferation, promoted apoptosis, and arrested the cell cycle at the G2/M phase in HCC cells with the decrease of Bcl-2, VEGF, cyclin B1, and cyclin D1 expression as well as JAK2 and STAT3 phosphorylation, resulting in the growth suppression of HCC cells. MARCH1 is highly expressed in HCC cells, and its expression was downregulated after curcumin treatment in a dose-dependent manner. The knockdown of MARCH1 by siRNA decreased the phosphorylation levels of JAK2 and STAT3 and inhibited the growth of HCC cells. In contrast, opposite results were observed when HCC cells overexpressed MARCH1. A xenograft tumor model in nude mice also showed that curcumin downregulated MARCH1 expression and decelerated the growth of transplanted HCC with the downregulation of JAK2/STAT3 signaling and functional molecules. The ADC value of MRI analysis showed that curcumin slowed down the progression of HCC.

Conclusion: Our results demonstrated that curcumin may inhibit the activation of JAK2/STAT3 signaling pathway by downregulating MARCH1 expression, resulting in the growth suppression of HCC. MARCH1 may be a novel target of curcumin in HCC treatment.

Background: Colorectal cancer is a common malignant tumor, with about one million people diagnosed with it worldwide each year. Recent studies have found that metformin can inhibit the production of inflammatory factors and regulate the polarization of immune cells. However, whether metformin can regulate the inflammatory microenvironment and delay the progression of colorectal cancer by inhibiting the inflammatory response has not been deeply studied yet.

Objectives: This study aimed to explore the molecular mechanism by which metformin inhibits the expression of NLRP3 inflammasome, regulates the inflammatory microenvironment, and delays the progression of colorectal cancer through in vitro cell experiments.

Methods: In this research, NLRP3 was knocked down in human colorectal cancer cells, and metformin was added to them. Cell proliferation ability was detected by CCK8, and cell migration and invasion abilities were assessed by Transwell assay. The apoptosis rate was determined by flow cytometry. In addition, the expression of NLRP3 inflammatory vesicles and inflammatory factors in each group of cells was studied by qRT-PCR and Western blotting. Finally, clinical colorectal cancer samples were analyzed by immunohistochemistry.

Results: The results of the study showed that NLRP3 expression was significantly increased in colorectal cancer cell lines and human colorectal cancer tissues. Knockdown of NLRP3 significantly inhibited tumor cell proliferation, migration, and invasion. In addition, the proliferation, migration and invasion of tumor cells were also significantly reduced by the addition of metformin intervention. Furthermore, qRT-PCR and WB results demonstrated that the expression of IL-1β, IL-6, TNF- α, TGF-β, and IL-10 was down-regulated in LS1034 tumor cells after NLRP3 knockdown. In addition, metformin intervention also resulted in different degrees of downregulation of NLRP3 and inflammatory factor expression (p π0.05). Notably, the reduction in inflammatory factors was more pronounced after the combination of NLRP3 knockdown and metformin intervention.

Conclusion: Metformin can inhibit the expression of NLRP3 inflammasome, thereby suppressing the expression of inflammation-related factors, reducing the damage of the inflammatory microenvironment to normal cells, and delaying the progression of colorectal cancer.

Background: Lenvatinib is a tyrosine kinase inhibitor that can improve progression-free survival in patients with thyroid cancer and hepatocellular carcinoma. However, it is limited by adverse cardiovascular events, including hypertension and cardiac dysfunction. Activation of endoplasmic reticulum stress is involved in cardiomyocyte apoptosis.

Objective: This study aimed to confirm whether the cardiotoxicity of lenvatinib is associated with endoplasmic reticulum stress by targeting the activating transcription factor 6 (ATF6), inositol- requiring enzyme 1α (IRE1α) and protein kinase RNA-like ER kinase (PERK) signaling pathways.

Methods: Male C57/BL6 mice were intragastric administration with 30 mg/kg/day lenvatinib. Electrocardiography (ECG) and echocardiography were used to detect arrhythmias and cardiac function. Neonatal rat cardiomyocytes were treated with lenvatinib for 48h. Cell counting kit (CCK8), 2´,7´-dichlorodihydrofluoresceine diacetate (H2DCFHDA), Hoechst 33258 and dihydrorhodamine 123 were respectively used for evaluating cell viability, the level of reactive oxygen species (ROS), nuclear morphological changes and mitochondrial membrane potential (MMP) level.

Results: Lenvatinib remarkably decreased the posterior wall thickness of left ventricle during diastole and systole but caused little decrease to the left ventricular ejection fraction (LVEF, %). Furthermore, lenvatinib greatly prolonged the corrected QT interval (QTc) and altered the morphology of cardiomyocytes. No significant difference in fibrosis was found in mouse cardiac slices. Lenvatinib upregulates apoptosis-related protein expression. In addition, lenvatinib increased ERS-related proteins expression (GRP78, CHOP, and ATF6) and enhanced PERK phosphorylation. In neonatal rat cardiac myocytes, lenvatinib markedly decreased the viability of cardiomyocytes and induced apoptosis. Furthermore, ROS production increased and MMP decreased. Similar to the mice experiment, lenvatinib caused upregulation of apoptosis-related and ERS-related proteins and increased the phosphorylation levels of PERK and IRE1α.

Conclusion: Lenvatinib-induced cardiotoxicity is associated with ERS-induced apoptosis by targeting the ATF6, IRE1α, and PERK signaling pathways.

Background: Recent studies reported that terminal nucleotidyltransferase 5A (TENT5A) is highly expressed in glioblastoma and associated with poor prognosis. In this work, we aim to specify the expression level of TENT5A in different grades of glioma and explore its role in glioma progression.

Methods: GEPIA online tools were used to perform the bioinformatic analysis. qRT-PCR, Western blot, and Immunohistochemistry were performed in glioma cells or tissues. Furthermore, CCK8, colony formation, transwell, flow cytometry and scratch assays were performed.

Results: TENT5A was highly expressed in glioma and its level was associated with the pathological grade of glioma. Knockdown of TENT5A suppressed cell proliferation, colony formation ability, cell invasion and migration. Overexpression of TENT5A was lethal to the glioma cells.

Conclusion: Our data showed that the expression of TENT5A is associated with the pathological grade of glioma. Knockdown of TENT5A decreased the ability of proliferation, invasion and migration of glioma cells. High levels of TENT5A in glioma cells are lethal. Therefore, TENT5A could be a new target for glioma treatment.

Esophageal carcinoma, a lethal malignancy with limited treatment options and poor prognosis, necessitates understanding its underlying mechanisms and identifying novel therapeutic targets. Recent studies have highlighted the critical role of the immune microenvironment in esophageal carcinoma, particularly the interplay between tumor cells and immune cells mediated by exosomes and their cargos. Exosomes, small extracellular vesicles secreted by various cells, including tumor cells, facilitate intercellular communication by transferring bioactive molecules such as proteins, nucleic acids, and lipids to recipient cells. In the context of esophageal carcinoma, tumor-derived exosomes have been shown to play a significant role in shaping the immune microenvironment. In esophageal carcinoma, exosomal cargos have been found to modulate immune cell function and impact tumor progression. These cargos can carry immune inhibitory molecules, such as programmed death-ligand 1 (PD-L1), to suppress T-cell activity and promote immune evasion by tumor cells. Furthermore, exosomal cargos can activate antigen- presenting cells, enhancing their ability to present tumor-specific antigens to T cells and thereby promoting anti-tumor immune responses. Additionally, the cargos of exosomes have been implicated in the induction of immune regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) within the esophageal carcinoma microenvironment. These immunosuppressive effectors inhibit the activity of T cells, contributing to tumor immune evasion and resistance to immune therapies. In summary, exosomes and their cargo play a crucial role in the immune microenvironment of esophageal carcinoma. Understanding the mechanisms by which exosomal cargos regulate immune cell function and tumor progression may reveal novel therapeutic targets for this devastating disease.