Recent patents on anti-cancer drug discovery最新文献

Background: Mass spectrometry imaging (MSI) is an imaging method based on mass spectrometry technology that can simultaneously visualize the spatial distribution of various biological molecules. The use of MSI in cancer detection and drug discovery has been extensively investigated in recent years.

Objective: This review aims to summarize the latest advances of MSI and its specific applications in cancer detection and drug discovery, providing a basic understanding of the development and application of MSI in the past five years and offering references for the further application of MSI in cancer detection and drug discovery.

Methods: In the database, "mass spectrometry imaging", "cancer treatment", and "drug discovery" were used as keywords for literature retrieval, and the time range was limited to "2018- 2023". After organizing and analyzing the literature and patents, a review was conducted.

Results: Based on the literature, it was found that the updated progress of MSI in the past five years mostly focused on concrete methods, operation procedures, facilities, and composite applications. The patents of MSI were mainly correlated with the mass spectrometry imaging system and its application in cancer treatment. MSI is conducive to investigating the therapeutic schedule of cancer and searching for new drugs.

Conclusion: MSI is a convenient, fast and powerful technology that has made great progress in sample preparation, instrumentation, quantitation, and multimodal imaging. MSI has emerged as a powerful technique in various biomedical applications, which has strong potential in cancer detection, treatment, formation mechanism research, discovery of biomarkers, and drug discovery process.

Breast cancer is a public health issue in developing and developed countries. Nowadays, the concept of BCSC (breast cancer stem cell) is gaining popularity among oncology researchers. The breast cancer stem cell is a tiny cell fraction inside the tumor mass that shows features that look like stem cells that are implicated in the genesis, recurrence, and metastasis of breast cancer tumors. Extracellular cues, mutations, and epigenetic control all contribute to the intricacy of gene expression control in Breast cancer stem cells. Thus, signaling pathways identified in breast cancer are Hedgehog and NOTCH, signal transducer and transcription 3, wingless-type MMTV integration site family (Wnt)/-catenin, and nuclear factor-kappa B, particularly connected with a phenotype of stem cell. Furthermore, the tumor microenvironment, such as hypoxic regions, can impact these BCSCs. Various approved signaling pathway targeted molecules have been patented, which show protective effects against breast cancer and have been used in clinical uses. PARP inhibitors are found to be very useful in the treatment of breast cancer. Promoting studies on the molecular pathways underlying the development of cancer in breast cancer patients was one of the main objectives of this study topic. The objective of this review Topic was to discover new intrinsic and extrinsic molecular pathways. Research focusing on novel signaling pathways that may lead to novel treatments or identifying patients at-risk of not responding to standard therapy approaches were the areas of focus we highlighted. The paper covers the linkage between breast cancer stem cells and cellular signaling, the tumor microenvironment in BC, and the relevance of signaling pathways and their therapeutic interventions. The review also covered patent applications associated with these signaling pathways and their prospects.

Background: Oxidative stress refers to non-homeostatic elevation within intracellular reactive oxygen species (ROS) levels and is associated with several neuro-related pathological conditions. Diclofenac is a commonly prescribed non-steroidal anti-inflammatory drug (NSAID) for treating aches and pain by reducing inflammation. Diclofenac is also associated with the induction of apoptotic cell death by altering the homeostatic balance within mitochondria. In the present report, the neuroprotective effects of BNC formulation constituted by Bacopa monnieri leaves, Nigella sativa and Curcuma longa rhizome seeds were investigated.

Methods: The synthesized formulation was characterized using FT-IR and LC-MS along with organoleptic evaluation. Thereafter neuroprotective efficacy of BNC formulation was subsequently investigated against Diclofenac-induced oxidative stress in SH-SY5Y cells. The cells were pretreated with synthesized formulation and subsequently evaluated for amelioration in Diclofenac-induced cytotoxicity, and ROS augmentation. The neuroprotective effect of synthesized formulation was further explored by evaluating the changes in nuclear morphology, and apoptosis alleviation with concomitant regulatory effects on caspase-3 and -9 activation.

Results: Diclofenac was found to be considerably cytotoxic against human neuroblastoma SHSY5Y cells. Intriguingly, Diclofenac-mediated toxicity was reduced significantly in SH-SY5Y cells pretreated with BNC formulation. Augmented ROS levels within Diclofenac-treated SHSY5Y cells were also reduced in the BNC formulation pretreated SH-SY5Y cells. Furthermore, BNC formulation pretreated SH-SY5Y cells also exhibited reduced dissipation of mitochondrial membrane potential, caspase-3 and -9, along with apoptosis after Diclofenac treatment.

Conclusion: These findings indicated that, indeed, Diclofenac induces considerable ROSmediated apoptosis in SH-SY5Y cells, which further intriguingly ameliorated Diclofenacmediated cytotoxic effects on SH-SY5Y cells. This manuscript further collected information about available National and International patents published or granted in preparation of and thereof applications against motor and non-motor brain dysfunctions.

Background: Chronic constipation and irritable bowel syndrome (IBS) manifest as prevalent gastrointestinal disorders, while digestive tract cancers (DTCs) present formidable challenges to global well-being. However, extant observational studies proffer uncertain insights into potential causal relationships of constipation and IBS with susceptibility to DTCs.

Methods: We executed Mendelian randomization (MR) analysis to establish causal connections between these conditions and seven distinct categories of DTCs, including colorectal carcinoma (CRC), hepatocellular cancer (HCC), esophageal malignancy (ESCA), pancreatic adenocarcinoma (PAAD), biliary tract carcinoma (BTCs), gastric carcinoma (GC), and small intestine neoplasm (SIC). Leveraging instrumental variables (IVs) obtained from GWAS data of the FinnGen database, we employed a range of analytical methodologies, including inverse-variance weighting multiplicative random effects (IVW_MRE), inverse-variance weighting fixed effects (IVW_FE), maximum likelihood (ML), weighted median (WM), MR‒Egger regression, and the MR-PRESSO test.

Results: We observed a substantial linkage between genetically predicted constipation and increased vulnerability to PAAD (OR = 2.29, 95% CI: 1.422-3.69, P = 0.001) via the IVW method. Following the removal of outlier SNPs through MR-PRESSO, genetically predicted IBS was affiliated with an increased risk of CRC (OR = 1.17, 95% CI: 1-1.37, P = 0.05). Nonetheless, decisive causal correlations of constipation or IBS with other DTCs remain elusive.

Conclusion: In summary, genetically predicted constipation was associated with an augmented PAAD risk, and IBS was associated with an increased CRC susceptibility within European cohorts, in agreement with some observational studies. Nevertheless, the causal associations of constipation and IBS with other DTCs remain inconclusive.

Background: Accumulated evidence suggest that tumor microenvironment (TME) plays a crucial role in breast cancer (BRCA) progression and therapeutic effects.

Objective: This study aimed to characterize immune-related BRCA subtypes in TME, and identify genes with prognostic value.

Methods: RNA sequencing profiles with corresponding clinical data from The Cancer Genome Atlas (TCGA) database of BRCA patients were downloaded to evaluate immune infiltration using the single-sample gene set enrichment (ssGAEA) algorithm. Further, BRCA was clustered according to immune infiltration status by consensus clustering analysis. Using Venn analysis, differentially expressed genes (DEGs) were overlapped to obtain candidate genes. Kaplan-Meier (K-M) analysis was performed to identify prognostic genes, and the results were verified in the GEO and METABRIC datasets. RT-qPCR was conducted to detect the mRNA expression of prognostic genes.

Results: In the TCGA database, 3 immune-related BRCA subtypes were identified [cluster1 (C1), cluster2 (C2), and cluster3 (C2)]. The C2 subtype had better overall survival (OS) compared to the C1 subtype. Higher levels of immune markers and checkpoint protein were found in the C2 subtype than in others. By combining DEGs between BRCA and normal tissues, with the C1 and C2 subtypes associated with different OS, 25 BRCA candidate genes were identified. Among these, 8 genes were identified as prognostic genes for BRCA. RT-qPCR showed that the expressions of 2 genes were significantly elevated in BRCA tissues, while that of other genes were decreased.

Conclusion: Three BRCA subtypes were identified with the immune index, which may help design advanced treatment of BRCA. The data code used for the analysis in this article was available on GitHub (https://github.com/tangzhn/BRCA1.git).

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, 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: 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.

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, but molecular complexity and tumor heterogeneity make predictive models for HCC prognosis ineffective. Many recent studies have suggested that autophagy is important in tumor progression. Using autophagy-related genes (ARGs), we attempted to create a novel signature for individual prognosis prediction in patients with HCC.

Methods: Differentially expressed ARGs (DE-ARGs) in HCC and normal samples were screened using TCGA datasets. Univariate Cox and multivariate Cox regression analyses were performed to determine ARGs related to survival in HCC. An autophagy-based signature was constructed using LASSO, and its correlation with the prognosis and the immune infiltration of HCC patients was explored.

Results: In this study, we screened 32 survival-related DE-ARGs by analyzing TCGA datasets. Functional enrichment indicated that the 32 DE-ARGs may play important functional and regulatory roles in cellular autophagy, the regulation of multiple signaling pathways, as well as in the context of cancer and neurological diseases. Based on PPI Network, we identified several hub genes. LASSO Cox regression analysis selected five genes (CASP8, FOXO1, PRKCD, SPHK1, and SQSTM1) for a novel prognostic model. AUCs of 0.752, 0.686, and 0.665 in the TCGA whole set indicated that the model accurately predicted 1-, 3-, and 5-year overall survival, respectively. Cox regression analysis showed that the five-gene signature is an independent and robust predictor in patients with HCC. The high-risk group demonstrated higher levels of immune cell infiltration and exhibited a strong correlation with the immune microenvironment and tumor stem cells. In addition, we further identified PRKCD and SQSTM1 as critical regulators involved in HCC progression. The expression levels of PRKCD and SQSTM1 genes play a crucial role in chemotherapy drug sensitivity and resistance.

Conclusion: We introduce here a novel ARG-based predictive feature for HCC patients. Effective use of this signature will aid in determining a patient's prognosis and may lead to novel approaches to clinical decision-making and therapy.

Background: Arginine plays significant and contrasting roles in breast cancer growth and survival. However, the factors governing arginine balance remain poorly characterized.

Objective: We aimed to identify the molecule that governs arginine metabolism in breast cancer and to elucidate its significance.

Methods: We analyzed the correlation between the expression of solute carrier family 7 member 3 (SLC7A3), the major arginine transporter, and breast cancer survival in various databases, including GEPIA, UALCAN, Metascape, String, Oncomine, KM-plotter, CBioPortal and Prognosis. Additionally, we validated our findings through bioinformatic analyses and experimental investigations, including colony formation, wound healing, transwell, and mammosphere formation assays.

Results: Our analysis revealed a significant reduction in SLC7A3 expression in all breast cancer subtypes compared to adjacent breast tissues. Kaplan-Meier survival analyses demonstrated that high SLC7A3 expression was positively associated with decreased nodal metastasis (HR=0.70, 95% CI [0.55, 0.89]), ER positivity (HR=0.79, 95% CI [0.65, 0.95]), and HER2 negativity (HR=0.69, 95% CI [0.58, 0.82]), and increased recurrence-free survival. Moreover, low SLC7A3 expression predicted poor prognosis in breast cancer patients for overall survival. Additionally, the knockdown of SLC7A3 in MCF-7 and MDA-MB-231 cells resulted in increased cell proliferation and invasion in vitro.

Conclusion: Our findings indicate a downregulation of SLC7A3 expression in breast cancer tissues compared to adjacent breast tissues. High SLC7A3 expression could serve as a prognostic indicator for favorable outcomes in breast cancer patients due to its inhibitory effects on breast cancer cell proliferation and invasion.

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.