Recent patents on anti-cancer drug discovery最新文献

Background: Laryngeal squamous cell carcinoma (LSCC) is the most common cancer of head and neck cancer. Y-box binding protein-1 (YBX1) has tumor-promoting effects in some types of cancers. However, its role in LSCC remains unknown. This study set out to identify the role of YBX1 in LSCC.

Methods: Bioinformatics analysis of the Gene Expression Omnibus (GEO) database and our cohort data were used to explore the association of YBX1 expression with clinicopathological factors in LSCC. Then, cells with stably or transiently transfected with plasmid or siRNA were constructed to assess the effect of loss and gain of YBX1 on the biological phenotypes of LSCC cells in vitro. In addition, subcutaneous xenograft and orthotopic liver tumor mouse models were constructed for validation. The interrogated miRNA databases and subsequent luciferase reporter assays were used to confirm the miR-382-5p target of YBX1. At last, KEGG enrichment annotation from TGCA data was used for downstream analyses of miR-382-5p/YBX1 and verified by PCR and Western immunoblotting.

Results: The results showed that significant upregulation of YBX1 in LSCC tumors was correlated with advanced TNM stage and poor prognosis. Knockdown of YBX1 markedly impaired the proliferative, invasive, and migratory activity of Tu212 cells. We confirmed that miR-382-5p targets YBX1 to mediate LSCC progression both in vitro and in vivo. We further confirmed that miR-382-5p/YBX1 modulated the Ras/MAPK signaling axis to regulate the progression of LSCC.

Conclusion: Together, our results indicated that YBX1 is an important promoter of LSCC progression. And miR-382-5p/YBX1/RAS/MAPK signaling pathway can be perceived as a promising target in the treatment of LSCC.

Among the deadliest diseases, cancer is characterized by tumors or an increased number of a specific type of cell because of uncontrolled divisions during mitosis. Researchers in the current era concentrated on the development of highly selective anticancer medications due to the substantial toxicities of conventional cytotoxic drugs. Several marketed drug molecules have provided resistance against cancer through interaction with certain targets/growth factors/enzymes, such as Telomerase, Histone Deacetylase (HDAC), Methionine Aminopeptidase (MetAP II), Thymidylate Synthase (TS), Glycogen Synthase Kinase-3 (GSK), Epidermal Growth Factor (EGF), Vascular Endothelial Growth Factor (VEGF), Focal Adhesion Kinase (FAK), STAT3, Thymidine phosphorylase, and Alkaline phosphatase. The molecular structure of these drug molecules contains various heterocyclic moieties that act as pharmacophores. Recently, 1,3,4- oxadiazole (five-membered heterocyclic moiety) and its derivatives attracted researchers as these have been reported with a wide range of pharmacological activities, including anti-cancer. 1,3,4- oxadiazoles have exhibited anti-cancer potential via acting on any of the above targets. The presented study highlights the synthesis of anti-cancer 1,3,4-oxadiazoles, their mechanism of interactions with targets, along with structure-activity relationship concerning anti-cancer potential.

One of the major disturbing pathways within cancer is "The Kirsten rat sarcoma viral oncogene homolog (KRAS) pathway", and it has recently been demonstrated to be the most crucial in therapies and diagnostics. KRAS pathway includes numerous genes. This multi-component signaling system promotes cell growth, division, survival, and death by transferring signals from outside the cell to its interior. KRAS regulates the activation of a variety of signaling molecules. The KRAS oncogene is a key player in advancing a wide range of malignancies, and the mutation rank of this gene is a key feature of several tumors. For some malignancies, the mutation type of the gene may offer information about prognostic, clinical, and predictive. KRAS belongs to the RAS oncogene family, which consists of a compilation of minor GTP-binding proteins that assimilate environmental inputs and trigger internal signaling pathways that control survival, cell differentiation, and proliferation. This review aims to examine the recent and fascinating breakthroughs in the identification of new therapies that target KRAS, including the ever-expanding experimental approaches for reducing KRAS activity and signaling as well as direct targeting of KRAS. A literature survey was performed. All the relevant articles and patents related to the KRAS pathway, the mutation in the KRAS gene, cancer treatment, and diagnostics were found on PubMed and Google Patents. One of the most prevalent causes of cancer in humans is a mutation in the K-RAS protein. It is extremely difficult to decipher KRAS-mediated signaling. It allows transducing signals to go from the cell's outer surface to its nucleus, having an influence on a variety of crucial cellular functions including cell chemotaxis, division, dissemination, and cell death. Other involved signaling pathways are RAF, and the phosphatidylinositol 3 kinase also known as AKT. The EGFR pathway is incomplete without KRAS. The activation of PI3K significantly contributes to acquiring resistance to a mixture of MEK inhibitors and anti-EGFR in colorectal cancer cell lines which are mutated by KRAS. A series of recent patent studies towards cancer diagnostics and therapeutics reveals the paramount importance of mutated protein KRAS as an extensive driver in human tumors. For the prognosis, diagnosis, and treatment of colorectal cancer, KRAS plays a critical role. This review concludes the latest and vowing developments in the discovery of novel techniques for diagnosis and drugs that target KRAS, the advancements in experimental techniques for signaling and inhibiting KRAS function, and the direct targeting of KRAS for cancer therapeutics.

Background: Ribosome-inactivating proteins (RIPs) have been reported to exert antitumor and anti-virus activities. A recent patent CN202011568116.7 has developed a new method to prepare Momordica anti-HIV protein of 30 kDa (MAP30). MAP30 is a type I RIP, which kills various tumor cells through the N-glycosidase activity and irreversibly inhibits protein synthesis.

Objective: To assess the potential role of MAP30 in inducing apoptosis of human hepatocellular carcinoma HCC-LM3 cells and elucidate the molecular mechanism of MAP30.

Methods: CCK-8 assay was used to assess the proliferation of HCC-LM3 cells. Flow cytometry was used to measure the cycle, the level of ROS and apoptosis in HCC-LM3 cells. Western blots was used to measure protein levels.

Results: Treatment with MAP30 reduced survival and proliferation of human liver cancer HCCLM3 cells in a dose-dependent manner. PI staining showed cell cycle arrest in G0/G1 phase. Furthermore, MAP30 increased the level of ROS in HCC-LM3 cells in 24 h treatment. To further confirm the role of MAP30 in inducing cell apoptosis, immunoblotting was carried out to detect the change of apoptosis-related proteins including PARP poly (ADP-ribose) polymerase (PARP- 1), Casepase3 and Cleaved-Caspase9. We found that PARP-1 and Caspase-3 were downregulated, whereas Cleaved-Caspase9 was up-regulated in HCC-LM3 cells treated with MAP30.

Conclusion: This study indicated that MAP30 has the potential to be a novel therapeutic agent for human hepatocellular carcinoma.

mRNA emerged as an attractive therapy modality with the development of mRNA structure engineering techniques and delivery platforms. mRNA therapeutics, applied for vaccine therapy, protein replacement therapy, and chimeric antigen receptor (CAR) T cell-based therapy, has shown huge potential in treating a wide range of diseases, such as cancer and rare genetic diseases, with successful and exciting preclinical and clinical progress. In mRNA therapeutics, a potent delivery system is key to the success of its application for disease treatment. Herein, different types of mRNA delivery strategies, including nanoparticles produced from lipid or polymer materials, virus-based platforms, and exosome-based platforms, are mainly focused.

Introduction: This study aimed to explore the expression profiles of fatty acid metabolism- related genes (FAMRGs) in patients with bladder cancer (BLCA).

Methods: The corresponding clinicopathological features of BLCA patients and RNA sequencing data were downloaded from TCGA and GSE13507. Univariate Cox regression was used to determine the prognostic value of FRGS in BLCA patients. LASSO regression analysis was then performed to select potential risk genes and eliminate genes that might overfit the model. Based on the independent prognostication-related FRGs, the nomogram survival model was established using the root mean square value of the R packet to predict the 1-year, 3-year, and 5-year survival rates of BLCA patients. By determining the area under the curve (AUC) value, the time-dependent receiver operating characteristic curve (ROC) was used to evaluate the prognostic efficiency of our model.

Results: A total of 243 DEFRGs were identified. Twenty FRGs were found to be related to the prognosis of BLCA in the TCGA database. Survival curves showed that high-risk patients had significantly shorter OS than low-risk cases (p < 0.001). The AUC of risk was 0.784, which was superior to age, sex, and stage, suggesting that the risk score was more favorable in predicting OS than traditional pathologic prognostic factors. The AUC was 0.757 at 1 year, 0.732 at 3 years, and 0.733 at 5 year-OS.

Conclusion: In this study, we demonstrated that a FAMRG prognosis biomarker is associated with the tumor immune microenvironment in patients with BLCA.

Background: As the second most prevalent hematologic malignancy, multiple myeloma (MM) affects plasma cells and is characterized by chromosomal abnormalities, particularly involving the immunoglobulin heavy chain switch region. MM represents a biologically and clinically heterogeneous hematological malignancy that serves as a clonal evolution model, exhibiting clonal heterogeneity throughout all stages from monoclonal gammopathy undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to MM. Although significant progress has been made in the treatment of MM, leading to improved patient outcomes, concerns are arising regarding disease relapse due to the presence and selection of pre-existing resistant clones or selective pressure during therapy.

Case presentation: We present a case of multiple myeloma (MM) in a female patient, who underwent an 8-year course of treatment, including chemotherapy, immunomodulators, hematopoietic stem cell transplantation, CD38 monoclonal antibody, and chimeric antigen receptor T-cell (CAR-T), and was recently diagnosed with concurrent progressive MM and acute myeloid leukemia (AML). This patient has witnessed the evolution of MM treatment paradigms.

Conclusion: In this course, disease relapses occurred twice, one of which was manifested by a light chain escape (LCE). Moreover, through the course of the disease in this patient, we review the process of clonal evolution that may be relevant.

Background: Both apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) inhibition and melatonin suppress prostate cancer (PCa) growth.

Objective: This study evaluated the therapeutic efficiency of self-assembled and prostate-specific membrane antigen (PSMA)-targeted nanocarrier loading ¹²⁵I radioactive particles and encapsulating siRNA targeting APE1 (siAPE1) and melatonin for PCa.

Methods: The linear polyarginine R12 polypeptide was prepared using Fmoc-Arg-Pbf-OH. The PSMA-targeted polymer was synthesized by conjugating azide-modified R12 peptide to PSMA monoclonal antibody (mAb). Before experiments, the PSMA-R12 nanocarrier was installed with melatonin and siAPE1, which were subsequently labeled by ¹²⁵I radioactive particles. In vitro biocompatibility and cytotoxicity of nanocomposites were examined in LNCaP cells and in vivo biodistribution and pharmacokinetics were determined using PCa tumor-bearing mice.

Results: PSMA-R12 nanocarrier was ~120 nm in size and was increased to ~150 nm by melatonin encapsulation. PSMA-R12 nanoparticles had efficient loading capacities of siAPE1, melatonin, and ¹²⁵I particles. The co-delivery of melatonin and siAPE1 by PSMA-R12-¹²⁵I showed synergistic effects on suppressing LNCaP cell proliferation and Bcl-2 expression and promoting cell apoptosis and caspase-3 expression. Pharmacokinetics analysis showed that Mel@PSMA-R12-¹²⁵I particles had high uptake activity in the liver, spleen, kidney, intestine, and tumor, and were accumulated in the tumor sites within the first 8 h p.i., but was rapidly cleared from all the tested organs at 24 h p.i. Administration of nanoparticles to PCa tumors in vivo showed that Mel@PSMA-R12- ¹²⁵I/siAPE1 had high efficiency in suppressing PCa tumor growth.

Conclusion: The PSMA-targeted nanocarrier encapsulating siAPE1 and melatonin is a promising therapeutic strategy for PCa and can provide a theoretical basis for patent applications.

Background: Epithelial-to-mesenchymal transition (EMT) plays a role in the invasion and metastasis of cancer cells. During this phenomenon, Snail can promote tumor progression by upregulating mesenchymal factors and downregulating the expression of pro-apoptotic proteins.

Objective: Therefore, interventions on the expression rate of Snails may show beneficial therapeutic applications.

Methods: In this study, the C-terminal region of Snail1, capable of binding to E-box genomic sequences, was subcloned into the pAAV-IRES-EGFP backbone to make complete AAV-CSnail viral particles. B16F10 as a metastatic melanoma cell line, with a null expression of wild type TP53 was transduced by AAV-CSnail. Moreover, the transduced cells were analyzed for in vitro expression of apoptosis, migration, and EMT-related genes, and in vivo inhibition of metastasis.

Results: In more than 80% of the AAV-CSnail transduced cells, the CSnail gene expression competitively reduced the wild-type Snail functionality and consequently lowered the mRNA expression level of EMT-related genes. Furthermore, the transcription level of cell cycle inhibitory factor p21 and pro-apoptotic factors were promoted. The scratch test showed a decrease in the migration ability of AAV-CSnail transduced group compared to control. Finally, metastasis of cancer cells to lung tissue in the AAV-CSnail-treated B16F10 melanoma mouse model was significantly reduced, pointing out to prevention of EMT by the competitive inhibitory effect of CSnail on Snail1 and increased apoptosis of B16F10 cells.

Conclusion: The capability of this successful competition in reducing the growth, invasion, and metastasis of melanoma cells indicates that gene therapy is a promising strategy for the control of the growth and metastasis of cancer cells.