Current cancer drug targets最新文献

Background: Cisplatin resistance significantly affects the outcome of gastric cancer treatment. In this study, genes associated with cisplatin resistance were investigated and discussed.

Methods: We analyzed the sequencing data of GSE14208 patients from the GEO database using differential and enrichment analyses. Gastric cancer cells with high ADH1B expression and low ADH1B expression were selected by qPCR and WB to construct ADH1B overexpress and silence cells. The optimal cisplatin concentrations for treatment were determined via CCK-8 detection and WB. Furthermore, we assessed drug resistance, cellular activity, and invasion and migration capacities using IC50, CCK-8 assays, Transwell, and migration tests. Apoptosis was evaluated using flow cytometry and EDU staining. The pathway influenced by ADH1B was examined through WB and immunofluorescence. The impact of gene expression on the tumorigenic potential of gastric cancer cells was assessed by analyzing tumor size, mass, and histology in HE-stained tumor sections and Ki67 and protein pathway immuno-histochemistry in a mouse tumorigenesis model.

Results: This study revealed that ADH1B may exhibit a cancer-promoting effect, according to our database analysis, and is associated with drug resistance. Silencing ADH1B in AGS cells led to a reduced IC50, as well as decreased viability, invasion, and migration capabilities while increasing apoptosis rates. Conversely, overexpressing ADH1B in MKN-45 cells reversed these effects. Western blot and immunofluorescence results indicated that the expression levels of proteins involved in the EMT, PI3K, and MAPK pathways were altered following the silencing and overexpression of ADH1B. Moreover, silencing ADH1B not only reduced tumor volume and weight but also enhanced the tumor-reducing effects of cisplatin, as evidenced by changes in tumor structure; overexpression had the opposite effects. The alterations in pathway protein expression in tumor sections mirrored those observed in cells.

Conclusion: This study identified the gene ADH1B as a critical factor in the incidence and drug resistance of gastric cancer. It was demonstrated through cellular and tumorigenic assays that ADH1B promotes carcinogenesis and enhances cisplatin resistance in gastric cancer cells via the EMT signaling pathways.

Background: Bone cancer pain is a global medical concern with limited treatment options that significantly reduce the quality of life for cancer patients. Therefore, identifying a promising therapeutic target for bone cancer pain is urgently needed.

Objective: Our previous research indicated that KCC2 may be associated with the modulation of HDAC2 in a rat model of bone cancer pain. The current study aimed to investigate whether KCC2 in the lumbar spinal cord is a key downstream molecule in the modulation of HDAC2 related to bone cancer pain.

Methods: In this study, we assessed the expression levels of KCC2 and HDAC2 in the lumbar spinal cord of rats with bone cancer pain using Western blotting and RT-PCR. Mechanical hyperalgesia was evaluated using Von Frey hairs, and immunofluorescence was employed to localize KCC2 in central nervous system cells.

Results: The expression of KCC2 was down-regulated in a time-dependent manner in the lumbar spinal cord of rats with bone cancer pain. Furthermore, the use of an RNA-interfering lentivirus targeting HDAC2 restored KCC2 expression and alleviated mechanical hyperalgesia in these rats. Notably, the analgesic effect of the HDAC2-targeting lentivirus was completely reversed by the KCC2 inhibitor VU0240551.

Conclusion: KCC2 in the lumbar spinal cord mediated the modulation of HDAC2 in rat models of bone cancer pain, suggesting that KCC2 could be a promising therapeutic target for treating bone cancer pain.

Effective drug delivery to the brain is critically hindered by the blood-brain barrier (BBB), a selective barrier that complicates treatment for central nervous system (CNS) disorders, including brain tumors. Recent innovations in pharmaceutical sciences have introduced new strategies to surmount this challenge and enhance therapeutic efficacy. This review aims to assess recent advancements in engineered nanoplatforms designed to overcome the BBB, with a focus on their application in brain tumor targeting. It seeks to evaluate different drug delivery strategies and formulations that enhance brain penetration, improve targeting precision, and minimize systemic side effects. A comprehensive review of the literature and recent studies on brain-targeting strategies was conducted. The review examined the strategies to prolong blood circulation time and analyzed particularly the PEGylation approach, lipid-based nanocarrier, albumin binding strategies and red blood cell-based delivery. It also explored various strategies (e.g., peptides, prodrug, antibodies, nanotechnology, ligand-based delivery) and subcellular targeting techniques aimed at enhancing brain drug delivery and cellular uptake. PEGylation was found to significantly improve the ability of nano carriers to penetrate brain tumors by reducing macrophage-mediated clearance. Nanotechnology-based strategies coupled with ligand-based approaches effectively enhance brain delivery. Subcellular targeting strategies facilitated endolysosomal escape, leading to better therapeutic agent retention within brain tumor cells. Advances in nanotechnology and targeting strategies offer promising solutions for overcoming the BBB and improving brain tumor treatment. These novel strategies significantly enhance brain targeting while minimizing systemic effects. Continued research is essential to optimize these methods and achieve more effective therapeutic outcomes.

Cancer is one of the most challenging diseases to cure due to its complexity. Gli-oma, as a neuroepithelial cancer of the glial cells, is one of the rarest malignancies which has a low survival rate. The exact risk factors of glioma are still not clear, but allergy, ionizing radiation, and hereditary factors are reported to be associated with glioma. Nrf2 as an antiox-idant regulator has been reported to be highly expressed in malignances tissues like glioma. Nrf2 regulates the expression of various antioxidant and cytoprotective genes. In gliomas, Nrf2 activation helps tumor cells combat oxidative stress by enhancing the production of de-toxifying enzymes (e.g., glutathione peroxidase, NADPH quinone oxidoreductase). This al-lows glioma cells to survive and proliferate in toxic tumor microenvironments rich in reactive oxygen species (ROS). Although the role of Nrf2 in the apoptosis of cancerous glial cells is not clear yet, it has been shown that Nrf2 inhibition via different methods can increase the efficiency of the chemo-therapy agents to treat glioma. Elevated Nrf2 activity has been linked to drug resistance in gliomas. The activation of Nrf2 increases the expression of multidrug resistance-associated proteins (MRPs) and other detoxifying enzymes, which limit the effectiveness of chemother-apeutic agents like temozolomide (TMZ). Nrf2 inhibitors can suppress the signaling pathway of Nrf2 and decrease the expression of detoxifying enzymes like SOD, CAT, GPX, and GCL, which can increase the efficiency of chemotherapy agents. Using drugs that inhibit the Nrf2 expression in combination with classical chemotherapy agents can be a promising procedure to decrease chemoresistance and be effective in increasing the survival rate of patients with glioma. In this study, we focused on the association of glioma and Nrf2 expression and its targeting as a new therapeutic approach in glioma treatment.

Non-small cell lung cancer (NSCLC) includes various epithelial malignancies, such as squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Despite ad-vancements in surgical resection, chemoradiotherapy, and multimodal therapies, NSCLC prognosis remains challenging due to its complex molecular landscape, drug resistance, and high treatment costs. Recent research highlights the potential of natural compounds, particularly terpenes and terpenoids, derived from essential oils (EOs), to enhance NSCLC treatment. These compounds exhibit anticancer properties and modulate key pathways like the 4-oxo-retinoic acid pathway, TNF-α signaling, NF-κB activation, and histone deacety-lases (HDACs). Retinoids, a subclass of terpenes, show both chemopreventive and thera-peutic benefits, especially when combined with other agents, though challenges in dosing and delivery methods limit their clinical application. Terpenes may also synergize with emerging therapies, such as antiangiogenic treatments and immunotherapy, to improve outcomes. Biomarkers, including genomic, epigenomic, and proteomic markers, play a critical role in predicting responses to terpene-based treatments, supporting personalized medicine. The integration of terpenes into existing regimens, in combination with conven-tional therapies, holds promise in overcoming clinical challenges, improving patient out-comes, and advancing natural compound use in modern oncology. Future research should focus on optimizing terpene therapies and addressing clinical hurdles.

MCM2 belongs to the microchromosome maintenance [MCM] family and plays an essential role in initiating DNA replication as well as maintaining normal cellular cycle functions. Recent research indicates that there is the abnormal expression of MCM2 in various cancers, such as breast, cervical, ovarian, lung, hepatocellular carcinoma, nephroblastoma, prostate, and pancreatic cancers, where it shows a strong link to tumorigenesis, growth, invasion, migration, and adverse prognosis. Thus, MCM2 could serve as a significant biomarker for the early identification, diagnosis, and prognostic evaluation of multiple cancers. In addition, targeting MCM2 expression may open new possibilities for a full range of cancer treatments. In this paper, the protein structure, physiological function, and carcinogenic mechanism of MCM2 were reviewed.

Skin cancer is one of the most lethal cancers today, posing significant challenges to public health and potentially impacting global health and economic stability. Due to its high rate of incidence, innovative and effective treatments are crucial. Among these, immunothera-peutic approaches have emerged as transformative, offering new hope by harnessing the body's immune system to target and eliminate cancerous cells. Immunotherapy has changed the treatment landscape for skin cancer, providing options such as checkpoint inhibitors and adoptive cell transfer therapies that specifically enhance immune activity against tumors. De-spite these advancements, the broader adoption of immunotherapeutic modalities is challeng-ing due to concerns about their toxicity and variable efficacy. The side effects, such as im-mune-related adverse events, can be severe and sometimes limit their use. In response to these challenges, nanotechnology in cancer treatment has gained significant attention. Nanotechnol-ogy-based approaches show promise in improving the delivery and effectiveness of cancer therapies, particularly for skin cancer immunotherapy. Nanoparticles can deliver therapeutic agents directly to tumors, minimizing systemic toxicity and enhancing treatment precision. These strategies also boost the immune system's ability to target cancer cells while overcom-ing the limitations of current immunotherapies. This review explores various anticancer thera-peutic approaches for managing skin cancer, focusing on immunotherapy and its challenges. It highlights how integrating nanotechnology with cancer immunotherapy offers a promising av-enue for enhancing treatment efficacy and safety. The review also provides an overview of re-cent advancements in skin cancer treatment, showcasing how these innovative strategies are paving the way for more effective and less toxic therapeutic options in combating one of the deadliest cancers.

Pulmonary sarcomatoid carcinoma（PSC）is a rare pathological type of non-small cell lung cancer that combines the characteristics of epithelial and mesenchymal tu-mors and is an extremely malignant and highly heterogeneous malignant tumor. PSC is dif-ficult to diagnose and has a poor sensitivity to radiotherapy. In recent years, with the effica-cy breakthroughs of molecularly targeted drugs and immune checkpoint inhibitors in tumor therapy, the treatment of PSC is gradually exploring precise targeted therapy and immuno-therapy. In this article, we will provide a comprehensive review of the clinical features, di-agnostic points, and progress in the clinical therapeutic research of PSC. We hope to provide guidance and help with clinical treatment and scientific research.

Background: Glioblastoma (GBM), a common type of brain tumor, is currently treatable through radiation therapy. However, there is room for improvement in the effec-tiveness of treatment. Radiation can lead to an increase in the expression of PD-L1 and VEGF, which might reduce the responsiveness of the tumor to the therapy. This situation underlines the necessity for innovative treatment strategies.

Objectives: In this study, we investigated the potential of attenuated Salmonella carrying the co-expressing plasmid siPD-L1-Endo to effectively inhibit PD-L1 and VEGF expres-sion, thereby enhancing the anti-tumor effects of radiation therapy in GBM-bearing mice.

Methods: The regulatory mechanisms responsible for the treatment effect were detected by Flow cytometry, Immunohistochemistry, TUNEL, Immunofluorescence, H&E staining, and Western blot assays.

Results: Upon administration of attenuated Salmonella carrying siRNA-PD-L1 and co-expressing endostatin plasmids, the results exhibited significant suppression of tumor growth and tumor cell proliferation, as well as a concurrent decrease in PD-L1 and VEGF expression in tumor tissues. Moreover, the treatment led to reduced expression levels of tumor-related proteins p-Stat3, MMP2, Cyclin D1, and PCNA, an increase in the expres-sion of the apoptosis-related protein cleaved-caspase3, facilitated infiltration of CD4+ and CD8+ T cells within tumor tissues, and an elevation of the ratios of CD4+, CD8+ T cells, and NK cells in the spleen of tumor-bearing mice.

Conclusion: These findings highlight the ability of attenuated Salmonella carrying siR-NA-PD-L1 and co-expressing endostatin plasmids to effectively modulate PD-L1 and VEGF expression, thus strengthening the anti-tumor immune response in GBM-bearing mice subjected to radiation therapy. This combination therapy approach holds promise as a potential avenue for improving the efficacy of radiation therapy in the treatment of glio-blastoma.

Purpose: Previous research has shown, that ABC transporters gene expression level can predict the efficacy of therapy. However, other mechanisms of gene activity are rarely considered, especially in non-small cell lung cancer (NSCLC). Thus, the purpose of the work was to assess chromosomal aberrations of all 49 ABC transporters genes and the expression levels of some ABC genes, as well as their correlation with survival.

Materials and methods: The surgical material of 104 patients with NSCLC was used in this study. Treatment included surgery and 3 courses of adjuvant chemotherapy with "platinum doublets". DNA and RNA were isolated from the samples, followed by microarray analysis to assess the expression and chromosomal aberrations (deletions and amplifications) of ABC genes.

Results: Metastatic-free survival (MFS) was higher with ABCC1, ABCC2, and ABCG1 hypoexpression at a statistically significant level (p=0.01). The presence of deletion in ABCB1 correlates with 100% MFS (p=0.001). The survival rates with ABCG1 amplification are not higher than 45% (p<0.0001). ABCA11 deletion is associated with a low MFS rate (38%) versus 91% with normal copy number (p=0.006). ABCB9 analysis showed opposite results, with survival rates of 55% and 91% in the presence of amplification and normal copy number, respectively (p=0.006). ABCC subfamily genes showed a similar result in the presence of amplification, where ABCC3 and ABCC10 account for 64% and 60% survival, respectively (p=0.005, p=0.01).

Conclusion: Thus, not only expression but also chromosomal aberrations were found to be associated with patient survival. These findings could be a potential marker of metastatic-free survival.