Current cancer drug targets最新文献

Background: Cisplatin (DDP) is a commonly used chemotherapy agent. However, its resistance to the drug is a major challenge in its clinical application. Earlier research has suggested a connection between HEATR1 and chemoresistance in cancer. However, additional investigation is needed to better understand its involvement in resistance to DDP. In this study, we aimed to determine the regulatory effect of HEATR1 on the resistance of cisplatin in NSCLC.

Methods: We collected specimens of both DDP-resistant and non-resistant NSCLC to examine the expression of HEATR1. Additionally, we established cisplatin-resistant cells of NSCLC using the A549 cell line. Cell ability was examined by CCK-8 assay. Cell apoptosis and lipid ROS were examined by flow cytometry. The expressions of HEATR1, p53, SAT1, and ALOX15 were determined by qRT-PCR and Western blot. The tumor xenograft experiment was conducted to assess the impact of silencing HEATR1 on cisplatin resistance in vivo in NSCLC.

Results: The expression levels of HEATR1 were found to be significantly elevated in DDP-resistant tissues and cells of NSCLC as compared to non-resistant counterparts. Conversely, the expression levels of p53, SAT1, and ALOX15 were observed to be reduced in DDP-resistant cells. Through the inhibition of HEATR1, the proliferation of DDP-resistant cells was significantly suppressed, while the generation of lipid ROS was enhanced. This effect was achieved by activating ferroptosis and the p53/SAT1/ALOX15 pathway, as demonstrated both in vitro and in vivo. Conversely, the overexpression of HEATR1 exhibited opposite effects. Furthermore, the silencing of p53 and ALOX15 reversed the oncogenic effects of HEATR1 and inhibited ferroptosis in DDP-resistant NSCLC cells, suggesting the involvement of p53 and ALOX15 in HEATR1-mediated DDP resistance.

Conclusion: Finally, the findings revealed that HEATR1 silencing reduced DDP resistance in NSCLC by inducing ferroptosis via the p53/SAT1/ALOX15 axis. HEATR1 might become a potential target for overcoming DDP resistance in NSCLC treatment.

Central nervous system tumors are abnormal proliferations of neuronal cells within the brain and spinal cord. They can be primary or secondary and place a heavy financial, psychological, and physical burden on individuals. The highly selective blood-brain barrier, which only permits specific molecules to flow into the brain parenchyma, inhibits the efficacy of pharmacological medicines. Treatment options include surgery, chemoradiotherapy, and targeted therapy. Despite advances in therapy over the past few decades, the overall morbidity and mortality rates are still high, emphasizing the need for improved therapeutic choices to improve survival and quality of life further. Nano pharmaceuticals have demonstrated encouraging outcomes in in vivo trials using microscopic particles to enhance bioavailability and selectivity. The most successful clinical results to date have been achieved by liposomes, extracellular vesicles, and biomimetic nanoparticles; nevertheless, clinical trials are required to confirm their safety, efficacy, affordability, longterm impact, and success in patients from various demographics. Nano pharmaceuticals have the potential to change the paradigm of therapy for brain tumors, allowing better outcomes as primary and adjunctive therapy.

Background: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies in the world. Lamin B1 (LMNB1) is a key component of the nuclear skeleton structure. Recent studies have found that LMNB1 is overexpressed in tumor tissues and is associated with the prognosis of patients. However, the underlying mechanism remains unclear in HCC.

Objective: This study aims to explore the clinical significance and molecular mechanisms of LMNB1 in HCC.

Methods: The expression level of LMNB1 and its clinical values were analyzed with public databases, and the level of LMNB1 in HCC tissues and adjacent normal tissues was confirmed by qRT-PCR and IHC. Functional assays were conducted to explore the impact of LMNB1 knockdown on cell proliferation both in vivo and in vitro. Additionally, Genes and Genomes enrichment analysis, recovery analysis, and ChIP assays were employed to investigate its underlying molecular mechanisms. Finally, we carried out an analysis of the relationship between LMNB1 and immune cell infiltration in HCC.

Results: LMNB1 was found to be overexpressed in HCC and correlated with the pathological stage and unfavorable prognosis. Functional assays demonstrated that LMNB1 promotes HCC proliferation both in vitro and in vivo. Further analysis revealed that LMNB1 promotes the progression of HCC by regulating CDKN1A expression. Furthermore, the infiltration of immune cells in HCC tissues suggests a potential correlation between immune infiltration cell markers and the expression of LMNB1.

Conclusions: LMNB1 emerged as a promising therapeutic target and prognostic biomarker for HCC, with its expression showing a correlation with several immune infiltration cell markers.

Introduction/background: Because of the well-established link between angiogenesis and tumor development, the use of antiangiogenic therapeutics, such as those targeting VEGFR-2, presents a promising approach to cancer treatment. In the current study, a set of five hydrazine-1-- carbothioamide (compounds 3a-e) and three hydrazine-1-carboxamide derivatives (compounds 4a-c) were successfully synthesized from 3-phenoxybenzoic acid. These compounds were specially created as antiproliferative agents with the goal of targeting cancer cells by inhibiting VEGFR-2 tyrosine kinase.

Materials and methods: The new derivatives were synthesized by conventional organic methods, and their structure was versified by IR, 1HNMR, 13CNMR, and mass spectroscopy. In silico investigation was carried out to identify the compounds' target, molecular similarity, ADMET, and toxicity profile. The cytotoxic activity of the prepared compounds was evaluated in vitro against three human cancer cell lines (DLD1 colorectal adenocarcinoma, HeLa cervical cancer, and HepG2 hepatocellular carcinoma). The effects of the leading compound on cell cycle progression and apoptosis induction were investigated by flow cytometry, and the specific apoptotic pathway triggered by the treatment was evaluated by RT-PCR and immunoblotting. Finally, the inhibitory activities of the new compounds against VEGFR-2 was measured.

Results: The designed derivatives exhibited comparable binding positions and interactions to the VEGFR-2 binding site to that of sorafenib (a standard VEGFR-2 tyrosine kinase inhibitor), as determined by molecular docking analysis. Compound 4b was the most cytotoxic compound, achieving the lowest IC50 against HeLa cells. Compound 4b, a strong representative of the synthesized series, induced cell cycle arrest at the G2/M phase, increased the proportion of necrotic and apoptotic HeLa cells, and activated caspase 3. The EC50 value of compound 4b against VEGFR-2 kinase activity was comparable to sorafenib's.

Conclusion: Overall, the findings suggest that compound 4b has a promising future as a starting point for the development of new anticancer drugs.