Current Cancer Drug Targets - Online First

This study aimed to investigate the effect and mechanism of arctigenin (ARG) on the sensitization of dacarbazine (DTIC) via the regulation of mitophagy.

In vitro experiments were conducted to explore the effects of ARG on the biological behavior of melanoma cells, mitochondrial autophagy mediated by PINK1/Parkin, and the role of reactive oxygen species (ROS)-mitochondrial autophagy in the regulation of the biological behavior of melanoma cells by an ROS quenching agent, a mitochondrial autophagy inhibitor, and an activator. The effects of ARG and dacarbazine in nude mice were assessed.

CCK8 assays revealed that ARG inhibited the proliferation of the human melanoma cell lines A375 and SK-MEL-2. The observation of submicroscopic structures demonstrated mitochondrial damage. Flow cytometry further verified that ARG induced apoptosis. Western blot analysis revealed that the protein expression levels of cleaved caspase 3 and Bax increased, whereas that of Bcl-2 decreased. In addition, ARG increased ROS levels. LC3II/I, PINK1, and Parkin were increased. ARG-induced apoptosis was related to increased mitochondrial oxidative stress and promoted the occurrence of mitochondrial autophagy. After the addition of the autophagy inhibitor Mdivi-1 or the ROS quencher N-acetylcysteine (NAC), the antiproliferative effect of ARG was markedly attenuated. The expression levels of PINK1, Parkin, LC3II/I, cleaved caspase 3, and Bax were increased, whereas that of Bcl-2 was decreased. The formation of mitochondrial autophagosomes was observed by transmission electron microscopy. ARG inhibited the proliferation and induced the apoptosis of melanoma cells in vivo.

Autophagy-mediated cell apoptosis was activated through the PINK1/Parkin pathway by ARG, effectively inhibiting the proliferation of human melanoma cells.

Prosopis cineraria L. (PCL) is a herbal plant commonly used in Asia for the therapeutic intervention of different kinds of illnesses. Preclinical reports have revealed the beneficial effects of PCL against various types of life-threatening diseases, including cancer. However, studies targeting breast cancer (BCa) and bioactive for its mechanistic approach are limited or not available.

The current work utilized network pharmacology, built a network between plant compounds and BCa targets, and explored the effective phytocompounds of PCL and its possible mode of action. All phytoconstituents of PCL were segregated using the IMPPAT database, and thus, potential phytoconstituents were selected for this study. Phytocompounds and BCa target data were entered into Cytoscape software to compose the PCL network, and subsequently GO and pathway enrichment analysis were examined. Molecular docking and in vitro experiments were used to further validate the network pharmacology results.

We retrieved 24 phytocompounds from PCL and 301 potent BCa-associated targets for network construction, and obtained one main ingredient, luteolin of PCL. MMP9, GSK3Β, PARP1, CYP19A1, MMP2, ABCG2, ESR2, HMGCR, AR, and ABCB1 have been recognized as crucial targets of PCL in BCa treatment. Subsequent in vitro experiments showed that PCL and its final screened constituent, luteolin, inhibited the proliferation of MDA-MB-231 cells and reduced the expression level of MMP9 target genes.

Network analysis exhibited that PCL exerted a significant repressive impact on BCa by acting on tumor-associated signaling cascade, which would be helpful for future anticancer research of PCL against breast cancer.

Prior research has demonstrated that proteins play a significant role in the prognosis and treatments of various sarcomas, including Ewing sarcoma through the interplay of downstream signaling cascades. However, there is limited understanding about the strcucture conformation of EWSR1 and its structural implication in the prognosis of Ewsing Sarcoma by interaction with RNA molecules.

The primary goal of ongoing research is to determine how EWSR1 contributes to Ewing sarcoma.

The current study explores the complexity of EWSR1 structure and its conformational interactions with RNA in relation to Ewing sarcoma.

Here, we employed a comparative modeling approach to predict EWSR1 domains separately and assembled them into one structural unit using a DEMO server. Additionally, the RNA motifs interacting with EWSR1 were predicted, and the 3D model was built using RNAComposer. Protein-RNA docking and MD simulation studies were carried out to check the intermolecular interactions and stability behavior of docked EWSR1-RNA complexes.

The overall results explore the structural insights into EWSR1 and their interactions with RNA, which may play a momentous role in co- and post-transcriptional regulation to control gene expression.

Taken togather, our findings suggest that EWSR1 may be a useful therapeutic target for the diagnosis and management of Ewing sarcoma.

Historically, there has been a lack of focus on the mortality rates of individuals with both diabetes and Bladder Bancer (BC). Our study aimed to identify the risk factors associated with death from Diabetes Mellitus (DM) in BC patients.

Data was gathered from the SEER database on individuals who were diagnosed with BC between the years 2000 and 2017. Calculation of the Standardized Mortality Ratio (SMR) was performed to determine the mortality rate of DM in patients from BC. Potential risk factors for DM mortality were identified by a multivariate competing risk model. Hazard Ratios (HR), with 95% confidence intervals (95% CI) were used to indicate the degree of associated risk.

A total of 217,230 BC patients' data were collected from the SEER database for analysis. Among them, 98,880 patients passed away, and 1,783 patients encountered DM mortality. The overall SMR for DM mortality in BC patients was 3.32 (95% CI: 3.17-3.48). Results indicated that SMR increased with increasing years but decreased with increasing follow-up time. Multivariate competing risk analysis shows that BC patients with the following factors were at higher risk of developing DM mortality: advanced age, male, black, in situ tumor stage, early year of diagnosis, pathology type of transitional cell carcinoma, without chemotherapy or radiation therapy, and absence of spouse (including separated, divorced, widowed, and unmarried).

Individuals diagnosed with BC are at a considerably elevated risk of mortality from DM compared to the general population. It is of the utmost importance to identify high-risk groups and implement effective interventions for DM in order to enhance the survival rate among this patient population.

Quinoline derivatives, often incorporating other heterocyclic structures, have shown a wide range of therapeutic potential, especially in the treatment of cancer. These compounds have demonstrated significant anticancer activity against various cell lines, including HeLa (human cervical cancer) and MDA-MB-435 (melanoma), exhibiting strong inhibitory effects.

In this study, arylhydrazonopyrazole derivatives (3a-c) were employed in a series of multicomponent reactions to synthesize 3,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinoline and pyran derivatives. Pyrazolo[1,5-a]quinoline derivatives, due to their structural properties, are considered valuable scaffolds for the development of novel drugs targeting similar biological pathways, with the potential for improved therapeutic efficacy. This study aimed to demonstrate the use of simple arylhydrazonopyrazole derivatives in multicomponent reactions with cyclic ketones and aromatic aldehydes. The resulting compounds were then assessed for their cytotoxic and antiproliferative activities. Following these reactions, further heterocyclization processes were conducted, incorporating the quinoline moiety into the final structures. These findings underscore the potential of pyrazolo[1,5-a]quinoline derivatives as promising candidates for drug discovery, offering new avenues for targeting diseases with related molecular mechanisms.

The key starting compound in this study was 3,5-dimethyl-4-(2-phenylhydrazono)-4H-pyrazole, which has been utilized in numerous heterocyclization reactions. These reactions, involving various reagents, such as cyclic ketones and diketones in the presence of aromatic aldehydes, led to the formation of fused tetracyclic compounds. Arylhydrazonopyrazole derivatives (5a-c) were employed in multicomponent reactions to synthesize 3,5,6,7,8,9-hexahydropyrazolo[1,5-a]quinoline and pyran derivatives. The reactions were carried out using both conventional catalysts and ionic liquid-immobilized catalysts. Notably, the use of ionic liquid-immobilized catalysts resulted in higher yields of the desired compounds.

In this study, new compounds were synthesized, characterized, and evaluated for their cytotoxicity against six cancer cell lines: A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460. Additionally, the cytotoxic effects of the synthesized compounds were assessed against hepatocellular carcinoma (HepG2) and cervical carcinoma (HeLa) cell lines. Morphological studies of selected compounds were also conducted to further understand their effects on the cancer cells. Moreover, the cytotoxicity of the selected compounds was tested against seventeen different cancer cell lines, categorized by disease type. Morphological analyses of these selected compounds were also performed to gain deeper insights into their potential as anticancer agents.

The inhibition assays of the tested compounds demonstrated significant activity against c-Met enzymatic activity, with IC50 values ranging from 0.25 to 10.30 nM. Additionally, potent inhibition was observed in the prostate PC-3 cell line, with IC50 values ranging from 0.19 to 8.62 µM. These promising results highlight the potential of these compounds and encourage further research to explore their therapeutic applications in the future.