Current Cancer Drug Targets - Online First

Thiazolidinedione (TZD) derivatives have gained significant attention as anti-cancer agents due to their diverse biological activities. The objective of the research was to investigate the potential of thiazolidine derivatives as inhibitors of Carbonic anhydrase XII, an isoform overexpressed in hypoxic tumor environments, to explore their application as anticancer agents targeting breast cancer.

The study employed a computational approach to evaluate thiazolidine derivatives as potential CA XII inhibitors. Acute toxicity and safety were evaluated using ProTox 3.0. Molecular docking was conducted to study interactions with the zinc-bound active site of CA XII. Molecular dynamics simulations were performed to validate the stability of the ligand-enzyme complex over 250 ns.

TZD derivatives demonstrated favorable physicochemical properties, high gastrointestinal absorption, and low toxicity risks. Molecular docking studies showed strong binding affinities with key hydrogen bonding and zinc coordination at the CA XII active site. Toxicity predictions indicated that most compounds had acceptable safety margins, reinforcing their potential as safe and effective CA XII inhibitors.

The findings suggest that thiazolidine scaffolds could serve as promising small-molecule inhibitors of CA XII by targeting its zinc-bound catalytic site, a mechanism consistent with previously reported CA inhibitor pharmacology.

The study demonstrates that TZD derivatives possess promising characteristics as CA XII inhibitors, with favorable physicochemical properties, strong binding affinity, stable ligand-protein interactions, and acceptable safety profiles. These findings highlight their potential for further in vitro and in vivo validation, supporting the continued exploration of thiazolidinedione scaffolds in the development of targeted anticancer therapies.

The incidence of brain metastases in patients diagnosed with advanced lung cancer is high, drawing significant attention to the risk factors associated with this progression.

A total of 252 advanced non-small cell lung cancer (NSCLC) patients with brain metastases were enrolled in this study between July 2018 and December 2023 from our hospital. Additionally, driver genes, including EGFR, ALK, ROS1, KRAS, and RET, were documented. Next-generation targeted sequencing of a 168-gene panel was conducted on all collected samples to explore the association between tumor genomic complexity and risk factors for NSCLC with brain metastases.

Among 252 lung cancer patients with brain metastases enrolled in this research, the most prevalent driver gene was EGFR, accounting for 39.29% (99 patients). Other driver gene mutations, such as KRAS, ALK, ROS1, and RET, accounted for 3.57%, 7.14%, 2.78%, and 0.4%, respectively. Kaplan-Meier analysis showed that patients with EGFR mutations had a more favorable overall survival (OS) compared to those without the mutation (P < 0.0001). Additionally, patients with ALK fusions had longer survival times compared to those with wild-type genes (P = 0.0021). In this study, patients were divided into two groups based on the presence or absence of copy-number alterations. Further survival analysis revealed that patients with copy-number alterations experienced significantly shorter overall survival compared to the control group (P = 0.041).

This study underscores the crucial role of driver mutations and genomic instability in advanced NSCLC with brain metastases, where EGFR and ALK alterations are linked to better survival. In contrast, high genomic complexity is associated with worse outcomes.

Driver gene mutations are present in more than half of the patients with central nervous system (CNS) failure. Genomic instability, characterized by the number of co-occurring mutated genes and copy-number alterations, is a risk factor associated with shorter survival time.

Ovarian clear cell carcinoma (OCCC) accounts for about 5% of all epithelial ovarian cancers. Currently, its treatment mainly refers to high-grade serous carcinoma (HGSC). This study aimed to explore differences in clinical characteristics between OCCC and HGSC and studied the reasons for the differences.

The data of OCCC and HGSC cases were obtained from the SEER database. Univariate and multivariate Cox regression analyses were used to explore the prognostic factors. Next, whole exome sequencing (WES) was performed on 15 clinically selected OCCC cases and 16 HGSC cases to identify significantly mutated genes (SMGs). Further analysis included calculating tumor mutation burden (TMB) and predicting potential target drugs based on the identified mutations.

3493 OCCC and 10266 HGSC patients from the SEER database were included in the study. Survival analysis showed that the overall survival (OS) of stage I-II OCCC was better than that of stage I-II HGSC, while the OS of stage III-IV OCCC was worse than that of stage III-IV HGSC. Further subgroup analysis showed that for the OCCC group, age ≥ 60 years, bilateral tumor distribution, tumor size ≥ 87mm, and stage III-IV were independent risk factors for OS. For HGSC patients, tumor size ≥ 87mm was an independent protective factor for OS. WES results suggested that among the top 20 SMGs of OCCC in stage III-IV patients, DNAH2, LAMA5, MUC19, NOTCH1, PCLO, SYNE2, TACC2, and ZNF469 were 8 specific SMGs that distinguish III-IV OCCC from III-IV HGSC. In addition, the stage I-II OCCC group had the highest TMB, and the lowest was the stage III-IV OCCC.

Our findings challenge the conventional uniform therapeutic approach for ovarian carcinomas by revealing stage-dependent SMGs between OCCC and HGSC. However, limitations such as the retrospective SEER analysis, small WES cohort, and population-specific driver gene variations require cautious interpretation of the findings.

The independent prognostic factors identified in this study provide a theoretical basis for individualized prognosis judgment in OCCC and HGSC. The SMGs and TMB levels may serve as valuable indicators for prognosis and evaluating targeted therapy or immunotherapy efficacy. Druggable genes such as NOTCH1 and RYR3 offer promising therapeutic targets, while stage-specific pathway enrichments reveal potential intervention strategies. Further validation in larger cohorts is needed to confirm these findings. Our study advances the understanding of molecular heterogeneity in ovarian cancer and lays the groundwork for personalized treatment strategies, ultimately improving patient outcomes.

Colorectal cancer (CRC) is among the most widespread malignancies worldwide and is a leading cause for cancer mortality. The interstitial interaction between cancer and stem cells is important during cancer cell metastasis.

In this study, we aimed to elucidate the regulatory role and the underlying mechanisms controlling the activity of exosomes derived from cancer stem cells (CSCs).

Our group isolated exosomes from CSCs and non-CSCs to examine their regulatory mechanisms using Transwell migration, Cell Counting Kit-8 (CCK-8), and 5-ethynyl-2′-deoxyuridine (EdU) assays.

The role of Eukaryotic Translation Initiation Factor 3 Subunit B (EIF3B) in CRC was examined using an in vivo tumorigenesis mouse model. It was found that treatment with exosomes isolated from CD133⁺ cells (CD133+Exos) promoted the proliferation and migration of SW480 cells. The downregulation of EIF3B reduced the proliferation and migration-promoting effects of CD133⁺ Exos on SW480 cells. Furthermore, CD133⁺ Exos treatment promoted the tumorigenesis of SW480 cells.

Our findings demonstrate that CSC-derived exosomes transport EIF3B into CRC cells to initiate epithelial-to-mesenchymal transition (EMT) and promote metastasis.

Euphorbia humifusa Willd (EH) is a traditional medicinal herb in China. However, the anti-prostate cancer active compounds of EH and their molecular mechanisms have yet to be elucidated.

The peaks of EH water extract in the fingerprinting were analysed using liquid chromatography coupled to quadrupole time of flight mass spectrometry. The cell viability of 22RV1 cells was determined via MTT. The active compounds and potential targets were screened in silico. The prostate cancer-associated targets were collected from the GeneCards database. The herb-compound-target-disease (H-C-T-D) and PPI networks were constructed to predict key targets. The molecular docking analysis of the active compounds with key targets was conducted using Autodock Vina 1.1.2. Western blot analysis was performed to evaluate the protein expression.

LC-MS results demonstrated that EH water extract is a rich source of phenolics and flavonoids. EH water extract inhibited the viability of 22RV1 cells in a time-and dose-dependent manner. Moreover, the in silico screening results identified 17 active compounds from EH with 518 prostate cancer-related key genes. Moreover, an H-C-T-D network analysis combined with the PPI network results effectively identified seven chemical compounds, oestrogen receptor 1, and androgen receptor (AR) to be highly related to prostate cancer. Furthermore, molecular docking results showed that 4′,5-dihydroxyflavone, ensaculin, luteolin, hypolaetin, quercetin, and kaempferol had a strong binding affinity with AR. Finally, Western blot results demonstrated that EH water extract, quercetin, kaempferol, and luteolin significantly down-regulated the AR protein expression in 22RV1 cells.

These results suggest that EH may provide a new promising therapeutic for prostate cancer treatment.