Current Cancer Drug Targets - Online First

Esophageal squamous cell carcinoma (ESCC) stands as one of the deadliest cancers globally. Given the urgent clinical need for more precise and comprehensive therapeutic strategies, the phytocompound methylophiopogonanone A (MO-A) demonstrates the potential as a candidate for ESCC treatment. This study aimed to verify the therapeutic effect of MO-A against ESCC and unveil its underlying mechanism.

Three compound-protein interaction databases were utilized to predict the molecular targets of MO-A. Subsequently, potential therapeutic targets of ESCC were identified based on the GEO database. KEGG pathway and GO function enrichment analyses were then performed by using these two sets of targets, respectively. Through the integrative analysis of these two target sets, core targets of MO-A with therapeutic potential against ESCC were determined. Protein-protein interaction network analyses and molecular dockings were executed by using these targets. Two human-derived ESCC cell lines were enrolled for biological validation, including cell viability, colony formation, and cell cycle assays.

This study predicted 200 potential targets of MO-A and uncovered 138 key targets associated with the progression of ESCC. Enrichment analyses and PPI networks underscored the involvement of cell cycle-related genes in ESCC development. Four proteins were determined as core MO-A targets for ESCC treatment, including AURKA, AURKB, CDC25B, and TOP2A, which partake in the regulation of the cell cycle. Finally, the inhibitory effect of MO-A on ESCC cell proliferation was validated in vitro, primarily through inducing cell cycle arrest at the G2/M phase in ESCC cells.

These results revealed the anti-ESCC potential of MO-A, a plant-derived flavonoid, using integrated bioinformatics and biological experiments. While findings provide a mechanistic basis for the efficacy of MO-A, limitations include reliance on computational and in vitro models. Further studies should be conducted to evaluate the pharmacological properties and safety of MO-A across multiple models, alongside more comprehensive structure-activity relationship studies to inform drug optimization prior to clinical translation.

MO-A can impede ESCC growth by triggering cell cycle G2/M arrest, positioning it as a novel and promising phytocompound for ESCC therapy.

Breast cancer is the most common malignancy among women and the second leading cause of cancer-related deaths worldwide. Resveratrol, a polyphenolic stilbene derivative found in grapes, red wine, and other plants, possesses anti-cancer properties. Various studies have reported the potential of different nanomaterials to act as radiosensitizers against tumor cells. This study aimed to evaluate the antitumor and radiosensitizing effects of Resveratrol-Chitosan Nanoparticles (Res-Ch-NPs) in a DMBA-induced breast cancer mouse model.

Res-Ch-NPs were developed using the chitosan emulsification cross-linking technique. The particle size, entrapment efficiency, zeta potential, UV and FT-IR spectra, and drug release profile of Res-Ch-NPs were evaluated. The IC50 of Res-Ch-NPs, both individually and in combination with γ-irradiation, was calculated against the MCF-7 cell line using the MTT assay. The LD50 of Res-Ch-NPs was estimated, and 1/20 LD50 was used to assess the antitumor and radiosensitizing effects on breast cancer cell-bearing mice. The in vivo efficacy was evaluated in DMBA-induced breast cancer mice, examining tumor weight, volume, blood parameters (Hb%, RBCs, and WBCs), oxidative stress markers (MDA, GSH, SOD, and CAT), immune markers (INF-γ, TGF-β1, CD4, and CD8), and gene expression levels (p53, survivin, and STAT3). Additionally, histopathological examination of breast tissues was also carried out.

Res-Ch-NPs demonstrated high entrapment efficiency (82.46 ± 1.02), a polydispersity index (0.65 ± 0.03), and a particle size of 184.60 ± 17.36 nm with a zeta potential of -46.78 ± 0.57 mV. The UV spectra of resveratrol and Res-Ch-NPs showed strong absorption at 230 and 250 nm. FTIR analysis confirmed the chemical stability of resveratrol in Res-Ch-NPs. The maximum release of Res-Ch-NPs was recorded at 55.07% after 44 hours. The IC50 values of Res-Ch-NPs, both individually and combined with γ-irradiation, against MCF-7 cell viability were 38.26 and 24.8 ± 0.76 µg/mL, respectively. The LD50 of Res-Ch-NPs was found to be 2090 mg/kg body weight. Treatment of DMBA-injected mice with Res-Ch-NPs and γ-irradiation significantly reduced tumor weight and volume, improved blood Hb%, RBC, and WBC levels, as well as breast MDA, GSH, SOD, and CAT levels. Additionally, breast levels of INF-γ, TGF-β1, CD4, and CD8 were reduced in DMBA-injected mice treated with Res-Ch-NPs and γ-irradiation. Conversely, the combination treatment upregulated p53 in breast tissues and downregulated the expression of survivin and STAT3 genes.

The findings confirmed that Res-Ch-NPs enhanced radiosensitivity, facilitating tumor regression and immune restoration. The modulation of pro-inflammatory and antioxidant pathways suggests a dual therapeutic role, acting as both a radiation enhancer and a tumor-suppressing agent. However, further research is needed to optimize nanoparticle dosing, assess long-term safety, and facilitate clinical translation into human studies.

Resveratrol-grafted chitosan shows promise as a radiosensitizer for cancer treatment by enhancing the responsiveness of tumor cells to γ-irradiation through the modulation of proinflammatory and antioxidant markers. Understanding the interactions between p53, survivin, and STAT3 is crucial for developing effective breast cancer treatments. Targeting survivin and modulating STAT3 activity may offer potential for future 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.