Recent Patents on Anti-Cancer Drug Discovery - Volume 20, Issue 5, 2025

Natural compounds such as Berberine (Ber) have been considered due to favorable anticancer properties, low side effects, and availability along with chemotherapy treatments.

This study aimed to investigate the radiosensitizing and radioprotective properties of Ber.

In this systematic review that was performed according to PRISMA 2020 guidelines, we searched the publications before 25 Sep 2023 in Web of Science, PubMed, Scopus, Embase, and Cochrane Library databases. After determining inclusion and exclusion criteria, data were extracted and imported into an Excel form, and the results of the studies were reviewed.

Ber by reducing the levels of reactive oxygen species (ROS), malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta 1 (TGF-β1), and increasing interleukin 10 (IL-10) levels, showed its antioxidant and anti-inflammatory properties against ionizing radiation. Reducing cell cytotoxicity and apoptosis were other radioprotective properties of Ber. Conversely, in cancer cells, Ber, via inducing oxidative stress and accumulation ROS in tumor tissues, inducing DNA damage, mitochondrial dysfunction and hyperpolarization, inducing apoptosis, and cell cycle arrest, inhibits the up-regulation of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) revealed radiosensitizing properties.

Ber, via various mechanisms, showed favorable radioprotective and radiosensitizing properties in clinical and experimental studies. However, more clinical studies are needed in this field.

N6-methyladenosine (m⁶A) modifications of RNAs are associated with many cancer types. Nevertheless, the function of the m⁶A reader IGF2BP2 in oral squamous cell carcinoma (OSCC) has yet to be ascertained.

The objective of this investigation was to elucidate the role of IGF2BP2 in OSCC and delineate the associated mechanisms.

Elevated expression of IGF2BP2 was observed in OSCC, and this overexpression significantly correlated with adverse prognostic outcomes in patients with OSCC. In vitro analyses demonstrated that silencing of IGF2BP2 attenuated the proliferation, migration, and invasion capabilities of oral cancer cells while concurrently promoting apoptosis.

In vivo experiments demonstrated that IGF2BP2 promoted OSCC growth. RNA-seq and m⁶A-seq were utilized to elucidate the downstream targets of IGF2BP2. Through bioinformatic analysis, we identified the long noncoding RNA (lncRNA) UCA1 as a target. IGF2BP2 was found to maintain the stability of UCA1 in an m⁶A-dependent manner by binding to m⁶A-modified UCA1 and plays an oncogenic role in OSCC through UCA1.

In conclusion, we identified IGF2BP2 as a prognostic biomarker of OSCC, and the IGF2BP2-UCA1 axis was found to promote OSCC progression and may perform as a novel therapeutic target.

Ovarian cancer is one of the most common gynecological malignancies globally, and immunotherapy has emerged as a promising treatment strategy in recent years. However, the effectiveness of immunotherapy is often limited by immune escape mechanisms.

To unravel the immune response mechanisms in ovarian cancer, this study aimed to employ integrated Weighted Gene Co-expression Network Analysis (WGCNA), machine learning, and single-cell sequencing analysis to systematically investigate immune infiltration-related molecular features in ovarian cancer patients and experimentally validate the molecular mechanisms of the immune response. This research may provide a new theoretical foundation and treatment strategy for immune-based therapies in ovarian cancer.

Relevant ovarian cancer datasets were collected from public databases. The ConsensusClusterPlus and ggplot2 R packages were used to perform dimensionality reduction and clustering analysis of immune infiltration-related genes. Various algorithms were employed to select the best ovarian cancer prognostic model with OC consistency. The prognostic value of angiogenesis and immune-related gene expression was evaluated through Kaplan-Meier survival analysis, and the impact of immune infiltration on immune function in ovarian cancer patients was assessed. Functional pathways were identified using the Gene Set Enrichment Analysis (GSEA) method, and the infiltration abundance of immune and stromal components was inferred using the single-sample Gene Set Enrichment Analysis (ssGSEA) method. The influence of angiogenesis on the cellular level of Ovarian Cancer (OC) was explored in single-cell sequencing data, followed by in vitro cell experiments for further validation. The effect of the angiogenesis model on OC was evaluated through the above-mentioned research and experiments, aiming to investigate the mechanism of targeted therapy strategies in ovarian cancer.

Immune-related data were collected from ovarian cancer patients in this study. Through WGCNA analysis, the MEturquoise module was identified, and a total of 1018 hub genes were determined. A prediction model was constructed using machine learning, with CoxBoost+StepCox selected as the best model, leading to the identification of 10 genes associated with ovarian cancer. Patients with high AIDPS had shorter survival time, and GSEA analysis revealed enrichment in immune-related pathways. Single-sample gene set enrichment analysis demonstrated increased immune cell infiltration and malignant stromal changes in the high AIDPS group. Results from in vitro cell experiments showed that silencing RPL31 inhibited the proliferation and migration of ovarian cancer cells while enhancing immune response capability.

AIDPS holds significant clinical significance in Ovarian Cancer (OC) with poor prognosis observed in patients with high AIDPS. These patients exhibit more significant genomic variations, denser immune cell infiltration, and greater tolerance toward immune therapy. Importantly, inhibiting the expression of RPL31, a key component of AIDPS, can significantly suppress the proliferation, migration, and invasive properties of ovarian cancer cells, while stimulating the cytotoxicity of effector T cells and promoting immune response, thus slowing down the progression of ovarian cancer.

The precise function of Tolloid Like 2 (TLL2) remains uncertain within the context of Lung Adenocarcinoma (LUAD).

The primary objective of this investigation was to conduct a thorough analysis.

To assess its diagnostic utility, data from The Cancer Genome Atlas (TCGA) database were used to assess TLL2 expression in pan-cancer and LUAD. The study has also investigated the correlation between TLL2 expression levels and LUAD symptoms and prognosis. Furthermore, the study has explored possible regulatory networks involving TLL2, including its association with immune infiltration, tumor stemness index (mRNAsi), and drug sensitivity in LUAD. We have explored TLL2 expression in single-cell sequencing of LUAD and the genomic variation and clinical significance of TLL2 in LUAD. The expression of TLL2 has been validated in GSE87340 and cell lines by quantitative Real-time PCR (qRT-PCR).

An abnormal expression of TLL2 has been found in pan-cancer and LUAD. In LUAD patients, elevated levels of TLL2 were significantly related to the T stage (p = 0.046) and the pathological stage (p = 0.016). The expression of TLL2 in patients with LUAD was significantly associated with poorer Overall Survival (OS) (p < 0.001). The expression of TLL2 was determined to be an independent predictor of poorer OS (p = 0.042). TLL2 was associated with ribosome, neuroactive ligand-receptor interaction, allograft rejection, ECM receptor interaction, asthma, porphyrin and chlorophyll metabolism, focal adhesion, pentose and glucuronate inter-conversions, and ascorbate and aldarate metabolism. The expression of TLL2 in LUAD was correlated with immune infiltration and mRNAsi. The expression of TLL2 was significantly and negatively correlated with TAK-715, XMD13-2, STF-62247, OSI-930, and EHT-1864 in LUAD. The TLL2 gene was up-regulated in multiple individual LUAD cells. LUAD patients with altered TLL2 had a shorter PFS as opposed to those with unaltered TLL2. The expression of TLL2 was significantly increased in LUAD cells.

For patients with LUAD, TLL2 may serve as an immunotherapeutic target and a useful prognosis biomarker.

Platinum-based compounds are commonly used as an initial treatment for colorectal cancer (CRC). However, the development of drug resistance in patients with CRC necessitates the administration of high drug concentrations during clinical treatment, thereby augmenting the toxicity of platinum-based compounds and increasing the mortality rate. STAG2 is a significantly associated drug-resistance gene in many cancers, but it has not been studied in colorectal cancer. Therefore, the present study aimed to investigate the role and drug sensitivity of the cisplatin-resistant gene STAG2.

The effects of STAG2 on drug resistance and survival rates of patients with CRC were examined using the Genomics of Drug Sensitivity in Cancer (GDSC) and Kaplan-Meier (KM) plotter databases. Subsequently, a sh-STAG2-HT-29 cell line was generated using a knockdown test of STAG2, and the half-maximal inhibitory concentration (IC50) of the two cell lines was determined using a cell viability test. We then used various techniques, including the Cell Counting Kit-8 (CCK-8), plate cloning, 5-ethynyl-2’-deoxyuridine (EdU) fluorescence staining, flow cytometry for cell cycle detection, the scar assay, the Transwell invasion assay, and Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) fluorescence staining for apoptosis detection, to investigate the functionality of the four subgroups of cancer cell lines. Additionally, Western blotting (WB) was used to identify the potential pathways associated with the observed functional alterations. Finally, the phenotype, tumor weight, mouse weight, tumor volume, and tumor tissue structure of the developed tumors were assessed using the subcutaneous tumor formation method.

Database analysis indicated that STAG2 plays a role in facilitating drug resistance among individuals with CRC. Furthermore, mutations in this gene lead to increased sensitivity to cisplatin, and its overexpression was associated with an unfavorable prognosis. Following the successful development of STAG2 knockdown cells, differences in IC50 concentrations were observed between HT-29 and sh-STAG2-HT-29 cells. A treatment concentration of 10 μM cisplatin was selected, and the proliferation, migration, and invasion capabilities of cancer cells decreased after STAG2 knockdown. Additionally, the sensitivity of the cells to cisplatin therapy was increased, which was potentially mediated by the epithelial-mesenchymal transition (EMT) pathway. In mice, the tumorigenic potential of HT-29 cells was reduced by STAG2 knockdown, accompanied by a decrease in resistance to cisplatin therapy.

STAG2 acts as a proto-oncogene in CRC, and its resistance to cisplatin therapy is more prominent. This study confirmed the role of STAG2 in CRC and provided a theoretical basis for the further development of STAG2 as an auxiliary criterion for determining dosage when patients are treated with platinum drugs.

The emergence of drug resistance to oxaliplatin (OXA) is one of the critical obstacles in the therapy of advanced Hepatocellular Carcinoma (HCC). As an ethyl derivative of the natural compound epigallocatechin gallate (epigallocatechin-3-gallate, EGCG), Y6 was found to be able to enhance the sensitivity of HCC cells to doxorubicin. This study aimed to investigate the effect of Y6 on oxaliplatin resistance in HCC.

MTT was used to determine the reversal effect of Y6 on OXA resistance. To further explore the reversal mechanism, we treated OXA alone or in combination with Y6 or EGCG in drug-resistant cells and observed the morphological changes of the cells. At the same time, transwell assay was used to detect the invasion and migration ability of cells. Moreover, Real-time PCR and Western blot analysis were performed to determine the expression levels of the miR-338-3p gene, HIF-1α/TWIST proteins, and EMT-related proteins.

We found that Y6 could inhibit the proliferation of HCC cells and effectively reverse the drug resistance of oxaliplatin-resistant human liver cancer cells (SMMC-7721/OXA) to OXA, and the reversal effect was more significant than that of its lead drug EGCG. Most of the cells in the control group and OXA group showed typical mesenchymal-like cell morphology, while most of the cells in co-administration groups showed typical epithelioid cell morphology, and the ability of the cells to invade and migrate decreased dramatically, particularly in Y6 plus OXA group. At the same time, Y6 could up-regulate the EMT epithelial marker protein E-cadherin and down-regulate the interstitial marker protein Vimentin. In addition, in co-administration groups, the expression of miR-338-3p was up-regulated, while the expression of HIF-1α and TWIST was down-regulated.

Y6 significantly enhanced the susceptibility of drug-resistant cells to OXA, and the process may be related to the regulation of miR-338-3p/HIF-1α / TWIST pathway to inhibit EMT. Therefore, Y6 could be considered an effective medication resistance reversal agent, which could improve the therapeutic effect for hepatocellular cancer patients.

Radiofrequency ablation (RFA) is an effective therapy for hepatocellular carcinoma (HCC). However, incomplete radiofrequency ablation (IRFA) can promote the progression of residual cancer cells, which is a serious problem in the clinical application of RFA. Therefore, it is of great significance to explore the mechanism and countermeasures of the progression of residual tumors after IRFA. Our previous study confirmed that IRFA can activate the hypoxia/autophagy pathway of residual tumors in mice and then induce the proliferation of residual tumor cells. Additionally, we found a metal ruthenium complex [Ru(bpy)2(ipad)](ClO4)2 (Ru, where bpy = 2,2’-bipyridine and ipad = 2-(anthracene-9,10-dione-2-yl)imidazo[4,5-f][1,10]phenanthroline) can effectively inhibit hypoxia-inducible factor (HIF-1α) and has good anti-tumor effect in a hypoxic environment; however, whether Ru could suppress the proliferation of residual tumor cells after IRFA is unknown.

This study intends to evaluate the effect of Ru in suppressing the proliferation of residual hepatocellular carcinoma after IRFA in a mice model.

The Hepa1-6 xenograft mouse model was established in C57BL/6 mice to simulate clinical IRFA. H&E staining was used to evaluate the biosafety of major organs in the treated mice. TUNEL assay was employed to assess the antitumor effect. Immunohistochemically and immunofluorescence staining was performed to detect the expression of HIF-1α and autophagy-related proteins. The ELISA assay was used to examine the cytokines of interferon-gamma (IFN-γ) and interleukin 10 (IL-10).

Our findings revealed that the residual tumor relapsed via the HIF-1α/LC3B/P62 autophagy-related pathway after IRFA, while Ru could suppress this process. In addition, it was demonstrated that Ru could effectively activate the immune system of the mice and reverse the tumor immune suppression microenvironment after IRFA.

The ruthenium complex Ru could suppress the proliferation of residual hepatocellular carcinoma cells after IRFA in the mice model. This study introduces a novel approach that combines the use of ruthenium complexes with IRFA, offering a potential solution to address the reoccurrence of residual liver cancer following IRFA in clinical settings.

Triple-negative breast cancer (TNBC) has a poor prognosis with current treatment options. Novel therapeutic strategies are urgently needed to enhance treatment outcomes for TNBC.

This study evaluated the efficacy of a three-agent regimen compared to existing treatment regimens in a TNBC mouse model, and elucidated its potential mechanisms of action.

The TNBC xenograft tumor mouse model was established using a 4T1 cell line in female BALB/c mice. Mice were treated with the three-agent regimen and other comparative treatments. Tumor volume was monitored to assess the anti-tumor effects. Biochemical and pathological evaluations were conducted to examine the impact of the regimen on anti-tumor immunity, anti-tumor angiogenesis, and tumor cell apoptosis.

The three-agent regimen consisting of SIN+BEV+PAB demonstrated significant anti-tumor efficacy compared to controls, PAB alone, SIN+PAB, and BEV+PAB groups from day 9 of drug administration. The superior anti-tumor effect of SIN+BEV+PAB was primarily attributed to enhanced anti-tumor immunity, evidenced by increased percentages of CD4+ and CD8+ T cells, elevated IFN-γ levels, and decreased percentages of Tregs, reduced levels of TGF-β, IL-6, and IL-10. Additionally, the regimen showed potent anti-angiogenic effects by reducing VEGF expression and micro vessel density (MVD). Furthermore, it promoted tumor cell apoptosis through upregulation of BAX and cleaved caspase3, while downregulating Bcl2.

These findings suggest that the novel three-agent combination of SIN+BEV+PAB may prove beneficial in improving treatment outcomes for patients with TNBC. The development of this regimen, which may be eligible for patent protection, could facilitate its introduction as a new therapeutic option for advanced TNBC in clinical practice.

Colorectal cancer is a significant global public health challenge, contributing substantially to cancer-related mortality worldwide. Vitexin has been shown to promote the polarization of macrophages towards the M1 phenotype, a process dependent on the Vitamin D receptor. This polarization is crucial in the tumor microenvironment, as it helps mitigate the progression from chronic colitis to colorectal cancer. Despite its potential, the mechanisms of vitexin’s action and its impact on colon cancer remain unclear.

This study aims to evaluate the inhibitory effects of vitexin on cell proliferation and apoptosis in the Caco-2 colon cancer cell line, with a specific focus on its modulation of antioxidant enzyme activities, pro-apoptotic factors, and key signaling pathways involved in cell survival and proliferation.

The IC50 of vitexin against Caco-2 cells was determined. Cell viability and necrosis rates were assessed after 48 hours of incubation with vitexin at concentrations of 19.01, 38.01, and 76.02 µg/mL. Additionally, levels of superoxide dismutase (SOD), catalase (CAT), malondialdehyde (MDA), P53, Bax, TSC2, Sestrin 2, and PUMA, as well as the expression of AMPK, PI3K, Akt, and mTOR genes and proteins, were measured using q-PCR and Western blotting techniques in Caco-2 cells post-incubation.

Vitexin exhibited an IC50 of 38.01 ± 0.64 µg/mL against Caco-2 cells. Treatment with vitexin at the specified concentrations for 48 hours resulted in a significant decrease in cell viability by 28.40%, with inhibitory rates reaching 71.6%. Apoptosis rates increased to 93.81%, 171.41%, and 294.12%, respectively, with a corresponding rise in necrosis rates by 194.19%, 400.22%, and 811.44%. Pharmacological analysis revealed that vitexin significantly inhibited SOD and CAT activities while enhancing MDA production. Furthermore, vitexin treatment upregulated the expression of key apoptotic markers (P53, Bax, TSC2, Sestrin 2, and PUMA) and the expression of AMPK, PI3K, and Akt, while downregulating mTOR genes and proteins, implicating various signaling pathways.

This study demonstrates that vitexin induces apoptosis in Caco-2 colon cancer cells through multiple mechanisms, including modulation of antioxidant enzymes, upregulation of pro-apoptotic factors, and regulation of key signaling pathways involved in cell survival and proliferation. These findings suggest that vitexin’s mechanisms of action involve complex interactions with various cellular pathways, making it a promising candidate for further research and potential therapeutic applications in colorectal cancer.