Current Cancer Drug Targets - Volume 25, Issue 4, 2025

Lung adenocarcinoma (LUAD) is a highly lethal malignancy. Liquid-Liquid Phase Separation (LLPS) plays a crucial role in targeted therapies for lung cancer and in the progression of lung squamous cell carcinoma. However, the role of LLPS in the progression and prognosis of LUAD remains insufficiently explored.

This study employed a multi-step approach to identify LLPS prognosis-related genes in LUAD. First, differential analysis, univariate Cox regression analysis, Random Survival Forest (RSF) method, and Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression analysis were utilized to identify five LLPS prognosis-related genes. Subsequently, LASSO Cox regression was performed to establish a prognostic score termed the LLPS-related prognosis score (LPRS). Comprehensive analyses were then conducted based on the LPRS, including survival analysis, clinical feature analysis, functional enrichment analysis, and tumor microenvironment assessment. The LPRS was integrated with additional clinicopathological factors to develop a prognostic nomogram for LUAD patients. Immunohistochemical validation was performed on clinical tissue samples to further validate the findings. Finally, the relationship between KRT6A, one of the identified genes, and epidermal growth factor receptor (EGFR) mutations was investigated.

The LPRS was established using five LLPS-related genes: IGF2BP1, KRT6A, LDHA, PKP2, and PLK1. Higher LPRS was closely associated with poor survival outcomes, gender, progression-free survival (PFS), and advanced TNM stage. Furthermore, LPRS emerged as an independent prognostic factor for LUAD. A nomogram integrating LPRS, TNM stage, and age demonstrated remarkable predictive accuracy for prognosis among patients with LUAD. LLPS likely influences LUAD prognosis through the activity of IGF2BP1, KRT6A, LDHA, PKP2, and PLK1. KRT6A exhibits significant upregulation in LUAD, particularly in patients with EGFR mutations.

This study introduces a novel LPRS model that demonstrates high accuracy in predicting the clinical prognosis of LUAD. Moreover, the findings suggest that KRT6A may play a critical role in the LLPS-mediated malignant progression of LUAD.

Duk is a well-established traditional drug that has been used since time immemorial by Indian practitioners to cure various human ailments.

The purpose of this study was to explore the anti-cancer activity and the possible mechanism of Duk against diethylnitrosamine (DEN)-initiated hepatocarcinogenesis.

We administered Duk at 3 doses, viz., 75, 150, and 300 mg/kg/day, 2 weeks before the DEN and continued it for 16 weeks. After 1 week of DEN recovery, 2-aminoacetylflourine (2-AAF) was administered to promote hepatocarcinogenesis.

We found that Duk significantly reduced the DEN and 2-AAF induced phenotypical changes in rats and restored the levels of liver function markers. Furthermore, Duk counteracted the oxidative stress induced by carcinogens as observed by restoration in the levels of superoxide dismutase (SOD) and catalase (CAT). Duk significantly diminished the levels of malondialdehyde (MDA) in a dose dependent manner and restored the liver microarchitecture as assessed by histopathological studies. The results of immunohistochemical staining showed that Duk inhibited the DEN-induced decrease in the number of cells positive for Bid and Caspase-9. It also reduces the number of cells positive for Cyclin D.

Duk significantly protects rat liver from hepatocarcinogenesis by regulating oxidative damage and restoring liver function markers. The chemopreventive effect of Duk might be through the induction of apoptosis.

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.

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.

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.

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.

Glycyrrhizic Acid (GA), a compound derived from licorice, has exhibited promising anticancer properties against several cancer types, including Prostate Cancer (PCa) and Gastric Cancer (GCa).

This study has introduced a novel approach involving the encapsulation of GA and Licorice extract (Lic) into Polyethylene Glycol Liposomes (PEG-Lip) and assessed their efficacy against AGS (human gastric cancer) and PC-3 (human prostate cancer) cells, marking the first report of this endeavor.

We synthesized GA-loaded PEG-Lip (GA PEG-Lip) and Lic-loaded PEG-Lip (Lic PEG-Lip) through the reverse-phase evaporation method.

Characterization of these liposomal formulations revealed their size, drug encapsulation, and loading efficiencies to be 110 ± 2.05 nm, 117 ± 1.24 nm; 61 ± 0.81%, 34 ± 0.47%; and 8 ± 0.41% and 4.6 ± 0.21%, respectively. Importantly, the process has retained the chemical structure of both GA and Lic. Furthermore, GA and Lic have been released from the PEG-Lip formulations in a controlled manner.

In our experiments, both nanoformulations exhibited enhanced cytotoxic effects against AGS and PC-3 cells. Notably, GA PEG-Lip outperformed Lic PEG-Lip, reducing the viability of PC-3 and AGS cells by 12.5% and 15.9%, respectively.

These results have been corroborated by apoptosis assays, which have demonstrated GA PEG-Lip and Lic PEG-Lip to induce stronger apoptotic effects compared to free GA and Lic on both PC-3 and AGS cells.

This study has underscored the potential of encapsulating GA and Lic in PEG-Lip as a promising strategy to augment their anticancer efficacy against prostate and gastric cancers.

Sorafenib is currently the first choice for the treatment of patients with advanced hepatocellular carcinoma, but its therapeutic effect is still limited.

This study aims to examine whether WEE family kinase inhibitors can enhance the anticancer effect of sorafenib.

We analyzed the expression levels of PKMYT1 kinase and WEE1 kinase in HCC, studied the inhibitory effect of PKMYT1 kinase inhibitor RP-6306, WEE1 kinase inhibitor adavosertib combined with sorafenib on the proliferation of HCC cells, and detected the effect of drug combination on CDK1 phosphorylation.

We found that PKMYT1 and WEE1 were upregulated in HCC and were detrimental to patient survival. Cell experiments showed that both RP-6306 and adavosertib (1-100 μM) inhibited the proliferation of HCC cell lines in a dose-dependent manner alone, and the combination of the two drugs had a synergistic effect. In HCC cell lines, sorafenib combined with RP-6306 or adavosertib showed a synergistic antiproliferation effect and less toxicity to normal cells. Sorafenib combined with RP-6306 and adavosertib further inhibited the proliferation of HCC cells and caused complete dephosphorylation of CDK1.

Taken together, our findings provide experimental evidence for the future use of sorafenib in combination with RP-6306 or adavosertib for the treatment of HCC.

Colon cancer has high mortality rate which making it one of the leading causes of cancer deaths. Oxaliplatin is a common chemotherapeutic drug, but it has disadvantages such as drug resistance.

The purpose of this study is to explore the mechanism of exosomes in the resistance of oxaliplatin and verify whether elemene and STAT3 inhibitors reverse the resistance to oxaliplatin.

Related cell line models were constructed and the proliferation, migration, invasion, apoptosis and resistance to oxaliplatin were evaluated for all three cells of HCT116/L, sensitive cell HCT116 and HCT116+HCT116/L-exosomes (HCT116-exo). It was to explore probable signaling pathways and mechanisms by Western blotting.

HCT116-exo drug-resistant chimeric cells showed greater capacity for proliferation, migration and invasion than HCT116 sensitive cells. After the above cells were treated with oxaliplatin, the apoptosis rate of chimeric drug-resistant cells HCT116-exo and its IC50 increased compared with the sensitive cells HCT116. The proliferation, invasion and migration of cells treated with STAT3 inhibitor or β-elemene combined with oxaliplatin reduced compared with those treated with oxaliplatin or β-elemene alone. The STAT3 inhibitor or β-elemene in combination with oxaliplatin increased the rate of apoptosis relative to oxaliplatin or β-elemene alone. Drug-resistant cell exosomes could promote the EMT process, related to the participation of FGFR4, SHMT2 and STAT3 inhibitors.

Drug-resistant cell exosomes could induce resistance, and improve the capacity of colon cancer towards proliferate, invade, migrate and promote the EMT process. The β-elemene combined with oxaliplatin could reverse the above results which might be related to the STAT3 pathway and EMT pathway in colon cancer.

This study aimed to clarify the expression of a gene associated with Retinoid-Interferon-Induced Mortality-19 (GRIM-19) in Upper Urinary Tract Urothelial Carcinoma (UUTUC) and its prognostic significance for UUTUC patients.

Immunohistochemical (IHC) staining was used to determine the GRIM-19 expression in 70 paired samples. Progression-Free Survival (PFS) and Cancer-Specific Survival (CSS) were assessed using the Kaplan-Meier method. The independent prognostic factors for PFS and CSS were analyzed by multivariable Cox regression models.

IHC staining showed that GRIM-19 expression was significantly decreased in UUTUC, and its cellular location changed from being both cytoplasmic and nuclear to only cytoplasmic. Kaplan-Meier analysis revealed that the patients with tumors expressing low GRIM-19 had a significantly higher risk for tumor progression (P = 0.002) and cancer-specific mortality (P < 0.001) compared to those with high GRIM-19 levels. The Cox regression showed that both GRIM-19 expression (P = 0.025) and lymph node metastasis (LN) (P = 0.007) were independent predictors of progression in the muscle-invasive (MIC) subgroup. GRIM-19 expressions (entire cohort: P = 0.011; MIC subgroup: P = 0.025), LN (entire cohort: P = 0.019; MIC subgroup: P = 0.007), and progression (entire cohort: P < 0.001; MIC subgroup: P < 0.001) were independent predictors of cancer-specific survival.

Low expression of GRIM-19 in patients with UUTUC had significantly shorter PFS or CSS compared to those with high GRIM-19-expressing tumors. High GRIM-19 expression was also strongly associated with longer PFS in MIC patients. It indicates that GRIM-19 might serve as a promising prognostic biomarker for UUTUC patients.

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-1carbothioamide (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.

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.

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.

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