Triptonide inhibits growth and metastasis in HCC by suppressing EGFR/PI3K/AKT signaling.

Liver cancer represents one of the deadliest cancers, with a rising incidence worldwide. Triptonide is found in the traditional Chinese medicinal plant Tripterygium wilfordii Hook. This study aimed to examine the anticancer properties of triptonide in human hepatocellular carcinoma (HCC). HCC cells were administered with triptonide at various levels, and CCK-8 and colony formation assays were carried out for detecting HCC cell proliferation. Then, cell apoptosis and cell cycle distribution were evaluated by flow cytometry. Tumor growth was monitored noninvasively by ultrasound imaging. Cell migration and invasion were quantitated by wound healing and Transwell assays. A metastasis model was established via tail vein injection of HCC cells in nude mice. Immunoblot was performed to quantitate the expression of proteins involved in the EGFR/PI3K/AKT signaling and its downstream effectors. Triptonide repressed cell proliferation and induced cell cycle arrest and apoptosis in cultured HCC cells, and suppressed tumor growth in vivo. In addition, triptonide inhibited EMT, migration and invasion in cultured HCC cells, and lung metastasis in nude mice. Mechanistically, triptonide acted by inhibiting the EGFR/PI3K/AKT signaling and regulated its downstream effectors, e.g., the cell cycle-associated protein cyclin D1, the apoptosis-related protein Bcl-2, the EMT marker E-cadherin, and the invasion-related protein MMP-9. Triptonide suppresses proliferation, EMT, migration and invasion, and promotes apoptosis and cell cycle arrest by repressing the EGFR/PI3K/AKT signaling. Therefore, triptonide might be considered for liver cancer treatment.

Posterior reversible encephalopathy syndrome after anlotinib treatment for small cell lung cancer: A case report and literature review.

Anlotinib is an oral multi-targeted tyrosine kinase inhibitor as a third-line and subsequent treatment for patients with small cell lung cancer (SCLC) in China. The neurotoxicity is less reported. Posterior reversible encephalopathy syndrome (PRES) is characterized by headaches, seizures, encephalopathy, and visual disturbances, as well as focal reversible vasogenic edema seen on neuroimages. Here, we presented a case of PRES in a small cell lung cancer (SCLC) patient associated with anlotinib. A 37-year-old female patient, who had a history of diabetes, with extensive-stage SCLC received anlotinib after third-line chemotherapy. Ten cycles of anlotinib later, the patient experienced visual disturbance and was diagnosed with PRES based on the typical demyelination of white matter obtained in the brain magnetic resonance. During anlotinib therapy, the patient did not develop anti-VEGF therapy-induced hypertension. Subsequently, the patient stopped anlotinib, but she did not recover from symptoms. We also summarized the characteristics of fifty-four cases of PRES caused by antiangiogenic drugs in the literature. Based on our experience and the literature review, the incidence of PRES induced by antiangiogenic drugs is low, and the symptom can resolve upon stopping the medications. However, some cases still have a poor prognosis and the underlying mechanism requires further investigation. In addition, early detection and treatment of PRES are essential for physicians.

Cardiovascular Toxicity With PD-1/PD-L1 Inhibitors in Cancer Patients: A Systematic Review and Meta-Analysis.

Background: PD-1/PD-L1 inhibitors have significantly improved the outcomes of those patients with various malignancies. However, the incidence of adverse events also increased. This meta-analysis aims to systematically evaluate the risk of cardiovascular toxicity in patients treated with PD-1/PD-L1 inhibitors. Materials and methods: We searched PubMed, Embase, the Cochrane Library databases for all randomized controlled trials (RCTs) comparing all-grade and grade 3-5 cardiovascular toxicity of single-agent PD-1/PD-L1 inhibitors to placebo/chemotherapy, PD-1/PD-L1 inhibitors combined with chemotherapy to chemotherapy, or PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors to single-agent immune checkpoint inhibitors (ICIs) and pooled our data in a meta-analysis stratified by tumor types and PD-1 or PD-L1 inhibitors. The Mantel-Haenszel method calculated the odds ratio (OR) and its corresponding 95% confidence intervals (CIs). Results: A total of 50 trials were included in the analysis. Single-agent PD-1/PD-L1 inhibitors increased the risk of all-grade cardiotoxicity compared with placebo (OR=2.11, 95%CI 1.02-4.36, P=0.04). Compared with chemotherapy, patients receiving PD-1/PD-L1 inhibitors combined with chemotherapy had a significant higher risk of all-grade (OR=1.53, 95%CI 1.18-1.99, P=0.001) and grade 3-5 cardiotoxicity (OR=1.63, 95%CI 1.11-2.39, P=0.01) cardiotoxicity, especially patients with non-small cell lung cancer (NSCLC) [all-grade cardiotoxicity (OR=1.97, 95%CI 1.14-3.41, P=0.02) and grade 3-5 cardiotoxicity (OR=2.15, 95%CI 1.08-4.27, P=0.03)]. Subgroup analysis showed that PD-1 inhibitors combined with chemotherapy were associated with a higher risk of grade 3-5 cardiotoxicity (OR=2.08, 95%CI 1.18-3.66, P=0.01). Compared with placebo or chemotherapy, single-agent PD-1/PD-L1 inhibitors did not increase the risk of all-grade of myocarditis, arrhythmia and hypertension. However, PD-1/PD-L1 inhibitors combined with chemotherapy increased the risk of all-grade arrhythmia (OR=1.63, 95%CI 1.07-2.46, P=0.02) [PD-L1 inhibitor-containing treatment (OR=1.75, 95%CI 1.09-2.80, P=0.02)], and the risk of all-grade hypertension (OR=1.34, 95%CI 1.02-1.77, P=0.04) and grade 3-5 hypertension (OR=1.54, 95%CI 1.10-2.15, P=0.01). Conclusions: Our results suggest that single-agent PD-1/PD-L1 inhibitors increase the risk of all-grade cardiotoxicity, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of all-grade and grade 3-5 cardiotoxicity, especially in those patients treated with PD-1 inhibitor-containing treatment and those with NSCLC. In addition, PD-1/PD-L1 inhibitors combined with chemotherapy increase the risk of arrhythmia and hypertension. Therefore, this evidence should be considered when assessing the benefits and risks of PD-1/PD-L1 inhibitors in treating malignancies. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42022303115.

CCL2-targeted ginkgolic acid exerts anti-glioblastoma effects by inhibiting the JAK3-STAT1/PI3K-AKT signaling pathway.

AIMS: Glioblastoma (GBM) with aggressive nature and poor prognosis has become the most common intracranial tumor. Most clinical chemotherapeutic drugs fail to achieve the anticipated therapeutic outcome. This study identified the anti-GBM effects of ginkgolic acids (GAs) and elucidated the potential molecular mechanisms, exploiting the significant antitumor effects of GAs, which are widely present in the outer bark of Ginkgo biloba. MATERIALS AND METHODS: Two GBM cell lines, U251 and T98G, were selected for in vitro experiments to evaluate the antitumor effects of GA. Cell viability and proliferation were examined by MTT and colony formation assay. The effect of GA on apoptosis and the cell cycle was examined by flow cytometry. Scratch and Transwell assays reflected the migration and invasion ability. The molecular mechanisms were explored by using immunoblot analysis, RNA sequencing and bioinformatics. In the nude mouse transplantation tumor model, preclinical treatment effects were assessed by ultrasound and MRI. KEY FINDINGS: The present study showed that GA inhibited the proliferation, migration, invasion, stemness, epithelial-to-mesenchymal transition (EMT) of GBM cells and induced apoptosis by inhibiting CCL2, affecting the JAK-STAT and PI3K-AKT signaling pathways, and inhibiting the EMT regulators Snail and Slug. Finally, GA showed significant control of tumors in a GBM xenograft model. SIGNIFICANCE: GA inhibits the progression of GBM cells by targeting CCL2, affecting the JAK-STAT and PI3K-AKT signaling pathways, and inhibiting the EMT regulators Snail and Slug. The outstanding antitumor properties of GA provide a novel strategy for the GBM therapy.

Multifunctional Drug-Loaded Phase-Change Nanoparticles Inhibit the Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Affecting the Activity of Activated Hepatic Stellate Cells.

Objectives. Preparation of a multifunctional drug-loaded phase-change nanoparticle (NP), pirfenidone perfluoropentane liposome NPs (PPL NPs), and combined with low-intensity focused ultrasound (LIFU) to influence epithelial mesenchymal transition (EMT) for hepatocellular carcinoma (HCC) by inhibiting the activity of activated Hepatic Stellate Cells (a-HSCs). Methods. PPL NPs were prepared by the thin film dispersion method. The appearance, particle size, zeta potential, encapsulation efficiency, drug loading rate, drug release in vitro, and stability of PPL NPs were tested. The role of a-HSCs in HCC metastasis was studied by CCK-8, colony formation assay, apoptosis, cellular uptake assay, wound healing assay, and Transwell assay. Western blot was used to detect the related protein expression levels. In vitro and vivo, the acoustic droplet vaporization (ADV) of PPL NPs was tested at different times and LIFU intensities. Biosafety of the PPL NPs was assessed by measuring nude mouse body weight and hematoxylin and eosin (H&E) staining. Results. The results showed that the PPL NPs had good biosafety, with an average particle size of 346.6 ± 62.21 nm and an average zeta potential of -15.23 mV. When the LIFU power is 2.4 W/cm2, it can improve the permeability of cells, further promote the uptake of drugs by cells, and improve the toxicity of drugs. In vitro experiments showed that PPL NPs could inhibit the proliferation of a-HSCs cells, thereby affecting the metastasis of HCC, and were related to the TGFß-Smad2/3-Snail signaling pathway. Both in vivo and in vitro PPL NPs enhanced ultrasound imaging by LIFU-triggered ADV. Conclusion. The PPL NPs designed and prepared in this study combined with LIFU irradiation could significantly alter the EMT of HCC by inhibiting LX2. Clinically, PPL NPs will also be considered a promising contrast agent due to their ultrasound imaging capabilities.

PFP@PLGA/Cu12Sb4S13-mediated PTT ablates hepatocellular carcinoma by inhibiting the RAS/MAPK/MT-CO1 signaling pathway.

Hepatocellular carcinoma (HCC) is one of the most malignant tumors in the world, and patients with HCC face a poor prognosis. The conventional therapeutic strategies for HCC have undergone a challenge-riddled evolution owing to side effects and unsatisfactory efficacy. Here, aiming to provide a new method of HCC elimination, we formulated a novel multifunctional nanocapsule (PFP@PLGA/Cu12Sb4S13, PPCu) with applications in contrast-enhanced ultrasound imaging (CEUS) and photothermal therapy (PTT). These PPCu were successfully constructed with an average diameter of 346 nm (polydispersity index, PDI = 0.276). The reinforced contrast ratio of these PPCu was determined by CEUS, revealing their promising applications in image-guided monitoring of HCC treatment. Furthermore, the excellent photoabsorption and biocompatibility indicated by organ H&E staining indicated that PPCu meet quality expectations for use as photothermal transduction agent (PTA). PPCu treatment at 50 °C and higher temperatures efficiently repressed the proliferation, induced the apoptosis and decreased the motility of HCC cells. These effects might have been results of RAS/MAPK/MT-CO1 signaling pathway inhibition. In summary, PPCu were constructed to integrate CEUS and PTT successfully into therapy, which can lead to HCC elimination through RAS/MAPK/MT-CO1 signaling pathway repression.