Reduction In Tumor Size Research Articles

Semaglutide reprograms macrophages via the GLP-1R/PPARG/ACSL1 pathway to suppress papillary thyroid carcinoma growth.

The use of glucagon-like peptide-1 receptor (GLP-1R) agonists such as semaglutide, a novel class of antidiabetic medications, has raised concerns about potential adverse effects, particularly a possible association with thyroid cancer (TC). This study aims to evaluate whether semaglutide influences the progression of TC by modulating tumor-associated macrophages (TAMs). Semaglutide was administered to human papillary thyroid carcinoma (PTC) xenograft mouse models, co-culture systems consisting of human THP-1 macrophage cells and PTC cells, and primary murine peritoneal macrophages. Assessments included tumor size, M1/M2 macrophage ratio, PTC cell proliferation, and polarization marker expression. Semaglutide did not significantly impact the proliferation of PTC cells but reduced tumor size and inhibited the proliferation of PTC cells in co-culture systems. It increased M1 and decreased M2 macrophages, reprogramming polarization by downregulating PPARG expression. Co-treatment with semaglutide and a PPARG agonist in the co-culture system confirmed the upregulation of downstream genes RSAD2, ACSL1, and PLA2G7. Silencing ACSL1 inhibited lipid accumulation in THP-1 cells and promoted polarization towards the M2 macrophage phenotype. Semaglutide modulates macrophage lipid metabolism through the GLP-1R/PPARG/ACSL1 signaling pathway. This modulation promotes the conversion of TAMs to the M1 macrophage phenotype, enhancing their anticancer activity. These findings suggest that semaglutide may improve therapeutic strategies, reduce unnecessary thyroid nodule screenings, and broaden its clinical applications.

Research trends of neoadjuvant therapy for breast cancer: A bibliometric analysis

ABSTRACT The approach of neoadjuvant therapy for breast cancer, which involves administering systemic treatment prior to primary surgery, has undergone substantial advancements in recent decades. This strategy is intended to reduce tumor size, thereby enabling less invasive surgical procedures and enhancing patient outcomes. This study presents a comprehensive bibliometric analysis of research trends in neoadjuvant therapy for breast cancer from 2009 to 2024. Using data extracted from the Web of Science Core Collection, a total of 3,674 articles were analyzed to map the research landscape in this field. The analysis reveals a steady increase in publication output, peaking in 2022, with the United States and China identified as the leading contributors. Key institutions, such as the University of Texas System and MD Anderson Cancer Center, have been instrumental in advancing the research on neoadjuvant therapy. The study also highlights the contributions of influential authors like Sibylle Loibl and Gunter von Minckwitz, as well as major journals such as the Journal of Clinical Oncology. Emerging research topics, including immunotherapy, liquid biopsy, and artificial intelligence, are gaining prominence and represent potential future directions for clinical applications. This bibliometric analysis provides critical insights into global research trends, key contributors, and future developments in the field of neoadjuvant therapy for breast cancer, offering a foundation for future research and clinical practice advancements.

Myxoid liposarcoma: treatment outcomes, metastatic pattern and volumetric analysis.

Myxoid liposarcoma (MLPS) is arare subtype of soft tissue sarcoma. This entity has aspecific clinical behavior, characterized with adistinct pattern of hematogenous spread, as well as with aunique radiosensitivity and chemosensitivity. Oncologic results, metastatic patterns and treatment response after multimodal therapy were evaluated in aunicentric patient cohort. Patients with myxoid liposarcoma were retrospectively analyzed in asingle institution analysis (n = 31). Oncologic outcomes were evaluated in 28patients with localized MLPS treated with multimodal therapy in curative intent. Metastatic pattern was analyzed in additional 3patients with initially metastatic disease. In patients treated with concomitant MR-guided hyperthermia in the preoperative setting (n = 7), tumor size response was evaluated longitudinally during radio(-chemo)therapy in thermometry MRIs and before surgery (based on preoperative imaging). The median follow-up was 4.1 ± 1.0years. The most common anatomic localization was the lower extremity (78.6%). The 5‑year rates for oncologic outcomes in 28patients treated in curative intent were 91.7% (± 8.0%) for overall survival (OS), 77.4% (± 11.0%) for local control (LC), 60.1% (± 10.6%) for distant metastasis-free survival (DMFS) and 55.4% (± 11.1%) for disease free survival (DFS). Excellent 5‑year LC (94.7 ± 5.1%) was demonstrated for the cohort excluding 5patients treated for local recurrences. Most patients had good pathologic response (< 10% vital tumor tissue) following neoadjuvant treatment (82.4%, 14/17). However, this did not correlate with oncologic outcomes. Aspecific pattern of distant metastases has been observed, with predilection for soft tissues as the most common metastatic site. Furthermore, no isolated pulmonary metastases were observed. The MR analysis demonstrated asignificant tumor size reduction (≥ 25%) of the initial tumor volume in 85.7% (n = 6/7) patients. No local recurrences and no distant metastases were observed in patients with significant MR size reduction. Sequential MRIs during preoperative radiotherapy of myxoid liposarcoma show distinct patterns of the known size reduction of this specific subentity. Our analysis of metastatic patterns demonstrate mostly soft tissue metastases, no patient experienced isolated pulmonary metastases.

Conversion therapy strategy: A novel GPC3-targeted multimodal organic phototheranostics platform for mid-late-stage hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is typically diagnosed at intermediate to advanced stage, making surgical treatment unfeasible. Conversion therapy aims to reduce tumor stage, improve hepatic resection feasibility, and lower recurrence rates. Since traditional therapies are often accompanied by uncertainty of efficacy, there is an urgent need to explore new treatment strategies. Near-infrared phototheranostics technology provides a new way for HCC diagnosis and treatment by its excellent optical properties. However, complex preparation and poor biocompatibility of phototheranostics probes limit clinical application. In this study, we developed a fluorescence/magnetic resonance dual-modality imaging (FLI/MRI) as well as photothermal/photodynamic therapy (PTT/PDT) GPC3-targeted multifunctional phototheranostics probe, IR820-GPC3-Gd NPs (IGD NPs), to improve the efficiency of conversion therapy for HCC. The IGD NPs were simply prepared with the IR820 as the core. Conjugating the HCC-specific targeting molecule GPC3 peptide and the MRI agent DOTA-Gd through click chemistry. IGD NPs target HCC cells through GPC3, releasing heat and reactive oxygen species (ROS) under noninvasive 808nm laser irradiation to reduce tumor size and achieve downstaging. High-sensitivity FLI/MRI precisely delineates tumor boundaries, providing real-time surgical navigation and prognosis assessment. This novel probe offers a feasible and effective treatment option for advanced HCC.

EMILIN-1 suppresses cell proliferation through altered cell cycle regulation in head and neck squamous cell carcinoma.

Extracellular matrix (ECM) proteins play an important role in the pathological processes of tumor development and progression. Elastic Microfibril Interface Located Protein-1 (EMILIN-1), an ECM glycoprotein, has been linked to cell adhesion and migration. We previously identified from head and neck squamous cell carcinoma (HNSCC) tissues that downregulated-EMILIN-1 was associated with an increased risk of secondary primary malignancy development in HNSCC and hypothesized that EMILIN-1 functions as a tumor suppressor in HNSCC. In this study, we showed that EMILIN-1 expression in HNSCC tissues was specific to the stromal area and that secreted-EMILIN-1 level was higher in fibroblasts isolated from HNSCC tissues than in HNSCC cells. EMILIN-1 overexpression decreased cell proliferation, migration, and invasion in FaDu and CAL27 cells. Knockdown of EMILIN-1 in HNSCC cancer-associated fibroblasts (CAFs) induced cell proliferation and migration. The conditioned medium from EMILIN-1-knockdown CAFs increased HNSCC cell proliferation, and the co-culture system enhanced cancer cell migration and invasion. RNA-sequencing analysis revealed that the cell cycle and aurora kinase signaling are the most significant enrichment pathways, confirmed at the protein level. Furthermore, using an in ovo chick chorioallantoic membrane (CAM) model, overexpression of EMILIN-1 in FaDu cells reduced tumor size and Ki67-positivity and increased cleaved caspase-3 positive cells. Our findings suggest that EMILIN-1 suppresses HNSCC growth partly through the downregulation of cell cycle and aurora kinase signaling pathways.

Yttrium-90 Radioembolization for Intrahepatic Cholangiocarcinoma: Non-University Tertiary Care Center Experience.

Intrahepatic cholangiocarcinoma (ICC) presents a significant clinical challenge due to its high fatality rate and limited surgical candidacy. With only 30-40% of patients eligible for surgery upon diagnosis, alternative therapies are imperative. This study assesses the efficacy of Yttrium-90 (Y-90) radioembolization for unresectable ICC patients in a non-university tertiary care center (NUTCC). A retrospective analysis of 15 unresectable ICC patients treated with Y-90 radioembolization was conducted. Tumor response, survival, and adverse events were evaluated using RECIST criteria. 60% of patients exhibited partial response, and 20% showed stable disease, with notable tumor size reduction and a median survival of 14 months. Minimal adverse effects were observed, indicating Y-90's favorable safety profile. Y-90 radioembolization shows potential in reducing tumor burden and enhancing survival rates with minimal adverse effects for unresectable ICC. Larger prospective studies are needed to confirm its efficacy and define its role in ICC treatment protocols.

NEIL3 and TOP2A as key drivers of esophageal cancer through WNT signaling.

Esophageal cancer (EC) is a highly aggressive malignancy with limited treatment options. Nei like DNA glycosylase 3 (NEIL3) and DNA topoisomerase II alpha (TOP2A) have been identified as potential therapeutic targets, though their roles in EC remain unclear. This study investigates the effects of NEIL3 overexpression and TOP2A knockdown, focusing on the WNT signaling pathway. ECA109 esophageal cancer cells were used to assess the impact of NEIL3 overexpression and TOP2A knockdown on proliferation, colony formation, migration, invasion, and apoptosis. The involvement of the WNT signaling pathway was also explored. NEIL3 overexpression significantly enhanced proliferation, colony formation, migration, and invasion while reducing apoptosis. In contrast, TOP2A knockdown suppressed these functions and promoted apoptosis, independent of NEIL3. NEIL3 overexpression could not reverse the effects of TOP2A knockdown. Both NEIL3 and TOP2A acted through the WNT signaling pathway. In vivo, NEIL3 knockdown reduced tumor size and weight via WNT pathway modulation. NEIL3 and TOP2A play key roles in EC progression through the WNT signaling pathway. Targeting these molecules may offer promising therapeutic strategies for EC.

Unlocking the potential of Calculus bovis: A breakthrough in liver cancer treatment via Wnt/β-catenin pathway modulation.

Liver cancer remains a significant global health challenge, characterized by high incidence and mortality rates. Despite advancements in medical treatments, the prognosis for liver cancer patients remains poor, highlighting the urgent need for novel therapeutic approaches. Traditional Chinese medicine (TCM), particularly Calculus bovis (CB), has shown promise in addressing this need due to its multi-target therapeutic mechanisms. CB refers to natural or synthetic gallstones, traditionally sourced from cattle, and used in TCM for their anti-inflammatory, detoxifying, and therapeutic properties. In modern practice, synthetic CB is often utilized to ensure consistent supply and safety. This article aims to discuss the findings of Huang et al, who investigated the anti-liver cancer properties of CB, focusing on its ability to inhibit M2 tumor-associated macrophage (TAM) polarization via modulation of the Wnt/β-catenin pathway. Huang et al employed a comprehensive approach integrating chemical analysis, animal model testing, and advanced bioinformatics. They identified active components of CB using UPLC-Q-TOF-MS, evaluated its anti-neoplastic effects in a nude mouse model, and elucidated the underlying mechanisms through network pharmacology, transcriptomics, and molecular docking studies. The study demonstrated that CB significantly inhibited liver tumor growth in vivo, as evidenced by reduced tumor size and weight in treated mice. Histological analyses confirmed signs of tumor regression. CB was found to modulate the tumor microenvironment by inhibiting the polarization of M2 phenotype-TAMs, as shown by reduced expression of M2 markers and downregulation of mRNA levels of C-C motif chemokine 22, arginase-1, transforming growth factor-beta 2, and interleukin-10. The study further revealed that CB's antineoplastic activity involved the downregulation of Wnt5B and β-catenin and upregulation of Axin2, thus inhibiting the Wnt/β-catenin signaling pathway. These findings highlight the therapeutic potential of CB in liver cancer treatment through its modulation of the Wnt/β-catenin pathway and suppression of M2 phenotype-TAM polarization. This study underscores the value of integrating TCM with modern therapeutic strategies to develop novel effective treatments for liver cancer.

Abstract B018: GSK3β inhibition synergizes with radiation therapy to stimulate type-I interferon and anti-tumor effects in lung cancer

Abstract Radiation therapy (RT) is widely used to treat various tumor types to minimize the risk of recurrence. However, only a subset of patients experiences significant responses to RT, primarily due to inadequate immune responses within lung tumors. Therefore, there is a pressing need to develop innovative strategies to overcome tumor immunosuppression following RT. In this study, we investigated alternative mediators that could mitigate the effects of immunosuppression in lung cancer cells. We screened over 700 pharmacological inhibitors using an interferon beta-1(IFNβ1)-luciferase reporter system, identifying a group of glycogen synthase kinase 3 beta inhibitors (GSK3βi) that enhanced IFNβ1 expression. Notably, one GSK3βi agent, Kenpaullone, significantly induced IFNβ1 in multiple lung cancer cell lines. Compared to other GSK3β inhibitors, it exhibited superior synergy (over 20-fold) without inducing cellular cytotoxicity, even at high doses (30 µM). Furthermore, our syngeneic mouse models showed that GSK3βi and RT reduced tumor size more effectively than monotherapy and enhanced immunologic response in these tumors. This pharmacological-RT combination approach holds promise for improving the immunologic response to RT in lung cancer patients, potentially reducing tumor burden in those that already exhausted standard of care treatment options. Citation Format: Chen Braun Nan Li, Steven H. Lin. GSK3β inhibition synergizes with radiation therapy to stimulate type-I interferon and anti-tumor effects in lung cancer. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B018

Abstract B020: Quercetin sensitizes PDAC cells to radiation therapy in vitro and in vivo

Abstract Pancreatic ductal adenocarcinoma (PDAC) is one of the most treatment resistant cancers, accounting for 7% of total cancer deaths worldwide. One of the major challenges in treating PDAC with radiotherapy (RT) effectively is its proximity to sensitive GI organs. One strategy to increase the efficacy of RT is combination with radiosensitizing drugs targeting tumor physiology, to selectively increase the sensitivity of tumor cell killing by RT, without increasing toxicity to normal tissues. With this aim, we investigated quercetin, a nutraceutical flavonoid compound. Previously, Quercetin has been reported as having antioxidant, anti-inflammatory, and cancer preventative effects. On a cellular level, it can inhibit ATP-citrate lyase (ACLY), a key enzyme of de novo lipogenesis. Inhibition of lipogenesis has been found to promote cancer cell death via ferroptosis, and de novo lipid synthesis is necessary for cancer cell division during G2/M phase, both of which could alter sensitivity to RT. We hypothesized that as inhibitor of lipogenesis, quercetin might radiosensitize PDAC cells to RT. Thus, we investigated whether quercetin could radiosensitize mouse (PK5L1940) and human (AsPC-1, PANC-1 and BXPC-3) PDAC cells in vitro and in vivo. To understand the effect of quercetin on radiation response of various PDAC lines, we performed clonogenic survival assays. We pre-treated PDAC cells for 24 hrs. with quercetin (25 µM), then exposed to increasing doses RT (0 Gy, 2 Gy, 4Gy, 6 Gy and 8 Gy), and incubated for 7 days to determine clonogenic survival. Quercetin (25 µM) treatment sensitized the PDAC cells lines with dose modification factor (DMF) at D50 (Dose required to kill 50% of cell population) of 0.53, 0.07,0.45 and 0.58 in PK5L1940, AsPC-1, PANC-1 and BXPC-3, respectively. We further validated these in vitro results in vivo. We implanted flank tumors with PK5L1940 cells in C57BL/6 mice and treated with vehicle (DMSO,10%: PEG300,40%: Tween 80,5%: Saline, 45%), quercetin (100 mg/kg of body weight for 7 days), 16Gy RT + Vehicle, or 16Gy RT + quercetin. Tumor measurements were taken twice a week using vernier calipers and mice were euthanized when the average tumor volume of RT treated mice was reached 2000 mm3. Quercetin and RT individually did not significantly reduce the tumor volume or delay time to tumor endpoint. The combination of quercetin and RT however significantly reduced tumor size at all time points, and on the day of experiment termination, the average tumor volume of the combination group was 1127 mm3 compared to all 3 other groups whose average volume surpassed 2000 mm3. We performed PI FACS analysis of PK5L1940 cells treated with quercetin and found a significant G2/M delay compared to untreated cells. These data support quercetin radiosensitizing PDAC in vitro and in vivo, perhaps by causing a cell cycle arrest in the sensitive G2/M phase of the cell cycle through inhibition of de novo lipid synthesis. Citation Format: Adam C. Mueller, Vishwa Gandhi, Talya Laufer. Quercetin sensitizes PDAC cells to radiation therapy in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B020.

Phase I trial of hydroxychloroquine to enhance palbociclib and letrozole efficacy in ER+/HER2− breast cancer

Endocrine therapy with CDK4/6 inhibitors is standard for estrogen receptor-positive, HER2−negative metastatic breast cancer (ER+/HER2− MBC), yet clinical resistance develops. Previously, we demonstrated that low doses of palbociclib activate autophagy, reversing initial G1 cell cycle arrest, while high concentrations induce off-target senescence. The autophagy inhibitor hydroxychloroquine (HCQ) induced on-target senescence at lower palbociclib doses. We conducted a phase I trial (NCT03774472 registered in ClinicalTrials.gov on 8/20/2018) of HCQ (400, 600, 800 mg/day) with palbociclib (75 mg/day continuous) and letrozole, using a 3 + 3 design. Primary objectives included safety, tolerability, and determining the recommended phase 2 dose (RP2D) of HCQ. Secondary objectives included tumor response and biomarker analysis. Fourteen ER+/HER2− MBC patients were evaluable [400 mg (n = 4), 600 mg (n = 4), 800 mg (n = 6)]. Grade 3 adverse events (AEs) included hematological (3 at 800 mg), skin rash (2 at 600 mg), and anorexia (1 at 400 mg), with no serious AEs. The best responses were partial (2), stable (11), and progression (1). Tumor reductions ranged from 11% to 30%, with one 55% increase. The two partial responders sustained tumor size reductions of 30% to 55% over an extended treatment period, lasting nearly 300 days. Biomarker analysis in responders demonstrated significant decreases in Ki67, Rb, and nuclear cyclin E levels and increases in autophagy markers p62 and LAMP1, suggesting a correlation between these biomarkers and treatment response. This phase I study demonstrated that HCQ is safe and well-tolerated and the RP2D was established at 800 mg/day with continuous low-dose palbociclib (75 mg/day) and letrozole (2.5 mg/day). These findings suggest that adding HCQ could potentially enhance the efficacy of low-dose palbociclib and standard letrozole therapy, pending verification in larger randomized studies.

A Systematic Review of Indications and Clinical Outcomes of Electrochemotherapy in Pancreatic Ductal Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most difficult cancers to treat, with a dismal 5-year survival rate of only 8–10%. This challenging prognosis highlights the urgent need for innovative therapeutic approaches to improve outcomes for patients with PDAC. Electrochemotherapy (ECT), which enhances intracellular chemotherapeutic uptake via electric pulses, has been explored for resectable, borderline resectable (BR), locally advanced (LA), recurrent, and metastatic PDAC, either as a complement to conventional treatments or as an alternative when these are not feasible or effective, offering possible benefits in symptomatic palliation and local tumor control. Methods: A systematic review was performed in accordance with PRISMA guidelines for studies assessing the efficacy of ECT in PDAC. After searching Embase, PubMed/MEDLINE, Scopus, and Web of Science, five studies with a combined total of 43 patients in various disease stages were identified. Results: ECT showed promise in improving tumor control, alleviating cancer-related pain, and improving quality of life. One study noted a trend towards tumor size reduction of 8.3% at one-month and 16.1% at six-months follow-up (p = 0.211 and p = 0.315), although these findings were derived from studies conducted without specific comparative control groups. Severity of complication was mainly mild (Clavien–Dindo I-II), while severe complications occurred in only 2.3% of patients. Median overall survival was reported in two studies as 8 months (range 2–19) and 11.5 months (range 1–74). ECT showed efficacy for symptom management, with 60% of patients reporting reduced pain/discomfort and 40% showing enhanced quality of life in one study, while another reported pain scores as decreasing from 6 to 3 at one month and to 2 at six months. Conclusions: ECT appears to be a new promising and safe adjunct treatment modality in PDAC management across different disease stages, with potential benefits in tumor control, cancer-related pain reduction, and quality of life. Further studies are warranted to validate these findings and identify patients who could benefit most.

Anti-Cancer Efficacy of Acacia nilotica Nanoparticles: Apoptosis Induction and Tumor Regression in a DMBA-induced Breast Cancer Rat Model

Background Breast cancer remains a significant global health burden despite advancements in treatment. While conventional therapies often induce adverse effects, there is growing interest in exploring natural alternatives. Acacia nilotica, a traditionally used medicinal plant, has shown promise in cancer management. Purpose This study investigated the therapeutic potential of A. nilotica extract and nanoparticles against 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer in albino rats. Methods The formation of A. nilotica crude solution and nanoparticles was done and characterized via dynamic light scattering (DLS) and Fourier-transform infrared spectroscopy (FTIR). A total of 60 female Wistar albino rats were divided into six groups (10 rats/group) and received care in compliance with the state authorities following the Saudi Arabian rules of animal protection. The animals in the first group were given distilled water, while those in the second group were administered DMBA (50 mg/kg). The third and fourth groups were treated with 10 mg/kg of the A. nilotica crude solution and nanoparticles, respectively. In the fifth and sixth groups, A. nilotica crude solution and nanoparticles were administered with 10 mg/kg after DMBA-induced breast cancer in rats, respectively. After sacrificing the rats, the blood and breast tissues were collected from each rat and processed for histological and apoptotic markers analyses. Results Our findings indicated that the average size of nanoparticles was 162.5 nm in diameter with 0.145 as a polydispersity index (PDI). Functional groups were confirmed via FTIR analysis for A. nilotica crude solution and nanoparticles. Histopathological analysis revealed a marked reduction in tumor size and cellular proliferation in nanoparticle-treated groups. Our data demonstrated that both formulations significantly inhibited tumor growth and induced apoptosis, as evidenced by altered Bcl-2 and BAX expression. Conclusion These findings suggest that A. nilotica nanoparticles warrant further investigation as a potential therapeutic strategy for breast cancer.

Laser-Induced Thermal Therapy in the Management of Low-Grade Gliomas: A Narrative Review

Background: Low-grade gliomas (LGGs) are slow-growing, World Health Organization Grade I and II tumors that can transform into more aggres-sive malignancies over time. This transformation pre- sents significant challenges in managing the burden of health care. Laser-induced thermal therapy (LITT) has emerged as a promising minimally invasive treat-ment option for LGGs, offering precise tumor ablation with minimal damage to surrounding tissues. Method: This narrative review synthesizes data from relevant studies on the evolution, clinical manifestations, mo-lecular characteristics, and emerging management strategies for LGGs, with a focus on the role of LITT. Results: LITT, a minimally invasive technique, offers targeted tumor ablation with the added benefit of disrupting the blood-brain barrier to enhance drug delivery. Studies have shown that LITT can effectively reduce tumor size and improve survival rates in patients with both primary and recurrent gliomas. However, challenges such as procedure-related complications, including motor deficits and cerebral edema, as well as the need for further research on long-term efficacy, remain. Conclusion: LITT represents a significant advancement in the treatment of LGGs, combining precision and minimal invasiveness. Future studies should focus on optimiz-ing protocols, integrating molecular and genetic in-sights, and assessing long-term outcomes to enhance therapeutic efficacy and patient quality of life.

Anti-osteosarcoma activity of Corynoline via Src/JNK signaling-mediated cell cycle arrest and mitochondrial apoptosis.

Corynoline (COR) is an isoquinoline alkaloid derived from the traditional Chinese medicine Corydalis bungeana Turcz, known for its analgesic, antibacterial, neuroprotective, and osteoporosis-alleviating properties. However, its potential molecular effects against osteosarcoma (OS) remain unclear, warranting further investigation. This study demonstrated that COR inhibits OS cell proliferation and promotes apoptosis in a dose-dependent manner. Additionally, COR induced G2/M phase cell cycle arrest. Using an integrative computational and experimental approach, we found the Src/JNK pathway was identified as a significant target. Western blot analysis revealed that OS cells treated with COR showedan increase in levels was evident of p-Src, p-JNK, and p-c-JUN. Moreover, the JNK inhibitor SP600125 counteracted COR's anti-proliferative effects and reversed mitochondrial apoptosis and cell cycle arrest. In vivo, COR significantly reduced tumor size in OS xenograft nude mice without causing toxicity. Following COR treatment, elevated levels of p-JNK and cyclin B1 were observed, while Ki-67 decreased and JNK levels remained unchanged. We finally elucidated the COR inhibits OS via Src/JNK pathway. Given its multifaceted roles in regulating cell behavior in the context of OS, the Src/JNK pathway is being explored for therapeutic interventions. Targeting this pathway could potentially improve treatment outcomes by modulating the balance between cell survival and death in OS. Thus, understanding the Src/JNK pathway is essential for unraveling the intricate mechanisms underlying OS progression and for developing effective therapeutic strategies.

Fast-Relaxing Hydrogels Promote Pancreatic Adenocarcinoma Cell Aggressiveness through Integrin β1 Signaling.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense extracellular matrix (ECM) exhibiting high stiffness and fast stress relaxation. In this work, gelatin-based viscoelastic hydrogels were developed to mimic the compositions, stiffness, and fast stress relaxation of PDAC tissues. The hydrogels were cross-linked by gelatin-norbornene-boronic acid (GelNB-BA), thiolated macromers, and a 1,2-diol-containing linear synthetic polymer PHD. Controlling the thiol-norbornene cross-linking afforded tunable stiffness, whereas increasing PHD content led to hydrogels with PDAC-mimicking fast stress relaxation. In vitro studies, including proliferation, morphology, and mRNA-sequencing, showed that fast-relaxing hydrogels supported PDAC cell proliferation, epithelial-mesenchymal transition (EMT), and integrin β1 activation. Blocking integrin β1 in vitro led to upregulating EMT markers in both slow and fast-relaxing hydrogels. However, this strategy profoundly impacted tumor growth rate and reduced tumor size but did not alter metastasis patterns in an orthotopic mouse model. This suggests a need to further evaluate the antitumor effect of integrin β1 blockade.

Repurposing Linezolid in Conjunction with Histone Deacetylase Inhibitor Access in the Realm of Glioblastoma Therapies.

Since decades after temozolomide was approved, no effective drugs have been developed. Undoubtedly, blood-brain barrier (BBB) penetration is a severe issue that should be overcome in glioblastoma multiforme (GBM) drug development. In this research, we were inspired by linezolid through structural modification with several bioactive moieties to achieve the desired brain delivery. The results indicated that the histone deacetylase modification, referred to as compound 1, demonstrated promising cytotoxic effects in various brain tumor cell lines. Further comprehensive mechanism studies indicated that compound 1 induced acetylation, leading to DNA double-strand breaks, and induced the ubiquitination of RAD51, disrupting the DNA repair process. Furthermore, compound 1 also exhibited dramatic improvement in the orthotopic GBM mouse model, demonstrating its efficacy and satisfying BBB penetration. Therefore, the reported compound 1, provided with an independent therapeutic pathway, satisfying elongation in survival and tumor size reduction, and the ability to penetrate the BBB, was potent to achieve further development.

Huaier inhibits the proliferation and migration of gastrointestinal stromal tumors by regulating the JAK2 / STAT3 signaling pathway.

Gastrointestinal stromal tumor (GIST) is the most common mesenchymal tumor of the digestive tract, often accompanied by a high risk of recurrence and drug resistance. Huaier (Trametes robiniophila Murr), a traditional Chinese medicinal fungus, has demonstrated potent anticancer properties and is widely used as an adjuvant treatment for liver, breast, gastric, colon, and non-small cell lung cancers. However, its effects and molecular mechanisms in GIST remain unclear. This study aims to explore the inhibitory effects and underlying mechanisms of Huaier on GIST through network pharmacology and experimental validation. Initially, we utilized a publicly accessible database to identify the core targets and principal pathways associated with Huaier's therapeutic effects on gastrointestinal stromal tumors. To further evaluate its biological impact, cell viability, proliferation, migration, and invasion were assessed through CCK-8 and EdU assays, wound healing tests, and Transwell experiments. Apoptotic cell death was quantified using flow cytometry analysis. Additionally, the influence of Huaier extract on the expression levels of JAK2 and STAT3 proteins was examined via Western blotting. Finally, a subcutaneous xenograft mouse model was employed to investigate the anti-tumor efficacy of Huaier in vivo. In this study, GAPDH, TNF, STAT3, ESR1, EGFR, IL6, CCND1, PTGS2, BCL2L1, and MAPK3 were identified as shared molecular targets, with the JAK/STAT signaling pathway recognized as the pivotal regulatory mechanism. Experimental findings demonstrated that Huaier exerted inhibitory effects on the proliferation, migration, and invasion of GIST-T1 and GIST-882 cells, exhibiting both dose- and time-dependent responses. Furthermore, Huaier was found to promote apoptosis in these cells. Western blot analysis revealed that treatment with Huaier extract significantly decreased the phosphorylation levels of JAK2 and STAT3, thereby suppressing the activation of the JAK2 / STAT3 signaling cascade. In vivo experiments further substantiated these findings, showing that Huaier treatment markedly reduced tumor size and inhibited tumor progression. Our results suggest that Huaier may inhibit the growth of GIST cells by inhibiting the JAK2/STAT3 signaling pathway, reduce cell proliferation, induce apoptosis, reduce cell migration and invasion, and show anti-tumor effects in vivo and in vitro.

Integrated multi-omics analyses of oral squamous cell carcinoma reveal precision patient stratification and personalized treatment strategies.

Oral cavity squamous cell carcinoma (OSCC), a leading subtype of head and neck cancer, exhibits high global incidence and mortality rates. Despite advancements in surgery and radiochemotherapy, approximately one-third of patients experience relapse. To improve current targeted and immunotherapy strategies for recurrent OSCC, we conducted multi-omics analyses on pretreatment OSCC samples (cohorts 1 and 2, n=137) and identified A3A and EGFR, both at the RNA and protein levels, as inversely expressed markers for patient stratification and response prediction. Survival analysis demonstrated that elevated A3A or PD-L1 expression levels correlated to improved responses to anti-PD-1 therapy in patients (cohort 3a, n=50, IHC). In contrast, high RRAS expression (cohort 4, n=252, qRT-PCR) was significantly associated with OSCC recurrence. Cell-based experiments revealed that RRAS was involved in radiotherapy and cisplatin resistance through the EGFR/RRAS/AKT/ERK signaling pathway. In OSCC patient-derived xenograft (PDX) mouse models, treatments with cisplatin and cetuximab (anti-EGFR) effectively reduced tumor size in EGFR-high-derived (#34) but not A3A-high-derived (#22) PDX tumors. Our study demonstrated that A3A-high tumors were immune-hot and responsive to anti-PD-1 therapy, whereas EGFR-high tumors exhibited chr.7p11.2 gains and DNA repair alterations. Additionally, RRAS-high tumors were associated with OSCC recurrence via AKT and ERK phosphorylation and demonstrate improved clinical outcomes with cetuximab therapy (cohort 3b, n=49, IHC). This study emphasizes the significance of A3A and EGFR expression levels in OSCC patient stratification and precision therapy, suggesting the use of anti-PD-1 or anti-EGFR treatments, respectively based on these biomarkers. Furthermore, RRAS emerges as a novel prognostic marker for local recurrence.

Inhibition of IKK complex by (2 methyl butyryl) Shikonin, a naturally occurring naphthoquinone, abrogates melanoma growth and progression via modulation of the IKK/NFκB /EMT signaling axis.

Melanoma is an aggressive form of malignancy that originates from melanin-producing cells known as melanocytes underlying the basal layer of the epidermis with a poor prognosis, low survival rates, and limited treatment options. Although several specific and effective systematic strategies for treating melanoma have been established, the underlying molecular mechanism of melanoma progression, mortality and the promising therapeutic options remain elusive. Shikonin (SK), a natural naphthoquinone derived from a medicinal herbaceous plant, has been shown to inhibit the proliferation of several cancer cells. However, its role in the context of melanoma is poorly understood. In the present study, the anti-melanoma activity of (2-methylbutyryl) Shikonin was assessed under in vitro and in vivo models. In vitro findings revealed that (2-methylbutyryl) Shikonin significantly reduced the viability and promoted apoptosis in the B16F10 melanoma cells. Additionally (2-methylbutyryl) Shikonin significantly suppressed migration and invasion of melanoma cells by regulating IKK/NFκB/EMT signalling axis thereby attenuating nuclear translocation and subsequent transcription of NF-κB downstream target genes. Furthermore, (2-methylbutyryl) Shikonin administration significantly reduced tumor size and weight in the xenograft melanoma mice model. Our data presents novel insights that justify additional preclinical and clinical validations of (2-methylbutyryl) Shikonin for melanoma therapy.