Anti-Cancer Drugs最新文献

Chemotherapy resistance has long stood in the way of therapeutic advancement for lung cancer patients, the malignant tumor with the highest incidence and fatality rate in the world. Patients with lung adenocarcinoma (LUAD) now have a dismal prognosis due to the development of cisplatin (DDP) resistance, forcing them to use more costly second-line therapies. Therefore, overcoming resistance and enhancing patient outcomes can be achieved by comprehending the regulatory mechanisms of DDP resistance in LUAD. WD repeat domain 62 (WDR62) expression in LUAD tissues and in DDP-resistant or sensitive LUAD patients was analyzed bioinformatically, and a K-M plot was utilized to assess survival status. Real-time quantitative PCR was employed for WDR62 expression detection, cell-counting kit-8 assay for half maximal inhibitory concentration determination, flow cytometry for cell apoptosis detection, immunofluorescence for γ-H2AX expression analysis, and western blot for nonhomologous end joining repair and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway-related protein expression analysis. Poor prognosis was linked to WDR62, which was overexpressed in LUAD tissues and cells. Compared to sensitive cells, DDP-resistant cells had increased WDR62 expression. WDR62 knockdown may enhance DDP-induced cell apoptosis while reducing cell proliferation and DNA damage repair. Functional investigations verified that overexpressed WDR62's encouraging impact on DNA damage repair in A549/DDP cells could be reversed by MAPK inhibitors, increasing the cells' susceptibility to DDP. LUAD cells became less sensitive to DDP when WDR62 activated the MAPK/ERK pathway, which promoted DNA damage repair, indicating that DDP resistance might be reversed by treating LUAD with inhibitors of the MAPK pathway.

Tumor-associated macrophages play a critical role in regulating the progression of lung adenocarcinoma (LUAD). Platelet-derived protein thrombospondin-2 (THBS2) has been identified as a tumor marker and is known to be overexpressed in LUAD. However, the specific role of THBS2 in M2 macrophage polarization within LUAD remains unclear. We conducted bioinformatics analyses to assess the clinical significance of THBS2 expression in LUAD, which was subsequently validated using quantitative PCR. We examined the relationship between THBS2 expression and M2 macrophage infiltration. A coculture system of LUAD cells and M0 macrophages was established to investigate the influence of THBS2 on macrophage infiltration and polarization through immunofluorescence and ELISA. We explored the impact of THBS2 on fatty acid metabolism (FAM) using oil red O staining and relevant kits and elucidated the role of THBS2 in regulating M2 macrophage polarization and LUAD proliferation through cell counting kit-8 (CCK-8) and colony formation assays. Western blot was employed to assess expression changes of Bax and Bcl-2. THBS2 was highly expressed in LUAD and was associated with poor prognosis in patients. In-vitro experiments demonstrated that silencing THBS2 significantly inhibited macrophage infiltration and polarization. THBS2 primarily activated FAM pathways, inducing M2 macrophage polarization and promoting LUAD cell proliferation. THBS2 enhanced LUAD proliferation by regulating FAM to induce M2 macrophage polarization. These findings provide a theoretical basis for targeting THBS2 as a novel therapeutic strategy in LUAD.

Tumors with homologous recombination deficiency (HRD) can benefit from treatment with poly ADP-ribose polymerase inhibitors (PARPi). However, the methods for identifying HRD vary and are controversial. Several DNA repair genes in the homologous recombination repair pathway may be linked to PARPi susceptibility, and studies are underway to identify biomarkers that can predict the response to PARPi. We present a case of EGFR-tyrosine kinase inhibitor-resistant metastatic lung adenocarcinoma with a germline PALB2 mutation that was treated with fluzoparib (an orally administered PARPi). The treatment achieved surprising results and lasted for more than 4.5 months. Our study provided evidence that metastatic lung adenocarcinoma with germline PALB2 could benefit from PARPi, which improves patient outcomes.

Local radiotherapy or surgery is the standard of care for treating brain metastases among patients with breast cancer. However, affected by tumor subtype, more than 50% of human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer and brain metastases will still develop local recurrence or new brain lesions within 1 year after radiotherapy. As systemic therapies demonstrate higher and clinically relevant levels of intracranial activity and longer survival, there is limited evidence to guide how to weigh the options of radiotherapy versus systemic therapy (and deferral of radiation) in patients with progressive brain metastases, particularly those that are symptomatic. This study presents a case of progressive symptomatic HER2-positive brain metastases in a patient previously treated with whole brain radiotherapy and various targeted therapies. Due to limited access to novel HER2-targeted drugs, a new antibody-drug conjugate drug, disitamab vedotin (RC48) monotherapy, was chosen for postprogression treatment. The patient experienced rapid relief of neurological symptoms, partial regression of the brain tumor, and sustained disease remission for over 12 months without any treatment-related toxicity, also avoided reirradiation exposure and potential neurocognitive decline. The treatment of brain metastasis has been a topic of ongoing discussion. Our experience may offer valuable insights into managing HER2-positive progressive symptomatic brain metastases.

The aim of this study was to present a nationwide survey on the specialist's attitudes towards stereotactic body radiotherapy (SBRT) combined with poly (ADP-ribose) polymerase inhibitors (PARPi) with oligometastatic/oligoprogressive/oligorecurrent ovarian cancer (oMPR-OC) patients. The 19-item questionnaire was developed by specialists and distributed online. Replies were stratified by categories and analyzed using descriptive statistics. Respondents ( N = 100) were radiation oncologists (57%), medical oncologists (32%), and gynecologic oncologists (11%). Fifty-four percent of respondents considered medical oncologists as the primary oncologists for oMPR-OC, while 23% preferred radiation oncologists and 15% favored gynecologic oncologists. Seventy-three percent discuss these cases in the Multidisciplinary Tumor Board, while 15, 6, and 2% send the patients straight to SBRT, surgery, or chemotherapy, respectively. Seventy-four percent of the experts interviewed were treated with SBRT less than 10 oMPR-OC patients. Concomitant treatment was highly heterogeneous, but it had little to no reported side effects. A significant variation in how PARPi is managed during SBRT was found: 34% do not interrupt the administration, while 52% pause and restart it later. Forty-three percent of respondents believe that the PARPi dosage should not be reduced when administered concurrently with SBRT. Sixty-nine percent of respondents believe that the SBRT dose should not be decreased while receiving PARPi if the constraints are met. The majority of respondents (40%) favored expert consensus for enhancing the clinical management of oMPR-OC, while 34% preferred clinical guidelines. A lack of or low toxicity with the combination of PARPi and SBRT was perceived, and a significant degree of heterogeneity concerning clinical protocols for their combination. Moreover, it emphasizes the low number of patients who have received this treatment approach nationwide.

This study investigated whether the neddylation inhibitor MLN4924 induces aberrant DNA methylation patterns in acute myeloid leukemia and contributes to the reactivation of tumor suppressor genes. DNA methylation profiles of Kasumi-1 and KU812 acute myeloid leukemia cell lines before and after MLN4924 treatment were generated using the 850K Methylation BeadChip. RNA sequencing was used to obtain transcriptomic profiles of Kasumi-1 cells. Target genes were identified through a combined analysis of methylation and transcriptome data. Methylation-specific PCR and quantitative PCR validated the changes in methylation and expression. Prognostic analysis of target genes was performed using databases, and Pearson correlation was used to examine the relationship between methylation and expression levels. In Kasumi-1 and KU812 cells, 301 and 469 differentially methylated sites, respectively, were identified. A total of 4310 differential expression genes were detected in Kasumi-1. Combined analysis revealed that TRIM58 exhibited significant demethylation and upregulation after MLN4924 treatment, as confirmed by quantitative and methylation-specific PCR. Furthermore, database analysis revealed that both down-expression and promoter hypermethylation of TRIM58 were correlated with poor prognosis in acute myeloid leukemia. A negative correlation was observed between TRIM58 methylation and expression levels. This study suggests that MLN4924 alters DNA methylation patterns in acute myeloid leukemia and reactivates TRIM58, a potential tumor suppressor gene, through demethylation.

Intelligent hydrogels are promising in constructing scaffolds for the controlled delivery of drugs. Here, a dual thermo- and pH-responsive hydrogel called PCG [poly ( N -isopropyl acrylamide-co-itaconic acid)/chitosan/glycerophosphate (PNI/CS/GP)] was established as the carrier of 5-fluorouracil (5-FU) for triple-negative breast cancer (TNBC) treatment. The PCG hydrogel was fabricated by blending synthesized [poly ( N -isopropyl acrylamide-co-itaconic acid), pNIAAm-co-IA, PNI] with CS in the presence of GP as a crosslinking agent. The interaction between PCG hydrogel compositions was characterized by Fourier transforms infrared, NMR spectroscopy, and scanning electron microscopy. The PCG hydrogel presented an interconnected and porous structure with similar pore size, rapid swelling/deswelling rate in response to both temperature and pH change, and biocompatibility, upon which it was proposed as a great drug carrier. 5-FU had a dual thermo- and pH-responsive controlled release behavior from the PCG hydrogel and displayed an accelerated release rate in an acidic pH environment than in a neutral pH condition. The application of 5-FU-loaded PCG hydrogel exhibited a more promoted anticancer activity than 5-FU against the growth of TNBC cells both in vitro and in vivo . The outcomes suggested that the PCG hydrogel could be an excellent platform for local drug-delivery systems in the clinical therapy of TNBC.

This study explores the therapeutic potential of albumin-bound Zn(II)-thiosemicarbazone compounds (Alb-ZnTcA, Alb-ZnTcB) against breast cancer cells. Previous research indicates that these compounds hinder cancer cell proliferation by blocking DNA synthesis, promoting oxidative stress to induce apoptosis, and disrupting the cell cycle to inhibit cellular division. This study focuses on the loading and characterization of these potentially chemically unstable compounds on bovine serum albumin-based nanocarriers. Accordingly, unlike previous studies using albumin nanoparticles, in this study, ultraviolet light was used to precisely bind the therapeutic agent to albumin during the integration of thiosemicarbazones, achieving controlled nanoparticle size to control nanoparticle size. The mean diameter of Alb-ZnTcA nanoparticles was 32 nm, while Alb-ZnTcB exhibited an average diameter of 43 nm. Notably, Alb-ZnTcA displayed the highest cytotoxicity toward breast cancer cells, suggesting an optimal size for cellular uptake. Additionally, albumin-bound compounds showed enhanced cytotoxicity at lower concentrations, potentially minimizing adverse side effects. Apoptosis analysis indicated that both Alb-ZnTcA and Alb-ZnTcB induce cell death predominantly through apoptosis, effectively preventing the uncontrolled proliferation of cancer cells. These findings demonstrate the potential of Zn(II)-thiosemicarbazone compounds loaded on albumin-based nanocarriers for breast cancer treatment. The increased potency of Alb-ZnTcA and Alb-ZnTcB compared to free compounds, along with their ability to activate apoptotic signaling pathways in MCF-7 breast cancer cells, highlights a promising approach for future cancer therapies. This study suggests that albumin-bound Zn(II)-thiosemicarbazone compounds could offer a targeted and effective strategy in breast cancer treatment, leveraging the advantages of nanocarrier-based delivery systems.

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) effectively treat EGFR-mutant lung adenocarcinoma, demonstrating initial efficacy but eventually leading to acquired resistance. Small cell transformation is a rare resistance mechanism to EGFR-TKIs in lung adenocarcinoma, which can complicate clinical diagnosis and treatment. We present a patient with lung adenocarcinoma who underwent a prior pneumonectomy and adjuvant chemotherapy and was treated with osimertinib after the recurrence of lung cancer. Small cell transformation occurred approximately 20 months after starting osimertinib treatment. After this transformation, the patient underwent lung radiotherapy and cisplatin-etoposide chemotherapy, which stabilized the disease. Following the confirmation of small cell lung cancer (SCLC) via thyroid puncture, treatments with irinotecan, irinotecan plus atezolizumab, thyroid radiotherapy, adrenal radiotherapy, and head radiotherapy were sequentially administered, yet the disease continued to progress. The patient succumbed to the disease in May 2023 because of progression and organ failure, with an overall survival of 52.7 months, including 16 months post small cell transformation. This case highlights the possibility of osimertinib causing lung adenocarcinoma to transform into SCLC and underscores rebiopsies' importance in identifying resistance mechanisms to EGFR-TKIs. Increased levels of neuron-specific enolase and pro-gastrin releasing peptide can signal early transformation into SCLC.