RESUMO
Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.
Assuntos
Vacinas Anticâncer , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Imunoterapia , Nanopartículas , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/farmacologia , Animais , Imunoterapia/métodos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Nanopartículas/química , Camundongos , Humanos , Células Dendríticas/imunologia , Células Dendríticas/efeitos dos fármacos , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BL , Feminino , Imidazóis/farmacologia , Imidazóis/uso terapêutico , Microambiente Tumoral/efeitos dos fármacos , Antígenos de Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Neoplasias/tratamento farmacológico , NanovacinasRESUMO
A spontaneously occurring temperature increase in solid tumors has been reported sporadically, but is largely overlooked in terms of cancer biology. Here we show that temperature is increased in tumors of patients with pancreatic ductal adenocarcinoma (PDAC) and explore how this could affect therapy response. By mimicking this observation in PDAC cell lines, we demonstrate that through adaptive changes in lipid metabolism, the temperature increase found in human PDAC confers protection to lipid peroxidation and contributes to gemcitabine resistance. Consistent with the recently uncovered role of p38 MAPK in ferroptotic cell death, we find that the reduction in lipid peroxidation potential following adaptation to tumoral temperature allows for p38 MAPK inhibition, conferring chemoresistance. As an increase in tumoral temperature is observed in several other tumor types, our findings warrant taking tumoral temperature into account in subsequent studies related to ferroptosis and therapy resistance. More broadly, our findings indicate that tumoral temperature affects cancer biology.
Assuntos
Carcinoma Ductal Pancreático , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Gencitabina , Metabolismo dos Lipídeos , Neoplasias Pancreáticas , Ferroptose/efeitos dos fármacos , Humanos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Linhagem Celular Tumoral , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/genética , Metabolismo dos Lipídeos/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Temperatura , Animais , CamundongosRESUMO
BACKGROUND: Lenvatinib, programmed cell death 1 (PD-1) antibodies, and gemcitabine and oxaliplatin (GEMOX) chemotherapy have shown significant antitumor activity as first-line therapy against biliary tract cancer. This study evaluated their efficacy and safety as non-first-line therapy in advanced gallbladder cancer (GBC). METHODS: Patients with advanced GBC who received lenvatinib combined with anti-PD-1 antibodies and GEMOX chemotherapy as a non-first-line therapy were retrospectively analyzed. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR) and safety. RESULTS: A total of 36 patients with advanced GBC were included in this study. The median follow-up time was 11.53 (95% confidence interval (CI): 2.2-20.9) months, and the ORR was 36.1%. The median OS and PFS were 15.1 (95% CI: 3.2-26.9) and 6.1 (95% CI: 4.9-7.2) months, respectively. The disease control rate (DCR) and clinical benefit rate (CBR) were 75% and 61.1%, respectively. Subgroup analysis demonstrated that patients with programmed cell death-ligand 1 (PD-L1) expression had significantly longer PFS and OS than those without PD-L1 expression. Additionally, patients with a neutrophil-lymphocyte ratio (NLR) < 5.57 had a longer OS than those with an NLR ≥ 5.57. All patients experienced adverse events (AEs), with 61.1% experiencing grade 3 or 4 AEs, including myelosuppression (13.9%) and fatigue (13.3%), alanine transaminase or aspartate transaminase levels (8.3%), and diarrhea (8.3%). No grade 5 AEs were reported. CONCLUSION: Anti-PD-1 antibodies combined with lenvatinib and GEMOX chemotherapy are effective and well-tolerated as a non-first-line therapy in advanced GBC. PD-L1 expression and baseline NLR may potentially predict treatment efficacy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Neoplasias da Vesícula Biliar , Compostos de Fenilureia , Receptor de Morte Celular Programada 1 , Quinolinas , Humanos , Feminino , Masculino , Neoplasias da Vesícula Biliar/tratamento farmacológico , Neoplasias da Vesícula Biliar/mortalidade , Pessoa de Meia-Idade , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Quinolinas/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Estudos Retrospectivos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adulto , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Gencitabina , Idoso de 80 Anos ou mais , Compostos OrganoplatínicosRESUMO
Objective: This study aimed to investigate the efficacy, long-term prognosis and safety of combining chemotherapy with regorafenib and immune checkpoint inhibitors as first-line treatment for patients with advanced biliary tract carcinoma (BTC). Methods: In this single arm phase II trial, twenty-nine patients with advanced BTC were included, all of whom received gemcitabine-based chemotherapy combined with regorafenib and immune checkpoint inhibitors as the first-line treatment. And the study analyzed anti-tumor efficacy, long-term prognosis, and adverse reactions. Results: Among the patients, 0 patient achieved complete response, 18 patients (62.1%) achieved partial response, 8 patients (27.6%) had stable disease, and 3 patients (10.3%) experienced progressive disease. The corresponding objective response rate (ORR) was 18/29 (62.1%), and the disease control rate (DCR) was 26/29 (89.7%). The median overall survival (OS) was 16.9 months (95% confidence interval [CI]: 12.0 -21.8) and the median progress free survival (PFS) was 10.2 months (95% CI: 7.8- 12.6). The 1-year OS and PFS were 65% (95% CI: 0.479-0.864) and 41% (95% CI: 0.234-0.656), respectively. The incidence of adverse reactions was 27/29 (93.1%), and the incidence of grade III/IV adverse reactions was 5/29 (17.2%). Conclusion: The combination of chemotherapy, regorafenib, and immune checkpoint inhibitors as a first-line treatment for patients with advanced BTC may has good anti-tumor efficacy without causing serious adverse reactions, and can significantly improve the long-term prognosis.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Biliar , Inibidores de Checkpoint Imunológico , Compostos de Fenilureia , Piridinas , Humanos , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Piridinas/efeitos adversos , Compostos de Fenilureia/administração & dosagem , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Feminino , Masculino , Pessoa de Meia-Idade , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/mortalidade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores de Checkpoint Imunológico/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/administração & dosagem , Adulto , Resultado do Tratamento , Gencitabina , Prognóstico , Estadiamento de NeoplasiasRESUMO
INTRODUCTION: This study assesses the effectiveness of durvalumab with platinum and gemcitabine for biliary tract cancers (BTC). It aims to confirm the TOPAZ-1 trial results in a real-world context and explore the link between BTC molecular profiles and patient outcomes. METHODS: A retrospective analysis was conducted on 102 BTC patients treated with durvalumab, platinum, and gemcitabine at five cancer centers in Austria and one in Germany from 2022 to 2024. Molecular profiling used targeted DNA and RNA assays. Clinical endpoints, including progression-free survival (PFS) and overall survival (OS), were assessed using log-rank tests and Cox regression, with correlations to second-line molecular-targeted therapies. RESULTS: Among 102 patients, 60.8% had intrahepatic cholangiocarcinoma. The treatment achieved a disease control rate of 71.57% and an overall response rate of 35.11%. Median PFS was 6.51 months, and OS was 13.61 months. Patients under 65 had significantly better OS. Alterations in chromatin remodeling or homologous recombination repair genes were not predictive of survival benefit (HR: 0.45; p = 0.851 and HR: 1.63; p = 0.26, respectively). Patients with molecular-informed second-line therapy showed a trend toward survival benefit (HR: 0.23; p = 0.052). CONCLUSION: This study confirms the phase 3 trial results of durvalumab with platinum and gemcitabine, providing a substantial real-world dataset with detailed molecular characterization. No specific patient subgroup showed a markedly better response to durvalumab based on conventional NGS panels. Further research is needed to explore the link between immunotherapy responses and molecular subgroups.
Assuntos
Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias do Sistema Biliar , Humanos , Masculino , Feminino , Neoplasias do Sistema Biliar/tratamento farmacológico , Neoplasias do Sistema Biliar/mortalidade , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Adulto , Gencitabina , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Idoso de 80 Anos ou maisRESUMO
OBJECTIVE: The prognosis of extra-nodal NK/T cell lymphoma (ENKTL) is poor, and the optimal therapy remains controversial. This study aims to evaluate the safety and efficacy of a new combined modality therapy. METHODS: Phase-2 study of pegaspargase, etoposide and gemcitabine (PEG) combined with involved field radiation therapy (IFRT) in newly-diagnosed patients with early-stage ENKTL. Patients received 4 course of PEG followed by IFRT. The primary endpoints were complete response (CR), partial response (PR), and objective response rate (ORR) after IFRT. Secondary endpoints included progression-free survival (PFS), overall survival (OS) and adverse events. RESULTS: 34 consecutive patients with Ann Arbor stage I/II were enrolled. 3 patients progressed on PEG, while the remaining 31 received IFRT. The ORR was 88.2% (30/34), included 28 (82.4%) complete and 2 (5.8%) partial responses. With a median follow-up of 56.0 months (Interquartile Range [IQR], 36.0-66.9 months), the estimated 5-year PFS and OS were 87.4% (95% Confidence Interval [CI],69.5%-94.8%) and 97.1% (95%CI, 80.1%-99.6%), respectively. Most adverse events were hematological and easily managed. CONCLUSIONS: PEG followed by IFRT is a safe and effective initial therapy for early-stage ENKTL, demonstrating impressive PFS and OS rates. This promising approach warrants further validation in a randomized controlled trial (Registered at Clinicaltrials.gov NCT02705508).Trial registration: ClinicalTrials.gov identifier: NCT02705508.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Asparaginase , Desoxicitidina , Etoposídeo , Gencitabina , Linfoma Extranodal de Células T-NK , Polietilenoglicóis , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Linfoma Extranodal de Células T-NK/radioterapia , Linfoma Extranodal de Células T-NK/mortalidade , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/terapia , Masculino , Feminino , Pessoa de Meia-Idade , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Asparaginase/administração & dosagem , Asparaginase/uso terapêutico , Asparaginase/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Etoposídeo/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
Purpose: Erythrocytes and fibroblasts in the pancreatic cancer tumor microenvironment promote tumor cell growth and invasion by providing nutrients and promoting immunosuppression. Additionally, they form a barrier against the penetration of chemotherapeutic drugs. Therefore, the search for diversified tumor-targeting materials plays an essential role in solving the above problems. Methods: Physicochemical characterization of Graphene fluorescent nanoparticles (GFNPs) and nanomedicines were analyzed by transmission electron microscopy (TEM), elemental analyzers and ultraviolet fluorescence (UV/FL) spectrophotometer. Localization of GFNPs in cell and tissue sections imaged with laser confocal microscope, fluorescence scanner and small animal in vivo imager. Qualitative detection and quantitative detection of GFNPs and GFNPs-GEM were performed using High performance liquid chromatography (HPLC). Results: Based on the 3 nm average dimensions, GFNPs penetrate vascular endothelial cells and smooth muscle cells, achieve up to label 30% tumor cells and 60% cancer-associated fibroblasts (CAFs) cells, and accurately label mature red blood cells in the tumor microenvironment. In orthotopic transplanted pancreatic cancer models, the fluorescence intensity of GFNPs in tumors showed a positive correlation with the cycle size of tumor development. The differential spatial distribution of GFNPs in three typical clinical pancreatic cancer samples demonstrated their diagnostic potential. To mediate the excellent targeting properties of GFNPs, we synthesized a series of nanomedicines using popular chemotherapeutic drugs, in which complex of GFNPs and gemcitabine (GFNPs-GEM) possessed stability in vivo and exhibited effective reduction of tumor volume and fewer side effects. Conclusion: GFNPs with multiple targeting tumor microenvironments in pancreatic cancer possess diagnostic efficiency and therapeutic potential.
Assuntos
Desoxicitidina , Gencitabina , Grafite , Nanopartículas , Neoplasias Pancreáticas , Microambiente Tumoral , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Nanopartículas/química , Linhagem Celular Tumoral , Humanos , Camundongos , Desoxicitidina/análogos & derivados , Desoxicitidina/química , Desoxicitidina/farmacologia , Desoxicitidina/administração & dosagem , Microambiente Tumoral/efeitos dos fármacos , Grafite/química , Nanomedicina , Fibroblastos Associados a Câncer/efeitos dos fármacos , Modelos Animais de DoençasRESUMO
PURPOSE: In high-risk non-muscle-invasive bladder cancer (NMIBC), intravesical Bacillus Calmette-Guérin (BCG) is the standard adjuvant therapy post-transurethral resection of bladder tumor (TURBT). Intravesical gemcitabine, used as an alternative or second-line therapy amid BCG shortages, lacks outcome studies in the Korean population. MATERIALS AND METHODS: Patients who received weekly intravesical gemcitabine for 6 weeks after TURBT from 2019 to 2022 were retrospectively investigated. Based on the American Urological Association risk classification, patients with high- or very high-risk NMIBC who refused cystectomy were included. Maintenance treatment was performed depending on their risk. Recurrence was defined as histologic confirmation on subsequent cystoscopic biopsies or TURBT. Disease free survival (DFS) was evaluated by the Kaplan-Meier method. RESULTS: The study included 60 patients, comprising 45 high-risk (group 1) patients with a median age of 76 years and 15 very high-risk (group 2) patients with a median age of 68 years. Among them, 28 patients had previously received intravesical BCG. Over a median follow-up of 22 months, recurrence occurred in 31 patients in group 1 and 11 in group 2. The DFS rates of the high-risk group and the very high-risk group were 57.8% versus 40% at 1 year, 20.7% versus 21.3% at 2 years and 20.7% versus 21.3% at 3 years, respectively (p=0.831). Tis stage (p=0.042) and prostatic urethra invasion (p=0.028) were significant predictors of DFS. Cancer-specific mortality rates were 2.2% in group 1 and 6.7% in group 2 (p=0.441). CONCLUSIONS: Similar DFS outcome between high-risk and very high-risk patients were observed based on short-term results in Korea. This finding is crucial for clinical practice; however, studies analyzing more patients and long-term outcomes are needed.
Assuntos
Antimetabólitos Antineoplásicos , Desoxicitidina , Gencitabina , Invasividade Neoplásica , Neoplasias da Bexiga Urinária , Humanos , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/cirurgia , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Masculino , Administração Intravesical , Idoso , Feminino , República da Coreia/epidemiologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Antimetabólitos Antineoplásicos/administração & dosagem , Resultado do Tratamento , Fatores de Tempo , Idoso de 80 Anos ou mais , Neoplasias não Músculo Invasivas da BexigaRESUMO
The combination of gemcitabine, PI3K-Akt pathway inhibitors, and radiation in human glioma cell lines shows potential to enhance radiation sensitivity in aggressive brain tumors. Inhibiting the overactive PI3K-Akt pathway may increase tumor vulnerability to treatment. However, variability in responses among different glioma cell lines highlights the need for personalized approaches. Future research should focus on identifying biomarkers to tailor treatment for individual patients. Additionally, addressing safety concerns and the challenges of translating preclinical findings into clinical practice is crucial. Further studies should explore the therapy's molecular mechanisms and evaluate its clinical potential.
Assuntos
Neoplasias Encefálicas , Desoxicitidina , Gencitabina , Glioma , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais , Humanos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Glioma/tratamento farmacológico , Glioma/patologia , Glioma/radioterapia , Glioma/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Transdução de Sinais/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismoRESUMO
PURPOSE: The retrospective study was to explore the effectiveness and safety of GemOx (gemcitabine, oxaliplatin) plus sintilimab (belongs to the class of drugs known as immune checkpoint inhibitors, particularly targeting the PD-1 receptor) in relapse or refractory nodal PTCLs. METHODS: Patients with nodal PTCL who initiated salvage therapy with sintilimab and GemOx between January 2020 to September 2021 were identified from the database of the hematology department of the Second Affiliated Hospital of Zhejiang University School of Medicine. All patients received 2-4 cycles (3 weeks/cycle) of treatment of sintilimab (200 mg, I.V, D1) in combination with GemOx. Treatment response was assessed every six weeks during the salvage treatment phase. Eligible patients received maintenance therapy according to the investigator's decision. Follow-ups were routinely conducted every three months. RESULTS: 31 patients with r/r nodal PTCLs were enrolled, including 23 PTCL-NOS, 4 AITL, and 4 ALCL. 21 (67.7%) patients received at least two lines of therapy. 71.0% (95% CI, 53.4%-83.9%) of patients documented objective response of 2-4 cycles of sintilimab plus GemOx therapy, including 9 complete response and 13 partial response. 21 (67.7%) patients received consolidation therapy, including 5 autologous stem-cell transplantation and 12 histone deacetylase inhibitors. After a median 25.6 months follow-up, the median PFS was 22.0 (95% CI,11.8-24.7) months, and the median OS was 26.2 (95% CI, 24.4 -NA) months. 29 (93.5%) patients experienced at least one adverse event, and 26 (83.9% patients only had mild (grade 1-2) AEs.Univariable Cox regression showed the progression risk of AITL is 22.7 (3.9- 131.0, p < 0.01) times of PTCL-NOS, while the HR of ALCL was 1.14 (0.33-3.96,p = 0.833). CONCLUSION: Sintilimab plus GemOx showed encouraging activity and manageable toxicity for patients with r/r PTCL.
Assuntos
Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Gencitabina , Linfoma de Células T Periférico , Terapia de Salvação , Humanos , Masculino , Feminino , Terapia de Salvação/métodos , Pessoa de Meia-Idade , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/patologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Estudos Retrospectivos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Idoso , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Desoxicitidina/efeitos adversos , Oxaliplatina/administração & dosagem , Oxaliplatina/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/patologia , Adulto Jovem , Compostos OrganoplatínicosRESUMO
Liposomal irinotecan has shown promising antitumor activity in patients with advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who have undergone prior gemcitabine-based therapies. This randomized, double-blind, parallel-controlled, multicenter phase 3 study (NCT05074589) assessed the efficacy and safety of liposomal irinotecan HR070803 combined with 5-fluorouracil (5-FU) and leucovorin (LV) in this patient population. Patients with unresectable, locally advanced, or metastatic PDAC who had previously received gemcitabine-based therapies were randomized 1:1 to receive either HR070803 (60 mg/m2 anhydrous irinotecan hydrochloride, equal to 56.5 mg/m2 free base) or placebo, both in combination with 5-FU (2000 mg/m2) and LV (200 mg/m2), all given intravenously every two weeks. The primary endpoint of the study was overall survival (OS). A total of 298 patients were enrolled and received HR070803 plus 5-FU/LV (HR070803 group, n = 149) or placebo plus 5-FU/LV (placebo group, n = 149). Median OS was significantly improved in the HR070803 group compared to the placebo group (7.4 months [95% CI 6.1-8.4] versus 5.0 months [95% CI 4.3-6.0]; HR 0.63 [95% CI 0.48-0.84]; two-sided p = 0.0019). The most common grade ≥ 3 adverse events in the HR070803 group were increased gamma-glutamyltransferase (19.0% versus 11.6% in placebo group) and decreased neutrophil count (12.9% versus 0 in placebo group). No treatment-related deaths occurred in the HR070803 group, while the placebo group reported one treatment-related death (abdominal infection). HR070803 in combination with 5-FU/LV has shown promising efficacy and manageable safety in advanced or metastatic PDAC in the second-line setting, representing a potential option in this patient population.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma Ductal Pancreático , Desoxicitidina , Fluoruracila , Gencitabina , Irinotecano , Leucovorina , Lipossomos , Neoplasias Pancreáticas , Humanos , Fluoruracila/administração & dosagem , Feminino , Masculino , Leucovorina/administração & dosagem , Leucovorina/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Pessoa de Meia-Idade , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Irinotecano/administração & dosagem , Irinotecano/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Adulto , Método Duplo-Cego , Metástase NeoplásicaRESUMO
BACKGROUND: Metastatic pancreatic ductal adenocarcinoma (mPDAC) patients have very poor prognosis highlighting the urgent need of novel treatments. In this regard, repurposing non-oncology already-approved drugs might be an attractive strategy to offer more-effective treatment easily tested in clinical trials. Accumulating evidence suggests that epigenetic deregulation is a hallmark of cancer contributing to treatment resistance in several solid tumors, including PDAC. Histone deacetylase inhibitors (HDACi) are epigenetic drugs we have investigated preclinically and clinically as anticancer agents. Valproic acid (VPA) is a generic low-cost anticonvulsant and mood stabilizer with HDAC inhibitory activity, and anticancer properties also demonstrated in PDAC models. Statins use was reported to be associated with lower mortality risk in patients with pancreatic cancer and statins have been shown to have a direct antitumor effect when used alone or in combination therapy. We recently showed capability of VPA/Simvastatin (SIM) combination to potentiate the antitumor activity of gemcitabine/nab-paclitaxel in vitro and in vivo PDAC preclinical models. METHODS/DESIGN: VESPA is a patient-centric open label randomized multicenter phase-II investigator-initiated trial, evaluating the feasibility, safety, and efficacy of VPA/SIM plus first line gemcitabine/nab-paclitaxel-based regimens (AG or PAXG) (experimental arm) versus chemotherapy alone (standard arm) in mPDAC patients. The study involves Italian and Spanish oncology centers and includes an initial 6-patients safety run-in-phase. A sample size of 240 patients (120 for each arm) was calculated under the hypothesis that the addition of VPA/SIM to gemcitabine and nab-paclitaxel-based regimens may extend progression free survival from 6 to 9 months in the experimental arm. Secondary endpoints are overall survival, response rate, disease control rate, duration of response, CA 19.9 reduction, toxicity, and quality of life. The study includes a patient engagement plan and complementary biomarkers studies on tumor and blood samples. CONCLUSIONS: VESPA is the first trial evaluating efficacy and safety of two repurposed drugs in oncology such as VPA and SIM, in combination with standard chemotherapy, with the aim of improving mPDAC survival. The study is ongoing. Enrollment started in June 2023 and a total of 63 patients have been enrolled as of June 2024. TRIAL REGISTRATION: EudraCT number: 2022-004154-63; ClinicalTrials.gov identifier NCT05821556, posted 2023/04/20.
Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Gencitabina , Paclitaxel , Neoplasias Pancreáticas , Sinvastatina , Ácido Valproico , Humanos , Ácido Valproico/uso terapêutico , Ácido Valproico/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/patologia , Sinvastatina/administração & dosagem , Sinvastatina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Paclitaxel/administração & dosagem , Paclitaxel/uso terapêutico , Albuminas/administração & dosagem , Albuminas/uso terapêutico , Feminino , Masculino , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Pessoa de Meia-Idade , Idoso , Reposicionamento de Medicamentos/métodos , AdultoRESUMO
The Nab-paclitaxel combined with gemcitabine (AG) regimen is the main chemotherapy regimen for pancreatic cancer, but drug resistance often occurs. Currently, the ability to promote sensitization in drug-resistant cases is an important clinical issue, and the strategy of repurposing conventional drugs is a promising strategy. This study aimed to identify a classic drug that targets chemotherapy resistance's core signaling pathways and combine it with the AG regimen to enhance chemosensitivity. We also aimed to find reliable predictive biomarkers of drug combination sensitivity. Using RNA sequencing, we found that abnormal PI3K/Akt pathway activation plays a central role in mediating resistance to the AG regimen. Subsequently, through internal and external verification of randomly selected AG-resistant patient-derived organoid (PDO) and PDO xenograft models, we discovered for the first time that the classic anti-inflammatory drug sulindac K-80003, an inhibitor of the PI3K/Akt pathway that we focused on, promoted sensitization in half (14/28) of AG-resistant pancreatic ductal adenocarcinoma cases. Through RNA-sequencing, multiplex immunofluorescent staining, and immunohistochemistry experiments, we identified cFAM124A as a novel biomarker through which sulindac K-80003 promotes AG sensitization. Its role as a sensitization marker is explained via the following mechanism: cFAM124A enhances both the mRNA expression of cathepsin L and the activity of the cathepsin L enzyme. This dual effect stimulates the cleavage of RXRα, leading to large amounts of truncated RXRα, which serves as a direct target of K-80003. Consequently, this process results in the pathological activation of the PI3K/Akt pathway. In summary, our study provides a new treatment strategy and novel biological target for patients with drug-resistant pancreatic cancer.
Assuntos
Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica , Desoxicitidina , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Paclitaxel , Neoplasias Pancreáticas , Sulindaco , Ensaios Antitumorais Modelo de Xenoenxerto , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Humanos , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Camundongos , Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Sulindaco/farmacologia , Sulindaco/análogos & derivados , Linhagem Celular Tumoral , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Carcinoma Ductal Pancreático/tratamento farmacológico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/metabolismo , Masculino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Glioma remains a significant clinical challenge and poses a dismal patient prognosis. This study focused on the long noncoding ribonucleic acid growth arrest-specific transcript 5 (GAS5) and explored the role of GAS5 and GAS5-related m6A genes in glioma. We explored the mechanisms of GAS5 expression in glioma using bioinformatic analysis based on glioma data from the Cancer Genome Atlas, GSE1142, and Chinese Glioma Genome Atlas databases. Kaplan-Meier curve analysis, nomogram construction, immune cell infiltration, drug sensitivity, mutations, and pathway analyses were performed to determine the GAS5 mechanism in glioma. Spearman correlation and weighted gene co-expression analyses were used to identify the GAS5-related m6A gene. Furthermore, we explored the correlation between GAS5, GAS5-related m6A gene, and clinical traits using analysis of variance. The Kaplan-Meier curve analysis suggested that patients with high expressions of GAS5 had better survival. The nomogram constructed indicated that GAS5 was an independent prognostic factor. Furthermore, GAS5 significantly correlated with plasma cells. GAS5 expression was significantly associated with biological processes, including oxidative phosphorylation, proteasome, and ribosome mitotic spindle. GAS5 expression was associated with sensitivity to erlotinib and gemcitabine. Differentially expressed GAS5 was significant in histology (Pâ =â 2.8e-09), grade (Pâ =â 3.7e-05), isocitrate dehydrogenase (IDH) mutation (Pâ =â 3.4e-17), 1p/19q co-deletion (Codel) status (Pâ =â 1.7e-08), and IDH mutation status and 1p/19q Codel status (Pâ =â 2.9e-18). Heterogeneous nuclear ribonucleoproteins C1/C2 (HNRNPC) gene was significant in IDH mutation (Pâ =â .008) and IDH mutation status and 1p/19q Codel status (Pâ =â 2.1e-05). GAS5 and HNRNPC expressions reflected the malignant grade of glioma and are associated with prognosis. The abnormal expression of GAS5 could be an important biomarker for guiding erlotinib and gemcitabine use in glioma treatment. GAS5 and heterogeneous nuclear ribonucleoproteins C1/C2 are potential diagnostic and prognostic markers for glioma.
Assuntos
Glioma , RNA Longo não Codificante , Humanos , RNA Longo não Codificante/genética , Glioma/genética , Glioma/patologia , Masculino , Prognóstico , Feminino , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Pessoa de Meia-Idade , Estimativa de Kaplan-Meier , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Nomogramas , Isocitrato Desidrogenase/genética , Mutação , GencitabinaRESUMO
Cholangiocarcinoma (CCA) is an extremely aggressive malignancy arising from the epithelial cells lining the bile ducts. It presents a substantial global health issue, with the highest incidence rates, ranging from 40100 cases/100,000 individuals, found in Southeast Asia, where liver fluke infection is endemic. In Europe and America, incidence rates range from 0.42 cases/100,000 individuals. Globally, mortality rates range from 0.22 deaths/100,000 personyears and are increasing in most countries. Chemotherapy is the primary treatment for advanced CCA due to limited options from latestage diagnosis, but its efficacy is hindered by drugresistant phenotypes. In a previous study, proteomics analysis of drugresistant CCA cell lines (KKU213AFR and KKU213AGR) and the parental KKU213A line identified cullin 3 (Cul3) as markedly overexpressed in drugresistant cells. Cul3, a scaffold protein within CUL3RING ubiquitin ligase complexes, is crucial for ubiquitination and proteasome degradation, yet its role in drugresistant CCA remains to be elucidated. The present study aimed to elucidate the role of Cul3 in drugresistant CCA cell lines. Reverse transcriptionquantitative PCR and western blot analyses confirmed significantly elevated Cul3 mRNA and protein levels in drugresistant cell lines compared with the parental control. Short interfering RNAmediated Cul3 knockdown sensitized cells to 5fluorouracil and gemcitabine and inhibited cell proliferation, colony formation, migration and invasion. In addition, Cul3 knockdown induced G0/G1 cell cycle arrest and suppressed key cell cycle regulatory proteins, cyclin D, cyclindependent kinase (CDK)4 and CDK6. Bioinformatics analysis of CCA patient samples using The Cancer Genome Atlas data revealed Cul3 upregulation in CCA tissues compared with normal bile duct tissues. STRING analysis of upregulated proteins in drugresistant CCA cell lines identified a highly interactive Cul3 network, including COMM Domain Containing 3, Ariadne RBR E3 ubiquitin protein ligase 1, Egl nine homolog 1, Proteasome 26S Subunit NonATPase 13, DExHbox helicase 9 and small nuclear ribonucleoprotein polypeptide G, which showed a positive correlation with Cul3 in CCA tissues. Knocking down Cul3 significantly suppressed the mRNA expression of these genes, suggesting that Cul3 may act as an upstream regulator of them. Gene Ontology analysis revealed that the majority of these genes were categorized under binding function, metabolic process, cellular anatomical entity, proteincontaining complex and proteinmodifying enzyme. Taken together, these findings highlighted the biological and clinical significance of Cul3 in drug resistance and progression of CCA.
Assuntos
Neoplasias dos Ductos Biliares , Proliferação de Células , Colangiocarcinoma , Proteínas Culina , Resistencia a Medicamentos Antineoplásicos , Humanos , Colangiocarcinoma/metabolismo , Colangiocarcinoma/genética , Colangiocarcinoma/tratamento farmacológico , Colangiocarcinoma/patologia , Proteínas Culina/metabolismo , Proteínas Culina/genética , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias dos Ductos Biliares/metabolismo , Neoplasias dos Ductos Biliares/genética , Neoplasias dos Ductos Biliares/patologia , Neoplasias dos Ductos Biliares/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Fenótipo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Gencitabina , Movimento Celular/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Antineoplásicos/farmacologiaRESUMO
Nerve invasion (NI) is a characteristic feature of pancreatic cancer. Traditional dichotomous statements on the presence of NI are unreasonable because almost all cases exhibit NI when sufficient pathological sections are examined. The critical implications of NI in pancreatic cancer highlight the need for a more effective criterion. This study included 511 patients, who were categorized into a training group and a testing group at a ratio of 7:3. According to the traditional definition, NI was observed in 91.2 % of patients using five pathological slides in our study. The prevalence of NI increased as more pathological slides were used. The criterion of 'two points of intraneural (endoneural) invasion in the case of four pathological slides' has the highest receiver operating characteristic (ROC) score. Based on this new criterion, NI was proved to be an independent prognostic factor for overall survival (OS) and disease-free survival (DFS) and was also correlated with tumor recurrence (P = 0.004). Interestingly, gemcitabine-based chemotherapy regimen is an independent favorable factor for patients with high NI. In the high NI group, patients who received a gemcitabine-based regimen exhibited a better prognosis than those who did not receive the gemcitabine-based regimen for OS (P = 0.000) and DFS (P = 0.001). In conclusion, this study establishes assessment criteria to evaluate the severity of NI in order to predict patient outcomes.
Assuntos
Invasividade Neoplásica , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Idoso , Adulto , Intervalo Livre de Doença , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Gencitabina , Curva ROC , Idoso de 80 Anos ou mais , PrognósticoRESUMO
PURPOSE: To evaluate the long-term efficacy and safety of GP and TPF sequential chemotherapy regimens in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: From 2005 to 2016, a total of 408 LA-NPC patients treated with GP or TPF sequential chemoradiotherapy were retrospectively included. Propensity Score Matching (PSM) was employed to balance the baseline variables. Survival outcomes and acute toxicities were compared between both groups. RESULTS: A total of 230 patients were selected by 1:1 PSM. At a median follow-up of 91 months, no significant differences were observed between the matched GP and TPF groups regarding 5-year overall survival, progression-free survival, distant metastasis-free survival, and locoregionally relapse-free survival (83.4% vs. 83.4%, P = 0.796; 75.6% vs. 68.6%, P = 0.301; 86.7% vs. 81.1%, P = 0.096; and 87.4% vs. 87.2%, P = 0.721). Notable disparities in adverse effects were identified, with higher incidences of grade 3/4 thrombocytopenia in the GP group while grade 3/4 leukopenia and neutropenia in the TPF group. Though not recorded in our cohort, combined with the FAERS database, thrombotic adverse reactions are a concern for the GP regimen, while the TPF regimen requires vigilance for life-threatening adverse reactions such as septic shock, acute respiratory distress syndrome, and laryngeal edema. CONCLUSION: No significant difference in long-term outcomes was observed between the GP and TPF sequential chemotherapy regimens for LA-NPC. Differences in adverse effects should be noted when choosing the regimen.
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Protocolos de Quimioterapia Combinada Antineoplásica , Quimiorradioterapia , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Pontuação de Propensão , Humanos , Masculino , Feminino , Carcinoma Nasofaríngeo/terapia , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/tratamento farmacológico , Pessoa de Meia-Idade , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Neoplasias Nasofaríngeas/terapia , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/tratamento farmacológico , Neoplasias Nasofaríngeas/mortalidade , Estudos Retrospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Adulto , Idoso , Resultado do Tratamento , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Cisplatino/efeitos adversos , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Gencitabina , Seguimentos , Compostos OrganoplatínicosRESUMO
Objective: Nivolumab, recently proven in a phase 3 clinical trial (CheckMate 901) to enhance survival when combined with gemcitabine-cisplatin for advanced urothelial carcinoma. This study aimed to assess its cost-effectiveness against gemcitabine-cisplatin alone, from US and Chinese payers' perspectives. Methods: A partitioned survival model was established to assess the life-years, quality-adjusted life-years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) of nivolumab plus gemcitabine-cisplatin versus gemcitabine-cisplatin alone as first-line treatment for advanced urothelial carcinoma. Univariate, two-way, and probabilistic sensitivity analyses were conducted to assess the model's robustness. Additionally, subgroup analyses were performed. Results: Nivolumab plus gemcitabine-cisplatin and gemcitabine-cisplatin achieved survival benefits of 4.238 life-years and 2.979 life-years for patients with advanced urothelial carcinoma, respectively. Compared with gemcitabine-cisplatin, nivolumab plus gemcitabine-cisplatin resulted in ICERs of $116,856/QALY in the US and $51,997/QALY in China. The probabilities of achieving cost-effectiveness at the current willingness-to-pay thresholds were 77.5% in the US and 16.5% in China. Cost-effectiveness could be reached if the price of nivolumab were reduced to $920.87/100mg in China. Subgroup analyses indicated that the combination had the highest probability of cost-effectiveness in patients under 65 or with an Eastern Cooperative Oncology Group (ECOG) performance-status score of 0 in the US and China. Conclusion: Nivolumab plus gemcitabine-cisplatin first-line treatment for advanced urothelial carcinoma results in longer life expectancy than gemcitabine-cisplatin, but is not cost-effective in China at current price. However, cost-effectiveness is likely to be achieved in most patient subgroups in the US.
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Protocolos de Quimioterapia Combinada Antineoplásica , Cisplatino , Análise Custo-Benefício , Desoxicitidina , Gencitabina , Nivolumabe , Humanos , Cisplatino/economia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/economia , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/economia , Nivolumabe/economia , Nivolumabe/administração & dosagem , Nivolumabe/uso terapêutico , China , Estados Unidos , Masculino , Anos de Vida Ajustados por Qualidade de Vida , Feminino , Pessoa de Meia-Idade , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/economia , Neoplasias Urológicas/tratamento farmacológico , Neoplasias Urológicas/mortalidade , Neoplasias Urológicas/economia , IdosoRESUMO
INTRODUCTION: Osteosarcoma is the most common primary malignancy of the bone. There is a lack of effective treatments for patients who experience relapsed osteosarcoma. One treatment for relapsed patients is gemcitabine and docetaxel combination chemotherapy (GEMDOX). This systematic review aimed to establish the efficacy of this chemotherapy regimen, as well as identify the common severe toxicities that are associated with it. Resistant osteosarcoma cell lines developed from MG-63 and HOS-143B were used to represent relapsed osteosarcoma patients in a pre-clinical study. RESULTS: We identified 11 retrospective and Phase II studies that were suitable for inclusion in our review. 10.65% of patients had a response to gemcitabine and docetaxel combination therapy and the disease control rate was 35% (n = 197). 36%, 35.3% and 18.04% of patients experienced grade 3 or 4 neutropenia, thrombocytopenia and anaemia respectively (n = 133). Male patients (X2 = 9.14, p < 0.05) and those below the age of 18 (X 2 = 10.94, p < 0.05) responded better to GEMDOX treatment than females and patients older than 18 years. The resistant osteosarcoma cell lines remained sensitive to either single-agent gemcitabine, docetaxel, and the combination of both. Cisplatin-resistant models (MG-63/CISR8 & HOS-143B/CISR8) were the most responsive to GEMDOX treatment compared to doxorubicin, methotrexate, and triple-combination resistant models. CONCLUSION: GEMDOX treatment has potential efficacy in relapsed osteosarcoma patients especially those with cisplatin resistance. To directly compare the efficacy of GEMDOX therapy against other therapies randomised phase III clinical trials with adequate patient follow up must be performed to improve treatment options for osteosarcoma.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Ósseas , Desoxicitidina , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Gencitabina , Osteossarcoma , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologia , Humanos , Docetaxel/uso terapêutico , Docetaxel/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Desoxicitidina/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Taxoides/uso terapêutico , Taxoides/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Linhagem Celular Tumoral , Masculino , Feminino , Resultado do Tratamento , AnimaisRESUMO
Pancreatic cancer remains one of the most lethal malignancies due to its aggressive nature and resistance to conventional therapies. This study investigates the anti-proliferative, pro-apoptotic, and anti-migratory effects of Gemcitabine (GC) and Withaferin A (WFA) on pancreatic cancer cell lines PANC-1 and Hs766t. The MTS assay revealed that both compounds effectively inhibit cell proliferation, with WFA showing a stronger effect in Hs766t cells. Flow cytometry analysis demonstrated that GC and WFA, particularly in combination, significantly induce apoptosis in both cell lines. Migration assays confirmed the potent inhibition of cell migration by both compounds, with the combination treatment being the most effective. Furthermore, actin cytoskeleton analysis indicated substantial changes in cell morphology and stiffness, suggesting that GC and WFA disrupt the structural integrity of cancer cells. Additionally, the study highlights a ROS-mediated mechanism underlying the effects of GC and WFA, as evidenced by increased ROS levels following treatment, which were attenuated by N-acetylcysteine. Importantly, NF-κB activity was significantly modulated, with WFA reducing NF-κB activation induced by GC, potentially contributing to the synergistic pro-apoptotic effect of the combination. These findings suggest that the combination of GC and WFA may offer a synergistic therapeutic approach for treating pancreatic cancer by targeting multiple aspects of tumor cell behavior.