ABSTRACT
The effective and targeted treatment of resistant cancer cells presents a significant challenge. Targeting cell ferroptosis has shown remarkable efficacy against apoptosis-resistant tumors due to their elevated iron metabolism and oxidative stress levels. However, various obstacles have limited its effectiveness. To overcome these challenges and enhance ferroptosis in cancer cells, we have developed a self-powered photodynamic therapeutic tablet that integrates a ferroptosis inducer (FIN), imidazole ketone erastin (IKE). FINs augment the sensitivity of photodynamic therapy (PDT) by increasing oxidative stress and lipid peroxidation. Furthermore, they utilize the Fenton reaction to supplement oxygen, generating a greater amount of reactive oxygen species (ROS) during PDT. Additionally, PDT facilitates the release of iron ions from the labile iron pool (LIP), accelerating lipid peroxidation and inducing ferroptosis. In vitro and in vivo experiments have demonstrated a more than 85% tumor inhibition rate. This synergistic treatment approach not only addresses the limitations of inadequate penetration and tumor hypoxia associated with PDT but also reduces the required medication dosage. Its high efficiency and specificity towards targeted cells minimize adverse effects, presenting a novel approach to combat clinical resistance in cancer treatment.
Subject(s)
Ferroptosis , Neoplasms , Humans , Treatment Outcome , Prostheses and Implants , IronABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a type of pulmonary disease that progresses acutely or slowly into irreversible pulmonary diseases, resulting in the end severe damages to patients' lung functions, as well as deaths. At present, the pathogenesis of pulmonary fibrosis is still not clear and there is no effective therapeutic measure available to control the progression of the disease. Research findings indicate that stem cells, being the origin of all cells of organisms, participate in the development of individuals at various stages and play an important role in repairing pulmonary tissue damage. Stem cells are attracting growing attention in the field of regenerative medicine, providing new ideas for treating IPF with transplanted stem cells. Herein, in order to better explore the potential applications of stem cell transplantation in treating IPF, we attempt to summarize preliminary studies of stem cell-mediated pulmonary remodeling after IPF, as well as cutting-edge clinical trials in stem cell-based IPF therapy.
Subject(s)
Idiopathic Pulmonary Fibrosis , Mesenchymal Stem Cell Transplantation , Humans , Idiopathic Pulmonary Fibrosis/therapy , Lung , Wound HealingABSTRACT
Immunogenic cell death (ICD) improves the T cell response against different tumors, indicating that ICD can enhance the antitumor immunity elicited by the anti-checkpoint antibody anti-programmed death 1 (anti-PD-1). In the present study, we reported a synergistic and durable immune-mediated antitumor response elicited by the combined treatment of SR-4835, a CDK12/13 specific inhibitor, with PD-1 blockade in a syngeneic mouse model. The developed combination therapy elicited antitumor activity in immunocompetent mouse tumor models. Furthermore, the SR-4835-treated tumor cells exhibited characteristics of ICD, including the release of high mobility group box 1 (HMGB1) and ATP and calreticulin (CRT) translocation. This activity led to a signiï¬cant T-cell-dependent tumor suppression. The enhanced dendritic cell (DC) and infiltration of T cells activation in the tumors treated with both SR-4835 and anti-PD-1 indicate that this combination treatment promotes an improved immune response. Therefore, the results of the present study demonstrate the potential of CDK12/13 inhibition combined with checkpoint inhibition in breast cancer treatment.
Subject(s)
Breast Neoplasms/drug therapy , CDC2 Protein Kinase/antagonists & inhibitors , Cyclin-Dependent Kinases/antagonists & inhibitors , Immune Checkpoint Inhibitors/administration & dosage , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Protein Kinase Inhibitors/administration & dosage , Animals , Breast Neoplasms/metabolism , Calreticulin/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Synergism , Female , Gene Expression Regulation, Neoplastic/drug effects , HMGB1 Protein/metabolism , Humans , Immune Checkpoint Inhibitors/pharmacology , Immunogenic Cell Death , MCF-7 Cells , Mice , Protein Kinase Inhibitors/pharmacology , Protein Transport , Xenograft Model Antitumor AssaysABSTRACT
The aim of this study was to investigate the therapeutic effects and underlying mechanism of tetramethylpyrazine (TMP) on lung development using a rat model of congenital diaphragmatic hernia (CDH). Nitrofen was used to induce CDH. Pregnant rats were divided into three groups: control, CDH, and CDH+TMP. In the CDH and CDH+TMP, fetuses only with left diaphragmatic hernias were chosen for analysis. Lung and body weight were recorded and lung histologic evaluations, image analysis, and western blot analysis of YAP, p-YAP and LATS1 were performed after lung processing. A markedly abnormal structure was observed, as evidenced by pulmonary hypoplasia and vascular remodeling, in the CHD. These abnormalities were improved in the CDH+TMP. There were significant differences between the CHD and CHD+TMP in percentage of medial wall thickness, arteriole muscularization, radial alveolar counts, AA%, and alveolar septal thickness. YAP expression was markedly increased in the CHD compared to the controls, which was not affected by antenatal TMP administration. However, prenatal TMP intervention significantly increased expression of LATS1 and phosphorylation of YAP in the CDH fetuses. Our results demonstrate that antenatal TMP administration improved vascular remodeling and promoted lung development in a rat model of CHD, potentially through increasing expression of LATS1 and phosphorylation of YAP.
