ABSTRACT
Targeted reprogramming of cancer-associated fibroblasts (CAFs) is one of the most essential cancer therapies. However, how to reprogram active CAFs toward deactivated state still remains immense challenge. To tackle this challenge, herein, one perylene N, N'-bis(2-((dimethylammonium)ethylene)-2-(methoxylethyl))-1, 6, 7, 12-tetrachloroperylene-3, 4, 9, 10-tetracarboxylic diimide (PDIC-OC) is prepared, which can trigger endogenous reactive oxygen species (ROS) burst to result in cytoskeletal dysfunction and cell apoptosis so that suppress transforming growth factor ß (TGF-ß) production. As a result, PDIC-OC can reprogram the activated CAFs and relieve immunosuppressive tumor microenvironment by efficient polarization of M2-typed macrophages into M1-typed ones, downregulation of alpha-smooth muscle actin (α-SMA), alleviation of hypoxic state to promote infiltration of cytotoxic T lymphocytes, and ultimately realizes outstanding antitumor performance on B16F10 tumor-xenografted and lung-metastatic mouse model even at low concentration of 1 mg kg-1 body weight. This work thus presents a novel strategy that cytoskeleton dysfunction and cell apoptosis cooperatively suppress the secretion of TGF-ß to reprogram CAFs and meanwhile clarifies intrinsic mechanism for perylene-triggered chemo-immunotherapy against hypoxic tumors.
Subject(s)
Cancer-Associated Fibroblasts , Cytoskeleton , Immunotherapy , Perylene , Animals , Perylene/analogs & derivatives , Perylene/pharmacology , Perylene/chemistry , Mice , Cytoskeleton/metabolism , Cytoskeleton/drug effects , Cancer-Associated Fibroblasts/metabolism , Cancer-Associated Fibroblasts/drug effects , Cancer-Associated Fibroblasts/pathology , Immunotherapy/methods , Cell Line, Tumor , Tumor Microenvironment/drug effects , Transforming Growth Factor beta/metabolism , Apoptosis/drug effects , Humans , Reactive Oxygen Species/metabolism , Mice, Inbred C57BLABSTRACT
BACKGROUND: Nonylphenol (NP) is a common environmental endocrine disruptor that is associated with the development of cardiovascular disease. However, the toxic effect of NP on mitochondria in the heart of offspring to exposed individuals remains exclusive. OBJECTIVE: To investigate whether perinatal NP exposure causes mitochondrial damage in the hearts of offspring of exposed individuals and determine its mechanism of action through both animal and cell experiments. METHODS AND RESULTS: For the in vivo experiment, pregnant rats were randomly divided into four groups: the control group (corn oil, C), low dose group (2.5 mg/kg/day, L-NP group), medium dose group (50 mg/kg/day, M-NP group), and high dose group (100 mg/kg/day, H-NP group), with 12 rats in each group. The NP concentration in the hearts of offspring at PND21 and PND90 increased with the increase of the NP dose. Perinatal NP exposure induced a gradual increase in systolic blood pressure in offspring at PND90. In the H-NP group, there was a high degree of inflammatory cell infiltration, myofibril breaks, inconspicuous or absent nuclei, and pink collagen deposition. At PND90, the membrane integrity of mitochondria in the H-NP group was disrupted, the cristae disorder was aggravated, and there was internal lysis with vacuolation. Compared to the control group, the mitochondrial membrane potential of offspring at PND21 and PND90 was decreased in each of the NP exposure groups. NP exposure decreased the activity of mitochondrial respiratory enzyme complex I (CI) and increased the activity of mitochondrial respiratory enzyme complex IV (CIV) in the offspring. At PND21 and PND90, the mRNA and protein expression levels of cardiac mitochondrial PGC-1α, NRF-1, and TFAM decreased with increasing NP dose in a dose-dependent manner. In the in vitro experiment, H9C2 cells were divided into the following four groups: the blank group, RSV group (15 µg/ml), RSV + NP group (15 µg/ml RSV + 120 mmol/L NP), and NP group (120 mmol/L). With increasing NP concentration, the cell survival rate gradually decreased. Compared to the control, the membrane potential was significantly decreased in the NP group; the protein expression levels of SIRT1, PGC-1α, NRF-1, and TFAM in the NP group were significantly lower. CONCLUSION: Perinatal NP exposure caused mitochondrial damage and dysfunction in the offspring of exposed individuals in a dose-dependent manner. This toxic effect may be related to NP-induced mitochondrial pathology in the offspring and the inhibition of both gene and protein expression involved in the PGC-1α/NRF-1/TFAM mitochondrial biogenesis signaling pathway following NP exposure.
