ABSTRACT
Drastic surges in intracellular reactive oxygen species (ROS) induce cell apoptosis, while most chemotherapy drugs lead to the accumulation of ROS. Here, we constructed an organic compound, arsenical N-(4-(1,3,2-dithiarsinan-2-yl)phenyl)acrylamide (AAZ2), which could prompt the ROS to trigger mitochondrial-dependent apoptosis in gastric cancer (GC). Mechanistically, by targeting pyruvate dehydrogenase kinase 1 (PDK1), AAZ2 caused metabolism alteration and the imbalance of redox homeostasis, followed by the inhibition of phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway and leading to the activation of B-cell lymphoma 2 (Bcl2)/Bcl2-associated X (Bax)/caspase-9 (Cas9)/Cas3 cascades. Importantly, our in vivo data demonstrated that AAZ2 could inhibit the growth of GC xenograft. Overall, our data suggested that AAZ2 could contribute to metabolic abnormalities, leading to mitochondrial-dependent apoptosis by targeting PDK1 in GC.
Subject(s)
Humans , Signal Transduction , Stomach Neoplasms/drug therapy , Reactive Oxygen Species/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Apoptosis , Proto-Oncogene Proteins c-bcl-2 , Cell Line, TumorABSTRACT
Breast cancer is globally the most common invasive cancer in women and remains one of the leading causes of cancer-related deaths. Surgery, radiotherapy, chemotherapy, immunotherapy, and endocrine therapy are currently the main treatments for this cancer type. However, some breast cancer patients are prone to drug resistance related to chemotherapy or immunotherapy, resulting in limited treatment efficacy. Consequently, traditional Chinese medicinal materials (TCMMs) as natural products have become an attractive source of novel drugs. In this review, we summarized the current knowledge on the active components of animal-derived TCMMs, including Ophiocordycepssinensis-derived cordycepin, the aqueous and ethanolic extracts of O.sinensis, norcantharidin (NCTD), Chansu, bee venom, deer antlers, Ostreagigas, and scorpion venom, with reference to marked anti-breast cancer effects due to regulating cell cycle arrest, proliferation, apoptosis, metastasis, and drug resistance. In future studies, the underlying mechanisms for the antitumor effects of these components need to be further investigated by utilizing multi-omics technologies. Furthermore, large-scale clinical trials are necessary to validate the efficacy of bioactive constituents alone or in combination with chemotherapeutic drugs for breast cancer treatment.
Subject(s)
Animals , Female , Humans , Breast Neoplasms/drug therapy , Cell Cycle Checkpoints , China , Deer , ImmunotherapyABSTRACT
Objective To investigate the mechanism of electro-acupuncture (EA) at different frequency in improving synaptic plasticity injury in Alzheimer's disease(AD) rats, and to provide the theoretical basis for the clinical application of electro-acupuncture for the treatment of AD. Methods Ninety Wistar rats were randomly divided into normal group, model group, sham-operation group, and 2 Hz, 30 Hz, 50 Hz acupuncture groups, 15 rats in each group. AD rat model was established by injection of amyloid β1-42 (Aβ1-42) into the lateral ventricle. The rats in EA groups were treated with EA on Baihui and Shenshu acupoints at different frequencies (2, 30, 50 Hz). Learning and memory ability and space exploration ability of rats in each group were measured by Morris water maze test. The synaptic ultrastructure of hippocampus was observed by transmission electron microscopy. Nerve fibers were stained using Golgi techniques. The protein and phosphorylation levels of glycogen synthase kinase 3 beta (GSK-3β) in the brain tissues were detected by Western blotting method. Results(1) Compared with the normal group, the average escape latency time in the model group was significantly prolonged (P < 0.05), and the number of platform crossing was significantly reduced (P < 0.05), indicating that AD model had been established successfully. The average escape latency of rats in EA groups was significantly shortened and the frequency of platform crossing was increased as compared with those of the model group (P < 0.05). (2) The synaptic morphology of the hippocampus showed that the anterior membrane, posterior membrane and the interspace of the synapses in the model group were blurred, and the membrane structures of synapses were incomplete and dissolved. But the synaptic ultrastructures of the 3 EA groups were improved.(3) In the model group, the neurofibrillary tangles were found in the brain tissue, while the neurofibrillary tangles were relieved and the nerve fibers became clear in EA groups.(4) The levels of GSK-3β and GSK-3β(pTyr216) in the model group were significantly higher than those in the normal group (P < 0.05), whearas the GSK-3β(pSer9) level was significantly down-regulated (P < 0.05). In the EA groups, the levels of GSK-3βand GSK-3β(pTyr216) were down-regulated, while GSK-3β(pSer9) level was increased with the frequency of EA, and there was significant difference compared with the model group (P<0.05). (5) Compared with 2 Hz and 30 Hz EA groups, the number of plateau crossing, the average escape latency and the protein and phosphorylation levels of GSK-3β in 50 Hz EA group were significantly improved (P < 0.05). The improvement of synaptic morphology and neurofibrillary tangles of 50 Hz EA group was superior to that of the other 2 EA groups. Conclusion EA at different frequency can improve the learning and memory ability of AD rats, and the effect of 50 Hz is stronger. The therapeutic effect might be achieved by regulating the expression level of GSK-3βprotein and phosphorylation levels, which can improve synaptic plasticity damage of AD rats.