The formulation of quercetin nanoliposomes (QUE-NLs) has been shown to enhance QUE antitumor activity in C6 glioma cells. At high concentrations, QUE-NLs induce necrotic cell death. In this study, we probed the molecular mechanisms of QUE-NL-induced C6 glioma cell death and examined whether QUE-NL-induced programmed cell death involved Bcl-2 family and mitochondrial pathway through STAT3 signal transduction pathway. Downregulation of Bcl-2 and the overexpression of Bax by QUE-NL supported the involvement of Bcl-2 family proteins upstream of C6 glioma cell death. In addition, the activation of JAK2 and STAT3 were altered following exposure to QUE-NLs in C6 glioma cells, suggesting that QUE-NLs downregulated Bcl-2 mRNAs expression and enhanced the expression of mitochondrial mRNAs through STAT3-mediated signaling pathways either via direct or indirect mechanisms. There are several components such as ROS, mitochondrial, and Bcl-2 family shared by the necrotic and apoptotic pathways. Our studies indicate that the signaling cross point of the mitochondrial pathway and the JAK2/STAT3 signaling pathway in C6 glioma cell death is modulated by QUE-NLs. In conclusion, regulation of JAK2/STAT3 and ROS-mediated mitochondrial pathway agonists alone or in combination with treatment by QUE-NLs could be a more effective method of treating chemical-resistant glioma.

Arsenic trioxide (ATO) has been demonstrated to induce apoptosis in retinoblastoma cells, however, mechanisms responsible for this phenomenon are not fully understood. In the present study, we determined whether ATO induced apoptosis by abnormal expression of microRNA. In an apoptosis model of retinoblastoma cells subjected to 4 μM ATO for 72 hours, we found 14 miRNAs changed more than 2-fold by using miRNA microarray analysis. Most of these aberrantly expressed miRNAs were confirmed by quantitative RT-PCR. MiR-376a, a significantly down-regulated miRNA, was selected for further study. The overexpression of miR-376a resulting from miR-376a mimic transfection significantly inhibited ATO-induced apoptosis. By contrast, miR-376a deficiency resulting from miR-376a inhibitor transfection aggravated ATO-induced apoptosis. Using bioinformatic algorithms, caspase-3, a key apoptosis executioner, was predicted as a putative target of miR-376a. The quantitative RT-PCR showed no effects of miR-376a mimic or inhibitor on caspase-3 mRNA level. However, the amount of caspase-3 proteins was reduced by miR-376a mimic, whereas increased by miR-376a inhibitor. Furthermore, the luciferase reporter assay confirmed caspase-3 to be a target of miR-376a, and the apoptosis caused by miR-376a inhibitor were abolished by a caspase-3 inhibitor. These results suggest that ATO -induced apoptosis in retinoblastoma cells is part mediated by decreasing expression of miR-376a, which subsequently increased caspase-3 expression.

Background The induction of pyroptosis holds great promise as a strategy for improving the tumor immune microenvironment. Previous pyroptosis inducers have faced limitations, including drug resistance, toxic side effects, and a lack of targeting capabilities. As a result, there is a growing demand for tumor therapeutic molecules that can overcome these obstacles. With this in mind, the objective of this study is to develop a multifunctional nanospheres that addresses these challenges by enabling high-precision targeting of tumor cells and effective pyroptosis induction. Results We prepared a mannose-modified MOF called mannose-doped Fe3O4@NH2-MIL-100, referred to as M-FNM. M-FNM has the ability to enter CAL27 cells through MR-mediated endocytosis, which results in a significant increase in intracellular ROS levels. This increase subsequently triggers endoplasmic reticulum stress (ER stress) and activates the PERK-eIF2α-ATF4-CHOP signaling pathway. CHOP then mediates the downstream cascade of Caspase-1, inducing pyroptosis. In in vivo experiments, M-FNM demonstrates excellent targeting ability and exhibits anti-tumor effects. Additionally, M-FNM reshapes the immune microenvironment by promoting the infiltration of anti-tumor immune cells, primarily T lymphocytes. Conclusions M-FNM significantly decreased tumor growth. This novel approach of inducing pyroptosis in tumor cells using M-FNM may offer new avenues for the development of effective immunotherapies for cancer treatment.