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.

As Notch receptors have been shown to induce chemoresistance, we hypothesized that delta-like ligand-4 (DLL4), a central Notch signalling ligand, might also participate in chemoresistance in breast cancer. To investigate this issue, overexpression of DLL4 was induced by transfection with expression vectors for DLL4 in the human breast cancer cell line Michigan cancer foundation-7 (MCF-7). It was found that DLL4 could be adaptively upregulated by docetaxel (DOC) treatment in a dose-dependent manner, but Notch1 was unaffected. Overexpression of DLL4 could significantly attenuate the cytotoxic effects of DOC by increasing Bcl-2 expression, while decreasing Bax expression, apoptosis rate and DNA damage. The protective effects of DLL4 made cells acquire chemoresistance against DOC and resulted in cancer cell survival. DLL4 is normally regarded as a regulator of vascular development. Our results expanded the understanding of DLL4. Since DLL4 may play an important role in the process of acquiring chemoresistance, it may be a promising target in overcoming chemoresistance in breast cancer.