St-N, a novel alkaline derivative of stevioside, reverses docetaxel resistance by targeting lysosomes <i>in vitro</i> and <i>in vivo</i>

by Yanxia Guo, Shikang Wang, Qun Liu, Yan Dong, Yongqing Liu

Drug resistance of cancers remains a major obstacle due to limited therapeutics. Lysosome targeting is an effective method for overcoming drug resistance in cancer cells. St-N (ent-13-hydroxy-15-kaurene-19-acid N-methylpiperazine ethyl ester) is a novel alkaline stevioside derivative with an amine group. In this study, we found that docetaxel (Doc)-resistant prostate cancer (PCa) cells were sensitive to St-N. Mechanistically, the alkaline characteristic of St-N led to targeting lysosomes, as evidenced by lysosomal swelling and rupture through transmission electron microscopy and Lyso-tracker Red staining. St-N destabilized lysosomal membrane by impairing lysosomal membrane proteins and acid sphingomyelinase. As a result, St-N caused cathepsins to release from the lysosomes into the cytosol, eventually triggering apoptotic and necrotic cell death. Meanwhile, the cytoprotective role of lysosomal activation under docetaxel treatment was interrupted by St-N, leading to significant synergistic cytotoxicity of docetaxel and St-N. In docetaxel-resistant PCa homograft mice, St-N significantly inhibited the growth of RM-1/Doc homografts and enhanced the anticancer effects of docetaxel, but did not show significant toxicity. Taken together, these findings demonstrated that St-N reversed docetaxel resistance in vitro and in vivo by destabilizing lysosomal membranes to promote cell death, thus providing a strong rationale for applying St-N in docetaxel-resistant PCa.

Association between stroke and venous leg ulcers: A Mendelian randomization study

Abstract

To investigate any potential bidirectional causal relationships between stroke and venous leg ulcers (VLUs), Mendelian randomization (MR) analyses were carried out in this study. The exposure factor was stroke, the outcome factor was VLUs. The two-sample MR study was carried out based on the online analysis platform (http://app.mrbase.org/). The association of stroke and VLUs was analysed via methods of Inverse Variance Weighted (IVW), Weighted Median, MR-Egger and weighted mode. IVW method suggested no association between stroke and VLUs ((β 1.06; SE 9.321; p = 0.9095)). Weighted median estimator (β 5.906; SE 11.99, p = 0.6223), MR-Egger (β −0.8677; SE 21.89; p = 0.9691) and weighted mode (β 9.336; SE 17.77; p = 0.6089) showed consistent results. Conversely, evidence indicating that the presence of VLUs increased the risk of stroke was lacking. According to this MR study, there is no causal connection between stroke and VLUs, which suggests that therapies targeting stroke may not be effective against VLUs.