Selenocystine (SeC) has been identified as a novel compound with broad-spectrum anticancer activities. Natural borneol (NB) is a monoterpenoid compound that has been used as a promoter of drug absorption. In the present study, we demonstrated that NB significantly enhanced the cellular uptake of SeC and potentiated its antiproliferative activity on HepG2 cells by induction of apoptosis. NB effectively synergized with SeC to reduce cancer cell growth through the triggering apoptotic cell death. Further mechanistic studies by Western blotting showed that treatment of the cells with NB and SeC activated the intrinsic apoptotic pathway by regulation of pro-survival and pro-apoptotic Bcl-2 family proteins. Treatment of the cells with NB and SeC induced the activation of p38MAPK and inactivation of Akt and ERK. NB also potentiated SeC to trigger intracellular ROS generation and DNA strand breaks as examined by Comet assay. Moreover, the thiol-reducing antioxidants effectively blocked the occurrence of cell apoptosis, which confirmed the important role of ROS in cell apoptosis. Taken together, these results reveal that NB strongly potentiates SeC-induced apoptosis in cancer cells by enhancement of cellular uptake and activation of ROS-mediated DNA damage. NB could be further developed as a chemosensitizer of SeC in treatment of human cancers.

The delivery of nanomedicines into internal areas of solid tumors is a great challenge for the design of chemotherapeutic drugs and the realization of their successful application. Herein, we synthesized stable and efficient selenium nanoparticles (SeNPs) with an ideal size and a transcellular transport capability for the penetration and treatment of a solid tumor, utilizing Tw-80 as a dispersing agent and mushroom polysaccharide lentinan (LET) as a decorator. In vitro cellular experiments demonstrated that this nanosystem, LET-Tw-SeNPs, renders significant cellular uptake of HepG2 by receptor-mediated endocytosis and exhibits predominant transcellular transport and penetration capacity towards HepG2 tumor spheroids. Moreover, this therapeutic agent simultaneously inhibits the proliferation and migration of HepG2 cells via a cell cycle arrest pathway. Internalized LET-Tw-SeNPs give rise to the overproduction of intracellular reactive oxygen species (ROS), thus inducing mitochondrial rupture. Meanwhile, pharmacokinetic analysis showed that LET-Tw-SeNPs displayed a long half-life in blood. Altogether, this study demonstrates an inventive strategy for designing nanosystems with high permeability and low blood clearance, in order to achieve efficient in-depth tumor drug delivery and future clinical treatment of solid tumors.