| Cancer is one of the leading causes of human death.There were 18 million new cancer cases and 9.6 million cancer deaths worldwide in 2018.The clinical treatments of cancer are not satisfactory.There are a series of disadvantages along with the clinical treatments of cancer,such as serious side effects,poor efficacy on metastatic tumors,and drug resistance et al.The biological functions of reactive oxygen species(ROS)and their potential roles in the development of cancer have been extensively exploited in recent years.The biological functions of ROS are two-sided in cancer.At low concentrations,ROS act as signaling molecules that facilitate tumorigenesis and heterogeneity,while at high levels they exhibit cytotoxicity,inhibit cancer cell proliferation and cause apoptosis,necrosis and autophagy.Cancer cells have an inherent elevated ROS level compared to normal cells.This may partly be due to an enhanced metabolism and mitochondrial dysfunction in cancer cells.The high levels of ROS in cancer cells make them more susceptible to further ROS insults.The differences between cancer cells and normal cells would provide a unique opportunity for selective killing of malignant cancer cells.However,cancer cells have also adapted to oxidative stress by activating antioxidant systems often through the upregulation of glutathione(GSH).Therefore,we hope to enhance the elevation of oxidative stress by generating ROS and depleting GSH in tumor cells,thereby utilizing a dual mechanism to kill cancer cells more efficiently.ROS-generating cinnamaldehyde increases the oxidative stress in tumor cells,thereby activating the apoptotic pathway of cells.Diallyl trisulfide can deplete intracellular GSH by a thiol-disulfide exchange reaction,thereby attenuating the antioxidant capacity of cancer cells.First,we evaluated the efficiencies of ROS-generating moieties including cinnamaldehyde,fisetin,and germacrone that induce ROS in vitro,and further assessed the efficacies of killing cancer by these ROS-generating moieties plus diallyl trisulfide.The results reveal that the combination of cinnamaldehyde and diallyl trisulfide showed the best effect over killing cancer cells.Furthermore,the flow cytometry analysis shows that the combined cinnamaldehyde and diallyl trisulfide can significantly increase ROS levels in cancer cells.It is also proved that the combination of cinnamaldehyde and diallyl trisulfide can significantly increase the apoptosis levels in cancer cells.Moreover,we used PLGA-PEG to encapsulate cinnamaldehyde and diallyl trisulfide to form a dual-drug nanomedicine.The nanomedicine was stable under physiological conditions,and was capable of continuously releasing drugs slowly.The MTT assay shows that the dual-drug nanomedicine(PP-CD)encapsulated with both cinnamaldehyde and diallyl trisulfide had the best effect over killing cancer cells in comparison with the single-drug nanomedicines of PP-C and PP-D.The flow cytometry analysis reveals that PP-CD can also greatly enhance the ROS level in cancer cells and thus significantly increase the level of apoptosis.The targeting peptide RGD was further modified on the surface of PP-CD,which could increase the uptake of the nanomedicine in cancer cells.Finally,the therapeutic effects of the nanomedicines were evaluated in a subcutaneous tumor models.The results show that PP-CD could more efficiently regress the growth of tumors compared with both of PP-C and PP-D,which suggests that cinnamaldehyde and diallyl trisulfide had the synergistic effect over the treatment of tumors.Moreover,the RGD-modified PPR-CD represented a higher efficiency than the no-tumor-targeting one,which confirms that RGD could enhance the accumulation of the nanomedicine in tumors.Taken together,the combination of cinnamaldehyde and diallyl trisulfide can effectively enhance the oxidative stress in cancer cells by generating ROS and depleting GSH,and therefore synergistically regress the growth of tumors.This study provides a potential new strategy for the treatment of tumors. |
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