The Application And Implied Mechanism Of Zinc Oxide Nanoparticles In Tumor Therapy

Various nanomaterials,including zinc oxide nanoparticles,can induce cell death by enhancement of autophagy.However,the mechanisms that autophagy elicited by zinc oxide nanoparticles(ZONs)potentiates cell death remain to be elucidated.Here,we show that hydrothermal synthesized ZONs induced authentic autophagy in HeLa and GFP-LC3/HeLa.Small molecular autophagy inhibitors and the silencing of Atg5,one of autophagy related genes,can significantly inhibit the cell death caused by ZONs.The reasults reveal the correlation of cell death with autophagy induced by ZONs.Moreover,we show that the release of zinc ion is the major cause of cell death and the intracellular zinc ion release is accelerated by the acidic conditions of the lysosomal cellular compartment where particles are abundantly internalized.And sequentially,it raised excessive ROS generation associated with nanoparticles-induced intracellular toxicity.Interestingly,autophagy inhibition by using specific inhibitors or silencing Atg5 significantly reduced the levels of intracellular zinc ion release and ROS generation.We illustrated the mechanism that autophagy elicited by ZONs potentiates cell death.ZONs induce cell death through autophagy,zinc ion release,and intracellular ROS generation.Cancer poses a great threaten to human health and is one of the main causes of human death.Chemotherapy is a common therapy for cancer,but it is still facing rigorous challenge because of the side effects and drug resistance of cancer cells.It is urgent to seek ways to improve the anti-cancer effect of chemotherapeutic drugs to normal cancer cells and drug-resistant cancer cells and to reduce the potential side effects of drugs.In this context,we showed that ZONs can enhance the chemotherapeutic effect of doxorubicin to HeLa and MCF-7-MDR via autophagy modulation and zinc ion release.It is revealed that the abilities of autophagy mediated tumor killing z elicited by ZONs have great potential in sensitizing chemotherapeutic killing of cancer cells.Additionally,we found that ZONs can induce autophagic degradation of mutant p53 and enhance the killing of cancer cells.P53 is an important tumor suppressor,but mutated in over 50%of cancers.Mutant p53(mtp53)up-regulates the expression of drug-resistant and cell proliferation-related oncogenes and acquire novel oncogenic functions(gain of function,GOF).It is considered to be an effective scheme for cancer therapy by inhibiting the synthesis or promoting the degradation of mtp53.In this context,we found ZONs could accelerate autophagy-mediated clearance of mtp53.Combined treatment of protein synthesis inhibitors show that the decrease of mtp53 caused by degradation.The more cancer cells died after the degradation of mtp53 induced by ZONs,indicating that the degradation of mtp53 is related to the cell death.Autophagy inhibitors inhibit the degradation of mtp53 caused by ZONs,indicating that ZONs degrade the mtp53 via autophagy-lysosomal pathway.