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Cuprous oxide nanoparticles trigger reactive oxygen species-induced apoptosis through activation of erk-dependent autophagy in bladder cancer.

ABSTRACT: Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer. However, as more than 50% of patients are ineligible for cisplatin-based chemotherapy, there is an urgent need to develop new drugs. Cuprous oxide nanoparticles (CONPs), as a new nano-therapeutic agent, have been proved to be effective in many kinds of tumors. In the present study, CONPs showed dose-dependent and time-dependent inhibitory effects on various bladder cancer cell lines (T24, J82, 5637, and UMUC3) and weak inhibitory effects on non-cancerous epithelial cells (SVHUCs). We found that CONPs induced cell cycle arrest and apoptosis in bladder cancer cells. We further demonstrated that the potential mechanisms of CONP-induced cytotoxicity were apoptosis, which was triggered by reactive oxygen species through activation of ERK signaling pathway, and autophagy. Moreover, the cytotoxic effect of CONPs on bladder cancer was confirmed both in orthotopic xenografts and subcutaneous nude mouse models, indicating that CONPs could significantly suppress the growth of bladder cancer in vivo. In further drug combination experiments, we showed that CONPs had a synergistic drug-drug interaction with cisplatin and gemcitabine in vitro, both of which are commonly used chemotherapy agents for bladder cancer. We further proved that CONPs potentiated the antitumor activity of gemcitabine in vivo without exacerbating the adverse effects, suggesting that CONPs and gemcitabine can be used for combination intravesical chemotherapy. In conclusion, our preclinical data demonstrate that CONPs are a promising nanomedicine against bladder cancer and provide good insights into the application of CONPs and gemcitabine in combination for intravesical bladder cancer treatment.

SUBMITTER: Xiong Q

PROVIDER: S-EPMC7224387 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Cuprous oxide nanoparticles trigger reactive oxygen species-induced apoptosis through activation of erk-dependent autophagy in bladder cancer.

Xiong Qiao Q Liu Anwei A Ren Qian Q Xue Yongping Y Yu Xiaowen X Ying Yidie Y Gao Hongliang H Tan Haoyuan H Zhang Zhensheng Z Li Wei W Zeng Shuxiong S Xu Chuanliang C

Cell death & disease 20200514 5

Cisplatin-based chemotherapy is the first-line treatment for patients with advanced bladder cancer. However, as more than 50% of patients are ineligible for cisplatin-based chemotherapy, there is an urgent need to develop new drugs. Cuprous oxide nanoparticles (CONPs), as a new nano-therapeutic agent, have been proved to be effective in many kinds of tumors. In the present study, CONPs showed dose-dependent and time-dependent inhibitory effects on various bladder cancer cell lines (T24, J82, 563 ...[more]

PMID: 32409654

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Project description:Environmental exposure to silica nanoparticles (SiNPs) is inevitable due to their widespread application in industrial, commercial, and biomedical fields. In recent years, most investigators focus on the evaluation of cardiovascular effects of SiNPs in vivo and in vitro. Endothelial injury and dysfunction is now hypothesized to be a dominant mechanism in the development of cardiovascular diseases. This study aimed to explore interaction of SiNPs with endothelial cells, and extensively investigate the exact effects of reactive oxygen species (ROS) on the signaling molecules and cytotoxicity involved in SiNPs-induced endothelial injury. Significant induction of cytotoxicity as well as oxidative stress, apoptosis, and autophagy was observed in human umbilical vein endothelial cells following the SiNPs exposure (P<0.05). The oxidative stress was induced by ROS generation, leading to redox imbalance and lipid peroxidation. SiNPs induced mitochondrial dysfunction, characterized by membrane potential collapse, and elevated Bax and declined bcl-2 expression, ultimately leading to apoptosis, and also increased number of autophagosomes and autophagy marker proteins, such as LC3 and p62. Phosphorylated ERK, PI3K, Akt, and mTOR were significantly decreased, but phosphorylated JNK and p38 MAPK were increased in SiNPs-exposed endothelial cells. In contrast, all of these stimulation phenomena were effectively inhibited by N-acetylcysteine. The N-acetylcysteine supplement attenuated SiNPs-induced endothelial toxicity through inhibition of apoptosis and autophagy via MAPK/Bcl-2 and PI3K/Akt/mTOR signaling, as well as suppression of intracellular ROS property via activating antioxidant enzyme and Nrf2 signaling. In summary, the results demonstrated that SiNPs triggered autophagy and apoptosis via ROS-mediated MAPK/Bcl-2 and PI3K/Akt/mTOR signaling in endothelial cells, and subsequently disturbed the endothelial homeostasis and impaired endothelium. Our findings may provide experimental evidence and explanation for cardiovascular diseases triggered by SiNPs. Furthermore, results hint that the application of antioxidant may provide a novel way for safer use of nanomaterials.

Dataset Information

Cuprous oxide nanoparticles trigger reactive oxygen species-induced apoptosis through activation of erk-dependent autophagy in bladder cancer.

Publications

Cuprous oxide nanoparticles trigger reactive oxygen species-induced apoptosis through activation of erk-dependent autophagy in bladder cancer.

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