Zhihai Huang

Inhibition of autophagy enhances the anticancer activity of silver nanoparticles.

Silver nanoparticles (Ag NPs) are cytotoxic to cancer cells and possess excellent potential as an antitumor agent. A variety of nanoparticles have been shown to induce autophagy, a critical cellular degradation process, and the elevated autophagy in most of these situations promotes cell death. Whether Ag NPs can induce autophagy and how it might affect the anticancer activity of Ag NPs has not been reported. Here we show that Ag NPs induced autophagy in cancer cells by activating the PtdIns3K signaling pathway. The autophagy induced by Ag NPs was characterized by enhanced autophagosome formation, normal cargo degradation, and no disruption of lysosomal function. Consistent with these properties, the autophagy induced by Ag NPs promoted cell survival, as inhibition of autophagy by either chemical inhibitors or ATG5 siRNA enhanced Ag NPs-elicited cancer cell killing. We further demonstrated that wortmannin, a widely used inhibitor of autophagy, significantly enhanced the antitumor effect of Ag NPs in the B16 mouse melanoma cell model. Our results revealed a novel biological activity of Ag NPs in inducing cytoprotective autophagy, and inhibition of autophagy may be a useful strategy for improving the efficacy of Ag NPs in anticancer therapy.

Silver nanoparticles: a novel radiation sensitizer for glioma?

Malignant gliomas are the most common primary intracranial tumors with a dismal prognosis. Previous investigations by our group demonstrated the radiosensitizing effect of silver nanoparticles (AgNPs) on glioma cells in vitro. The goal of the present study was to evaluate the efficacy of intratumoral administration of AgNPs in combination with a single dose of ionizing radiation at clinically relevant MV energies for the treatment of C6 glioma-bearing rats. AgNPs (10 or 20 μg/10 μl) were stereotactically administered on day 8 after tumor implantation. One day after AgNP injection, rats bearing glioma received 10 Gy radiation. The mean survival times were 100.5 and 98 days, the corresponding percent increase in life spans was 513.2% and 497.7%, and the cure rates were 41.7 and 38.5% at 200 days for the 10 and 20 μg AgNPs and radiation combination groups, respectively. In contrast, the mean survival times for irradiated controls, 10 and 20 μg AgNPs alone, and untreated controls were 24.5, 16.1, 19.4, and 16.4 days, respectively. Furthermore, a cooperative antiproliferative and proapoptotic effect was obtained when gliomas were treated with AgNPs followed by radiotherapy. Our results showed the therapeutic efficacy of AgNPs in combination with radiotherapy without apparent systemic toxicity, suggesting the clinical potential of AgNPs in improving the outcome of malignant glioma radiotherapy.

Is the autophagy a friend or foe in the silver nanoparticles associated radiotherapy for glioma

Malignant glioma is the most common intracranial tumor with a dismal prognosis. The radiosensitizing effect of silver nanoparticles (AgNPs) on glioma both in vitro and in vivo had been demonstrated in the previous studies of our group. However, the underlying mechanism is still unclear. Consistent with previous studies, a size and dose dependent antitumor effect and significant radiosensitivity enhancing effect of AgNPs were observed in our experiment system. We also found that cell protective autophagy could be induced by AgNPs and/or radiation, which was verified by the use of 3-MA. The mechanism through which had autophagy and the enhancement of radiosensitivity taken place was further investigated with inhibitors of ERK and JNK pathways. We demonstrated that ERK and JNK played pivotal roles in the radiosensitivity enhancement. Inhibiting ERK and JNK with U0126 and SP600125 respectively, we found that the autophagy level of the cells treated with AgNPs and radiation were attenuated. Moreover, SP600125 down-regulated the apoptosis rate of the co-treated cells significantly. Taken together, the present study would have important impact on biomedical applications of AgNPs and clinical treatment for glioma.

Exposure to silver nanoparticles does not affect cognitive outcome or hippocampal neurogenesis in adult mice.

Due to the unique antimicrobial and many other broad spectrum biotechnological advantages, silver nanoparticles (Ag-NPs) are widely used in biomedical and general applications. However, the current knowledge about the impact of Ag-NPs on the central nervous system is extremely limited. To assess whether Ag-NPs influence spatial cognition and adult hippocampal neurogenesis, male ICR mice received intraperitoneal administration of Ag-NPs (10, 25, and 50 mg/kg body weight) or vehicle every day for 7 days. At the end of this time period, Morris water maze test was performed for the spatial learning and memory. Subsequently, mice were injected with bromodeoxyuridine and sacrificed 1 day or 28 days after the last injection in order to evaluate cell proliferation, survival and differentiation in the hippocampus. Results showed that compared with the control group, both reference memory and working memory were not impaired in Ag-NPs exposed groups. In addition, no differences were observed in hippocampal progenitor proliferation, new born cell survival or differentiation. These data reveal that exposure to Ag-NPs does not affect spatial cognition or hippocampal neurogenesis in mice.

Colloidal silver nanoparticles improve anti-leukemic drug efficacy via amplification of oxidative stress.

Recently, increased reactive oxygen species (ROS) levels and altered redox status in cancer cells have become a novel therapeutic strategy to improve cancer selectivity over normal cells. It has been known that silver nanoparticles (AgNPs) display anti-leukemic activity via ROS overproduction. Hence, we hypothesized that AgNPs could improve therapeutic efficacy of ROS-generating agents against leukemia cells. In the current study, N-(4-hydroxyphenyl)retinamide (4-HPR), a synthetic retinoid, was used as a drug model of ROS induction to investigate its synergistic effect with AgNPs. The data exhibited that AgNPs with uniform size prepared by an electrochemical method could localize in the lysosomes, mitochondria and cytoplasm of SHI-1 cells. More importantly, AgNPs together with 4-HPR could exhibit more cytotoxicity and apoptosis via overproduction of ROS in comparison with that alone. Taken together, these results reveal that AgNPs combined with ROS-generating drugs could potentially enhance therapeutic efficacy against leukemia cells, thereby providing a novel strategy for AgNPs in leukemia therapy.

Continuous synthesis of size-tunable silver nanoparticles by a green electrolysis method and multi-electrode design for high yield

Although some methods have been developed, high-yield controllable synthesis of silver nanoparticles in aqueous solution is still challenging. Here, we report a green electrolytic synthesis of silver nanoparticles in a continuous flow system. Nanoparticle sizes could be tuned facilely by adjusting the flow velocity. Further, an improved multi-electrode electrolytic reactor was designed for increasing the yield.

Key Role of TFEB Nucleus Translocation for Silver Nanoparticle‐Induced Cytoprotective Autophagy

Transcription factor EB (TFEB) is a master regulator of autophagy and lysosomal biogenesis. Here, silver nanoparticles (Ag NPs)-induced cytoprotective autophagy required TFEB is shown. Ag NPs-induced nucleus translocation of TFEB through a well-established mechanism involving dephosphorylation of TFEB at serine-142 and serine-211 but independent of both the mTORC1 and ERK1/2 pathways. TFEB nucleus translocation precedes autophagy induced by Ag NPs and leads to enhanced expression of autophagy-essential genes. Knocking down the expression of TFEB attenuates the autophagy induction is demonstrated, and in the meantime, enhanced cell killing in HeLa cells treats with Ag NPs, indicating that TFEB is the key mediator for Ag NPs-induced cytoprotective autophagy. The results pinpoint TFEB as a potential target for developing more effective Ag NPs-based cancer therapeutics.