Sarmentosin Induces Autophagy-dependent Apoptosis via Activation of Nrf2 in Hepatocellular Carcinoma

Background and Aims:Hepatocellular carcinoma(HCC)is a common and deadly cancer.Accumulating evidence supports modulation of autophagy as a novel approach for determining cancer cell fate.The aim of this study to evaluate the effectiveness of sarmentosin,a natural compound,on HCC in vitro and in vivo and elucidated the underlying mechanisms.Methods:Cell functions and signaling pathways were analyzed in HepG2 cells using western blotting,real-time PCR,siRNA,transmission electron microscopy and flow cytometry.BALB/c nude mice were injected with HepG2 cells to produce a xenograft tumour nude mouse model for in vivo assessments and their tumors,hearts,lungs and kidneys were isolated.Results:We found that autophagy was induced by sarmentosin in a concentration-and timedependent manner in human HCC HepG2 cells by western blot assays and scanning electron microscopy.Sarmentosin-induced autophagy was abolished by the autophagy inhibitors 3-methyladenine,chloroquine,and bafilomycin A1.Sarmentosin activated Nrf2 in HepG2 cells,as shown by increased nuclear translocation and upregulated expression of Nrf2 target genes.Phosphorylation of mTOR was also inhibited by sarmentosin.Sarmentosin stimulated caspasedependent apoptosis in HepG2 cells,which was impaired by silencing Nrf2 or chloroquine or knocking down ATG7.Finally,sarmentosin effectively repressed HCC growth in xenograft nude mice and activated autophagy and apoptosis in HCC tissues.Conclusions:This study showed sarmentosin stimulated autophagic and caspase-dependent apoptosis in HCC,which required activation of Nrf2 and inhibition of mTOR.Our research supports Nrf2 as a therapeutic target for HCC and sarmentosin as a promising candidate for HCC chemotherapy.

A facile phototheranostic nanoplatform integrating NIR-Ⅱ fluorescence/PA bimodal imaging and image-guided surgery/PTT combinational therapy for improved antitumor efcacy

Phototheranostic with highly integrated functions is an attractive platform for cancer management. It remains challenging to develop a facile phototheranostic platform with complementary bimodal imaging and combinational therapy capacity. Herein, the small-molecule cyanine IR780 loaded liposomes have been harnessed as a nanoplatform to simultaneously realize photoacoustic(PA)/the second near-infrared window(NIR-Ⅱ) fluorescence imaging and image-guided surgery/adjuvant photothermal therapy(PTT).This nanoplatform exhibits attractive properties like uniform controllable size, stable dispersibility, NIR-Ⅱ fluorescence emission, photothermal conversion, and biocompatibility. Benefiting from the complementary PA/NIR-Ⅱ fluorescence bimodal imaging, this nanoplatform was successfully applied in precise vasculature delineation and tumor diagnosis. Interestingly, the tumor was clearly detected by NIR-Ⅱ fluorescence imaging with the highest tumor-to-normal-tissue ratio up to 12.69, while signal interference from the liver was significantly reduced, due to the difference in the elimination rate of the nanoplatform in the liver and tumor. Under the precise guidance of the image, the tumor was accurately resected, and the simulated residual lesion after surgery was completely ablated by adjuvant PTT. This combined therapy showed improved antitumor efcacy over the individual surgery or PTT. This work develops a facile phototheranostic nanoplatform with great significance in accurately diagnosing and effectively treating tumors using simple NIR light irradiation.