Xianzhi Qu,Jiyao Sheng,Luyan Shen,Jing Su,Yunjie Xu,Qi Xie,Yao Wu,Xuewen Zhang,Liankun Sun
The tumor cells have some metabolic characteristics of the original tissues, and the metabolism of the tumor cells is closely related to autophagy. However, the mechanism of autophagy and metabolism in chemotherapeutic drug resistance is still poorly understood. In this study, we investigated the role and mechanism of autophagy and glucose metabolism in chemotherapeutic drug resistance by using cholangiocarcinoma QBC939 cells with primary cisplatin resistance and hepatocellular carcinoma HepG2 cells. We found that QBC939 cells with cisplatin resistance had a higher capacity for glucose uptake, consumption, and lactic acid generation, and higher activity of the pentose phosphate pathway compared with HepG2 cells, and the activity of PPP was further increased after cisplatin treatment in QBC939 cells. It is suggested that there are some differences in the metabolism of glucose in hepatocellular carcinoma and cholangiocarcinoma cells, and the activation of PPP pathway may be related to the drug resistance. Through the detection of autophagy substrates p62 and LC3, found that QBC939 cells have a higher flow of autophagy, autophagy inhibitor chloroquine can significantly increase the sensitivity of cisplatin in cholangiocarcinoma cells compared with hepatocellular carcinoma HepG2 cells. The mechanism may be related to the inhibition of QBC939 cells with higher activity of the PPP, the key enzyme G6PDH, which reduces the antioxidant capacity of cells and increases intracellular ROS, especially mitochondrial ROS. Therefore, we hypothesized that autophagy and the oxidative stress resistance mediated by glucose metabolism may be one of the causes of cisplatin resistance in cholangiocarcinoma cells. It is suggested that according to the metabolism characteristics of tumor cells, inhibition of autophagy lysosome pathway with chloroquine may be a new route for therapeutic agents against cholangiocarcinoma.
Summary Background Nanoparticles have been explored recently as an efficient means to deliver photosensitizers for photodynamic therapy . However, it is largely unknown if polyhematoporphyrin (C 34 H 38 N 4 NaO 5 , Photosan-II, PS) or other photosensitizers can be efficiently delivered by hollow silica nanoparticles (HSNP). Methods Polyhematoporphyrin (C 34 H 38 N 4 NaO 5 , Photosan-II, PS) was loaded into hollow silica nanoparticles (HSNP) by one-step wet chemical-based synthetic route. Dynamic light scattering (DLS) and polydispersive index (PDI) were used for measurement of the particles size and size distribution. Transmission electron microscope and scanning electron microscopy were used for the microstructure, morphological and chemical composition analysis. Fourier transform infrared spectrometry spectra and fluorescence emission spectrum were obtained. The photobiological activity of the PS-loaded HSNP was evaluated on human cholangiocarcinoma QBC939 cells. The cellular viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Apoptotic and necrotic cells were measured by flow cytometry. Results DLS measurements showed that the size of the particles is in the range of 25–90 nm. PDI of the PS-loaded HSNP is 0.121 ± 0.01, indicating that samples have excellent quality with narrow size distribution to monomodal systems. In MTT assay , PS-loaded HSNP and free PS of the same concentration killed about 95.3% ± 2.0% and 55.7% ± 1.9% of QBC939 cells, respectively. The flow cytometry demonstrated that the laser induced cell death with PS-loaded HSNP was much more severe than that of free PS ( P < 0.05). Conclusions Photosan-II-loaded hollow silica nanoparticles not only can quickly deliver Photosan-II into cells but also can reach a more high concentration than free Photosan-II. HSNP is a desirable vehicle and the release system that shows promises for photodynamic therapy use, which not only improve the aqueous solubility, stability and transport efficiency of PS, but also increase its photodynamic efficacy compared to free PS.
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