Novel Zn-doped CuO nanocomposites inhibit tumor growth in vitro and in vivo:role of reactive oxygen species-dependent apoptosis and autophagy cross-linked by NF-kappaB pathway / 中国药理学与毒理学杂志

OBJECTIVE Zn-doped CuO nanocomposites (nZn-CuO NPs) are novel nanoparticles synthesized by sonochemical method.This study aimed to further investigate the antitumor effects and mechanism of nZn-CuO NPs, as well as the exact mechanism of reactive oxygen species (ROS) on nZn-CuO NPs-induced death using N-acetylcysteine (NAC). METHODS The antitumor effects of nZn-CuO NPs were evaluated by MTS assay and orthotopic transplantation tumor model in nude mice. The effects of nZn-CuO NPs with or without NAC on ROS production, DNA damage, apoptosis, mitochondrial damage, autophagy, lysosome impairment, and ER and Golgi stress were determined. Also,western blot was used to detect apoptosis and autophagy related proteins,as well as NF-κB pathway related proteins. RESULTS nZn-CuO NPs significantly inhibit tumor growth both in vitro and in vivo. nZn-CuO NPs were able to cause cytotoxicity, ROS production, DAN damage mitochondrial damage, apoptosis, and autophagy, and NAC can attenuate them. Further studies showed that nZn-CuO NPs induced changes of apoptosis, autophagy and NF-κB pathway related proteins, and NAC can restore them. CONCLUSION Overall, our data demonstrated that nZn-CuO NPs could inhibit tumor growth both in vitro and in vivo by ROS-dependent regulation of apoptosis and autophagy, which might be cross-linked by NF-κB pathways.

Granulin A synergizes with cisplatin to inhibit the growth of human hepatocellular carcinoma / 中国药理学与毒理学杂志

OBJECTIVE Granulin A (GRN A), a cytokinesis protein, is derived from proteolysis of progranulin. The previous study in our laboratory has shown that GRN A is able to inhibit cancer cell growth significantly. This study aimed to investigate the effect of combination of GRN A and cisplatin on in vitro and in vivo on the growth of hepatocellular carcinoma. METHODS The in vitro and in vivo antitumor effects of combination of GRN A and Cisplatin were evaluated with MTS assay and subcuta-neous transplantation tumor model.Chou-Talalay method was used to calculate the combination index (CI). Colony formation assay and flow cytometry were used to detect the effects of GRN A on apoptosis. The expression of apoptosis-related proteins were detected by Western blot. RESULTS MTS assay showed that GRN A significantly inhibit hepatocellular carcinoma cells growth with the IC50of 5.6 μmol·L-1, and GRN A combined with cisplatin synergistically inhibit hepatocellular carcinoma proliferation, with the CI<1.The colony-formation assay showed that GRN A significantly enhanced the inhibitory effects of cisplatin on cellular anchorage-independent growth. Flow cytometry showed that GRN A combined with cisplatin synergistically induced apoptosis,with the apoptotic rates of 5.87%,32.74%,35.67% and 67.15% in control, GRN A, Cisplatin, and combination of GRN A and Cisplatin groups, respectively. Western blot confirmed that the two drugs synergistically changed the expressions of proteins related to apoptosis.In vivo experiment indicated that combination of GRN A and cisplatin significantly suppressed tumor growth compared with single drug treatment groups.CONCLUSION The combination of GRN A and cisplatin resulted in synergistic antitumor effects against hepatocellular carcinoma both in vitro and in vivo.

Zn-doped CuO nanocomposites inhibit in vitro and in vivo growth of pancreatic cancer by inducing autophagy through AMPK/mTOR pathway / 中国药理学与毒理学杂志

OBJECTIVE Zn-doped CuO nanocomposites (Zn-CuO NPs) are novel nanoparticles synthesized by our research group.In this study,we assessed the in vitro and in vivo antitumor effects of Zn-CuO NPS on pancreatic cancer cells,as well as the potential mechanisms. METHODS MTS assay was used to detect the effects of Zn-CuO NPS on proliferation pancreatic cancer cells(Panc-mia and Aspc-1). The in vivo antitumor effects of Zn-CuO NPs were detected by xenografts model in nude mice. The effects of Zn-CuO NPS on autophagy were detected bytransmission electron microscopy (TEM) andflow cytometry. Autophagy related proteins were detected by Western blotting. RESULTS Zn-CuO NPS significantly inhibited the proliferation of Panc-mia cells and Aspc-1 cells.In vivo experi-ments showed that Zn-CuO NPS significantly inhibited the tumor growth in nude mice without affecting the body weight of the mice. TEM and flow cytometry showed that Zn-CuO NPS induced autophagy, and significantly increased the number of autophagosome.Western Blot showed that Zn-CuO NPS alterd the expression of autophagy related proteins,such as AMPK,mTORand Beclin-1.Also,AMPK inhibitor could significantly reduce Zn-CuO NPS-induced autophagy pathwayas analyzed byWestern blotting. CONCLUSION The findings suggested that Zn-doped CuO nanocomposites inhibited the in vitro and in vivo growth of pancreatic cancer by inducing autophagy through AMPK/mTOR pathway.

Water-soluble extract of clove inhibits in vitro and in vivo growth of colon cancer by inducing autophagy / 中国药理学与毒理学杂志

OBJECTIVE Cloves(Syzygium aromaticum L.)have been used as both a spice and a traditional Chinese medicinal herb for thousands of years. However, relatively little is known about its potential anticancer activity and mechanisms.In this study,we investigated the in vitro and in vivo anti-tumor effects and mechanisms of water extract of cloves(WEC)against colorectal cancer. METHODS MTS assay and Colony-formation assay were used to detect the anti-tumor activity of WEC on HT-29 cells.The in vivo anti-tumor effect of WEC was detected in a subcutaneous transplantation tumor model of human HT-29 cells.Autophagy was detected by flow cytometry and the expressions of autophagy related proteins(Beclin-1 and LC-3a/b)were determined by western blot. RESULTS MTS result showed that WEC significantly inhibited the viability of HT-29 cells,with the IC50values of 150 μg·mL-1.The colony-formation assay showed that the WEC significantly suppressed colon cancer cells proliferation.WEC also exhibited significant antitumor activity in tumor bearing nude mice. Flow cytometry result showed that WEC significantly induced autophagy, and the averaged relative values of fluorescence intensity were 206,251,341 and 356 in cells treated with 0,100,150 and 200 μg·mL-1WEC for 48 h.Western blot result showed that WEC treatment significantly increased Beclin-1 expression and ratios of LC3-II/LC3-I. CONCLUSION These result showed that WEC inhibited the growth of colon tumor both in vitro and in vivo, which might be related with autophagy induction, and WEC has potential to be developed as a novel anticancer agent for the treatment of colon cancer.

Progress of marine anticancer agents targeting cellular proapoptotic molecules / 药学学报

Apoptosis, a form of programmed cell death, is a critical defense mechanism against the formation and progression of cancer. In vivo, apoptosis functions to eliminate potentially deleterious cells without causing such adverse effects as inflammatory response, and to ensue scar formation. Therefore, activation of the apoptotic pathways becomes an intriguing strategy in the development of chemotherapeutic agents. Marine natural products have become an important source in the discovery of antitumor drugs now since it is more and more feasible to collect organisms from seas. Hundreds of marine compounds have been found to induce apoptosis in tumor cells in recent years and many of them have good antitumor activity. This review summarizes several such compounds, based on their effects on the apoptotic signaling pathways, and highlights the problems in the development of anti-cancer drugs from the natural products.