Antitumor activity of nervosine VII, and the crosstalk between apoptosis and autophagy in HCT116 human colorectal cancer cells.

Nervosine VII is one of the known saturated pyrrolizidine alkaloids isolated from the plant of Liparis nervosa. This is first study to investigate the antitumor activity of nervosine VII in vitro, and the results indicated that nervosine VII induced autophagy and apoptosis in HCT116 human colorectal cancer cells. Mechanistic studies showed that nervosine VII-induced apoptosis was associated with the intrinsic pathway by the activation of caspase-9, -3 and -7. Autophagy induced by nervosine VII was characteristic with the regulation of autophagic markers including the increase of LC3-II and beclin 1 proteins, and the decrease of p62 protein. Nervosine VII simultaneously induced autophagy and apoptosis by activated MAPKs signaling pathway including JNK, ERK1/2 and p38, suppressing the p53 signaling pathway.

Design, synthesis and biological evaluation of benzamide derivatives as novel NTCP inhibitors that induce apoptosis in HepG2 cells.

Sodium taurocholate cotransport polypeptide (NTCP) plays an important role in the development of hepatitis and acts as a switch to allow hepatitis virus to enter hepatic cells. As the entry receptor protein of hepatitis virus, NTCP is also an effective target for the treatment of hepatocellular carcinoma. Herein, twenty-five benzamide analogues were synthesized based on the virtual screening design and their anti-proliferative activities against HepG2 cells were evaluated in vitro. Compound 35 was found to be promising, with an IC50 value of 2.8 µM. The apoptosis induced by 35 was characterized by the regulation of markers, including an increase in Bax, cleaved-caspase 3, and cleaved-PARP proteins, and a decrease in Bcl-2 protein. Molecular docking and molecular dynamics (MD) simulation confirmed that compound 35 can bind tightly to NTCP. Western blot analysis also showed that NTCP was inhibited. Altogether, these results indicate that compound 35 acts as a novel NTCP inhibitor to induce apoptosis in HepG2 cells.

A novel small-molecule activator of Sirtuin-1 induces autophagic cell death/mitophagy as a potential therapeutic strategy in glioblastoma.

Sirtuin-1 (SIRT1), the mammalian ortholog of yeast Sir2p, is well known to be a highly conserved NAD+-dependent protein deacetylase that has been emerging as a key cancer target. Autophagy, an evolutionarily conserved, multi-step lysosomal degradation process, has been implicated in cancer. Accumulating evidence has recently revealed that SIRT1 may act as a tumor suppressor in several types of cancer, and thus activating SIRT1 would represent a possible therapeutic strategy. Thus, in our study, we identified that SIRT1 was a key prognostic factor in brain cancer based upon The Cancer Genome Atlas and tissue microarray analyses. Subsequently, we screened a series of potential small-molecule activators of SIRT1 from Drugbank, and found the best candidate compound F0911-7667 (hereafter, named Comp 5), which showed a good deacetylase activity for SIRT1 rather than other Sirtuins. In addition, we demonstrated that Comp 5-induced autophagic cell death via the AMPK-mTOR-ULK complex in U87MG and T98G cells. Interestingly, Comp 5-induced mitophagy by the SIRT1-PINK1-Parkin pathway. Further iTRAQ-based proteomics analyses revealed that Comp 5 could induce autophagy/mitophagy by downregulating 14-3-3γ, catalase, profilin-1, and HSP90α. Moreover, we showed that Comp 5 had a therapeutic potential on glioblastoma (GBM) and induced autophagy/mitophagy by activating SIRT1 in vivo. Together, these results demonstrate a novel small-molecule activator of SIRT1 that induces autophagic cell death/mitophagy in GBM cells, which would be utilized to exploit this compound as a leading drug for future cancer therapy.

Cytotoxic Lathyrane-Type Diterpenes from Seeds of Euphorbia lathyris.

We isolated two new lathyrane-type diterpenes L27 (1) and L28 (2) along with seven known compounds (3-9) from the seeds of Euphorbia lathyris. These compounds were identified by NMR, high-resolution electrospray ionisation (HR-ESI)-MS as well as IR spectroscopy. Compounds 1 and 2 were assigned NMR spectrums with 1H-NMR, 13C-NMR, distortionless enhancement by polarization (DEPT), correlation spectroscopy (COSY), heteronuclear multiple quantum coherence (HMQC), heteronuclear multiple bond connectivity (HMBC) and nuclear Overhauser effect spectroscopy (NOESY). Stereo configuration of 1 and 2 were confirmed by comprehensive interpretation of their nuclear Overhauser effect (NOE) relationship and showed they were first natural lathyrane-type diterpenes possessing α-configuration substitutes at C-3. Cytotoxicity assay of isolated compounds were evaluated against breast cancer cell lines MCF-7 or MDA-MB-231, 786-0 and liver cancer cell lines HepG2. As a result, Euphorbia factor L28 (2) showed strongly cytotoxicity to the 786-0 and HepG2 cell lines, with an IC50 value of 9.43 and 13.22 µM, respectively, which preliminarily suggested that the configuration of lathyrane-type diterpene at C-3 has a significant effect on its bioactivity.

Treatment of gastric precancerous lesions with Weiansan.

AIM: To observe the curative effect of Weiansan (WAS) on gastric precancerous lesions (GPL) and H pylori elimination. METHODS: Seventy-six patients with GPL were randomly divided into two groups: WAS group (n = 42) and Weifuchun (WFC) group (n = 34). The patients in the WAS group were administered 5 g WAS 3 times a day, and the patients in the WFC group took WFC (4 tablets) 3 times a day. To monitor inflammation of gastric mucosa, degree of glandular atrophy (GA), intestinal metaplasia (IM) and dysplasia, and H pylori infection, all patients underwent gastroscopy and biopsy with pathological examination before and after treatment. Fifty male Sprague-Dawley (SD) rats were used in animal experiments. Of these, 10 served as the control group (n = 10), 40 were given ranitidine combined with N-methyl-N(1)-nitro-N-nitrosoguanidine (MNNG) for 12 wk and divided into 4 groups randomly: model group (n = 10), high-dose WAS group (n = 10), low-dose WAS group (n = 10) and WFC group (n = 10). Twelve weeks later, all rats were killed and a 2 cm multiply 1 cm tissue was taken from the lesser curvature of the gastric antrum. H pylori infection was determined by the fast urease method. RESULTS: The curative effect in WAS groups was similar to that in WFC groups. There was no statistical difference in degree of GA, IM and dysplasia between WAS and WFC groups. The rate of H pylori infection in the model group (positive/negative: 9/1) was significantly higher than that in the control group (positive/negative: 1/9) (P < 0.01). H pylori elimination in the high-dose WAS group (positive/negative: 4/6) and low-dose WAS group (positive/negative: 6/4) was similar to that in the WFC group (positive/negative: 4/6) (P > 0.05). CONCLUSION: WAS improves clinical symptoms by suppressing GA, IM and dysplasia and eliminating H pylori.