New strategies and drugs are urgently needed to improve the treatment of hepatocellular carcinoma (HCC) Vasculogenic mimicry (VM) has been elucidated being associated with the progression of HCC and anti-VM could be a promising strategy Celastrus orbiculatu s extract (COE), a mixture of 26 compounds isolated from the Chinese Herb Celastrus Orbiculatus Vine, has been elucidated to be able to disrupt VM formation in HCC This study aims to dissect and identify the potential targets of COE on anti-VM formation both in vitro and in vivo that are distinct from our previous study Proteomics analysis was used to identify differential proteins in HCC cells treated with or without COE (Data are available via ProteomeXchange with identifier PXD022203) Cells invasion was examined using Transwell Matrigel was used to establish a 3-D culture condition for VM formation in vitro RT-PCR and Western Blot were used to examine changes of mRNA and protein respectively Clinical resected samples were applied to confirm association between VM formation and identified targets Subcutaneous xenograft tumor model was established to observe tumor growth and VM formation in vivo PAS-CD34 dual staining was used to detect VM in vivo A total of 194 proteins were identified to be differentially expressed in HCC cells treated with or without COE In the 93 down-regulated proteins EphA2 stood out to be regulated on both RNA and protein level Disruption EphA2 using COE or NVP inhibited VM formation and decreased VM associated biomarkers In xenograft mouse model, COE inhibited tumor growth and VM formation via down-regulating EphA2 Taken together, our results indicate that COE could be used in HCC treatment because of its promising anti-VM effect

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COE Inhibits Vasculogenic Mimicry by Targeting EphA2 in Hepatocellular Carcinoma, a Research Based on Proteomics Analysis.

BACKGROUND AND METHODS Chemotherapy remains one of the most important methods for the treatment of cancer. More recently in this context, some products derived from natural products have raised scientific interest which especially include many terpenes. Thereby, diterpenoids represent a special class, and within this class of important secondary natural products, especially compounds derived from Dehydroabietylamine (DA), are of particular interest. RESULTS This review not only gives a summary of the most important findings on the cytotoxic behavior of DAderived compounds but also shows some drawbacks of these compounds, such low bioavailability and/or poor solubility of several derivatives of DA. It focusses on the chemical aspects and summarizes the DA related biological effects without deep discussion of underlying biochemical pathways. CONCLUSION Dehydroabietylamine-derived cytotoxic compounds hold a high potential to be developed into efficient antitumor active drugs.

Cytotoxic Dehydroabietylamine Derived Compounds.

Metabolomics and molecular docking-directed antiarthritic study of the ethyl acetate extract from Celastrus orbiculatus Thunb.

The stem of Celastrus orbiculatus, a traditional Chinese herbal medicine exhibits prominent anti-inflammatory and anti-tumor activities. In the present study, we prepared terpenoids-enriched fraction termed TTC (Total Terpenoids of C. orbiculatus) and explored the potentials of TTC as a sensitizer of gemcitabine by targeting DNA damage response in treatment of pancreatic cancer. Initially, we characterized the chemical profile of TTC. TTC and constitutional terpenoids showed antitumor effects through prohibiting the proliferation of AsPC-1 and BxPC-3 cells using EdU incorporation assay. Next, we quantified the interaction between TTC and gemcitabine which produced synergistic effects under sub-IC50 concentrations. Moreover, TTC could further block S-phase entry or induce higher extent of apoptosis in the presence of gemcitabine. Of note, we observed that TTC caused DNA breaks in two PC cells assayed by single cell gel electrophoresis and metaphase spreading. We also ruled out the oxidative damage of DNA upon TTC exposure. Mechanically, TTC abrogated Chk1/RAD51, promoted accumulation of γH2AX and reversed replication stress associated DNA damage response triggered by gemcitabine. TTC destabilized nuclear Chk1 and RAD51 loading via proteasomal degradation. Additionally, the ectopic expression of hotspot mutant p53 (R175H, R248W and R273H) in p53-null AsPC-1 cells displayed increased expression of RAD51, which could be compromised by TTC. In an orthotopic mouse model of mCherry-BxPC-3 cells, we confirmed the in vivo anti-metastatic efficacy of TTC in combination with gemcitabine. These data provide insight into how TTC and molecules involved in DNA damage and repair could be effectively multi-targeted and confer chemosensitivity to gemcitabine toward pancreatic cancer.

Terpenoids-enriched fraction of Celastrus orbiculatus sensitizes gemcitabine by disrupting Chk1/RAD51-mediated DNA damage response in pancreatic cancer

Traditional Chinese medicine in the treatment of high incidence diseases in cold areas: the thrombotic diseases

Celastrus orbiculatus is a medicinal plant belonging to the Celastraceae family. In this survey on the secondary metabolites of plants for obtaining antitumor substances, the chemical constituents of the stems of C. orbiculatus were investigated. Nortriptonoterpene (1), a new C19-norabietane diterpenoid, together with six other known abietane-type diterpenoids (2–7) and five known kaurane-type diterpenoids (8–12) were isolated and identified from the EtOAc extract of C. orbiculatus. Their structures were elucidated on the basis of extensive spectroscopic methods, including UV, IR, HR-ESI–MS, ECD, and NMR experiments, and by comparison with literature data. Compound 1 is a new C19-norabietane diterpenoid with 19 carbons. All compounds except for 10 and 11 were isolated from C. orbiculatus for the first time. The NMR data of 9 were reported for the first time. Compounds 1, 7 and 11 showed cytotoxicities against SGC-7901 with IC50 values of 63.2, 80.9 and 56.7 μM, respectively.

Jia-Jun Xu

Papers

Cytotoxic abietane and kaurane diterpenoids from Celastrus orbiculatus