β-Elemonic acid inhibits the growth of human Osteosarcoma through endoplasmic reticulum (ER) stress-mediated PERK/eIF2α/ATF4/CHOP activation and Wnt/β-catenin signal suppression.

Osteosarcoma (OS) is a significant threat to the lives of children and young adults. Although neoadjuvant chemotherapy is the first choice of treatment for OS, it is limited by serious side-effects and cancer metastasis. β-Elemonic acid (β-EA), an active component extracted from Boswellia carterii Birdw., has been reported to exhibit potential anti-inflammatory and anticancer activities. However, the anti-tumor effects and underlying mechanisms on OS as well as pharmacokinetic characteristics of β-EA remain unknown. This study was aimed to investigating the anti-tumor effects of β-EA on human OS, the underlying mechanisms, and the pharmacokinetic and tissue distribution characteristics. Cell viability and colony formation assays were performed to determine the effect of β-EA cell on cell proliferation. Apoptosis rates, mitochondrial membrane potential and cell cycle features were analyzed by flow cytometry. qRT-PCR, Western blot, immunofluorescence and immunohistochemical assays were conducted to evaluate the expression levels of genes or proteins related to the pathways affected by β-EA in vitro and in vivo. Cell migration and invasion were evaluated in wound healing and Transwell chamber assays. The effects and pharmacokinetic characteristics of β-EA in vivo were evaluated by analyzing tumor suppression, pharmacokinetics and tissue distribution. Explorations indicated that endoplasmic reticulum (ER) stress conditions provoked by β-EA activated the PERK/eIF2α/ATF4 branch of the unfolded protein reaction (UPR), stimulating C/EBP homologous protein (CHOP)-regulated apoptosis and inducing Ca2+ leakage leading to caspase-dependent apoptosis. Furthermore, β-EA induced G0/G1 cell cycle arrest and inhibited metastasis of HOS and 143B cells by attenuating Wnt/β-catenin signaling effects, which included decreased levels of p-Akt(Ser473), p-Gsk3β (Ser9), Wnt/β-catenin target genes (c-Myc and CyclinD1) along with a decline in nuclear β-catenin accumulation. The fast absorption, short elimination half-life, and linear pharmacokinetic characteristics of β-EA were also revealed. The distribution of β-EA was detected in the tumor and bone tissues. Overall, both in vitro and in vivo investigations showed the potential of β-EA for the treatment of human OS. The pharmacokinetic profile and considerable distribution in the tumor and bone tissues warrant further preclinical or even clinical studies.

Zhao A ，Zhang Z ，Zhou Y ，Li X ，Li X ，Ma B ，Zhang Q ... -  《-》

Cinnamaldehyde Inhibits the Function of Osteosarcoma by Suppressing the Wnt/β-Catenin and PI3K/Akt Signaling Pathways.

Osteosarcoma (OS) is a primary bone tumor associated with locally aggressive growth and early metastatic potential that typically occurs in children and adolescents. Chinese traditional medicine Cinnamomum cassia Presl has been shown to have significant tumor-killing effect, in which cinnamaldehyde (CA) is the main active ingredient. To explore the anticancer effect of CA on the osteosarcoma cells and the possible molecular mechanism. Crystal violet assay, MTT assay and colony-forming assay were used to confirm the inhibitory role of CA in the proliferation of 143B and MG63 osteosarcoma cells. Hoechst 33258 staining and flow cytometry were used to observe apoptosis. The migration and invasion role of OS cells were evaluated using transwell assays and wound healing assays. Western blotting was used to analyse the protein expression levels. Nude mice were inoculated with 143B cells to establish an orthotopic OS tumor animal model and to investigate the effects of CA on OS tumors. According to crystal violet assay, MTT assay and colony-forming assay, CA significantly inhibited cell proliferation. Hoechst 33258 staining and flow cytometry analysis showed that CA-induced apoptosis in a concentration-dependent manner. In addition, transwell assays and wound healing assays showed that CA inhibited the migration and invasion of osteosarcoma cells. In vivo mouse models, CA inhibited the growth of osteosarcoma. The potential mechanisms could be that CA inhibited the transcriptional activity of Wnt/β-catenin and PI3K/Akt of the osteosarcoma. CA may inhibit the proliferation, migration, invasion and promote apoptosis of OS cells by inhibiting Wnt/β-catenin and PI3K/Akt signaling pathways. CA may be a potentially effective anti-tumor drug.

Huang Y ，Chen J ，Yang S ，Tan T ，Wang N ，Wang Y ，Zhang L ，Yang C ，Huang H ，Luo J ，Luo X ... -  《Drug Design Development and Therapy》

Pollen Typhae Total Flavone Inhibits Endoplasmic Reticulum Stress-Induced Apoptosis in Human Aortic-Vascular Smooth Muscle Cells through Down-Regulating PERK-eIF2α-ATF4-CHOP Pathway.

Chen MT ，Huang RL ，Ou LJ ，Chen YN ，Men L ，Chang X ，Wang L ，Yang YZ ，Zhang Z ... -  《-》

Ursolic acid inhibits proliferation and induces apoptosis by inactivating Wnt/β-catenin signaling in human osteosarcoma cells.

Zhang RX ，Li Y ，Tian DD ，Liu Y ，Nian W ，Zou X ，Chen QZ ，Zhou LY ，Deng ZL ，He BC ... -  《-》

Exploiting Honokiol-induced ER stress CHOP activation inhibits the growth and metastasis of melanoma by suppressing the MITF and β-catenin pathways.

There is increasing global incidence of highly metastatic melanoma and therapeutic strategies like those focusing on the downstream beta-catenin/MITF axis of invading melanoma cells are urgently needed. Targeting endoplasmic reticulum (ER) stress can promote cancer cell death and inhibit epithelial mesenchymal transition (EMT) in metastatic tumors. This study aimed to determine if Honokiol could promote ER stress-dependent apoptosis and regulate metastatic melanoma. The therapeutic efficacy of Honokiol was assessed using the highly metastatic melanoma xenograft mouse model for peritoneal metastasis and evaluated by computed tomography imaging. The ER stress marker, Calpain-10, delineated a novel proteolytic cleavage enzyme, while CHOP/GADD153-regulated apoptosis was used for gene silencing to determine the role of the β-catenin/MITF axis in melanoma cells. The results showed that Honokiol effectively decreased peritoneal dissemination and organ metastasis via ER stress activation and EMT marker inhibition. Knockdown Calpain-10 or CHOP/GADD153 blocked all of the biological effects in Honokiol-induced β-catenin/MITF cleavage, ERSE or TCF/LEF luciferase activity, and β-catenin kinase activity. These findings suggest that Honokiol can significantly thwart the progression of highly metastatic melanoma using the β-catenin/MITF axis via prompt Calpain-10 and CHOP/GADD153 regulated cascades.

Chiu CS ，Tsai CH ，Hsieh MS ，Tsai SC ，Jan YJ ，Lin WY ，Lai DW ，Wu SM ，Hsing HY ，Arbiser JL ，Sheu ML ... -  《-》