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》
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
... -
《-》
9-O-monoethyl succinate berberine effectively blocks the PI3K/AKT signaling pathway by targeting Wnt5a protein in inhibiting osteosarcoma growth.
Osteosarcoma (OS) is the most common primary bone malignancy, mainly affecting children, adolescents, and young adults, followed by the elderly, with a high propensity for local invasion and metastasis. Although surgery combined with chemotherapy has greatly improved the prognosis of patients with OS, the prognosis for metastatic or recurrent OS is still unsatisfactory. The research community has struggled to develop an effective chemotherapy treatment regimen for this tumor. For the creation of an OS drug, our research team has effectively developed and manufactured a new drug named 9-O-monoethyl succinate berberine (B2).
In this study, we aimed to investigate the roles and functions of B2 in the treatment of OS.
Human OS cell lines and mouse OS cell lines were used in vitro cell experiments, while BALB/c mice and BALB/c nude mice were used in vivo animal experiments. To investigate the molecular mechanism of B2 treatment, antibody microarray analysis, proteomic analysis, quantitative real-time PCR, immunohistochemical labeling, and western blotting analysis were mostly carried out. We assessed the impact of B2 on OS therapy and the underlying molecular pathways based on in vivo and in vitro studies.
Our findings demonstrated that B2 has the ability to inhibit the proliferation, migration, and invasion of OS cell lines, while also induce apoptosis in vitro. Additionally, our results suggested that B2 could effectively impede the growth of OS and has less heart and lung damage than cisplatin in vivo. In terms of mechanism, we discovered that the Wnt5a protein is significantly expressed in OS cell lines. Knockdown of Wnt5a can restrict OS cell lines proliferation, and overexpression of Wnt5a had the opposite results. B2 also had a strong affinity with Wnt5a and can inhibit the PI3K/AKT signaling pathway by targeting Wnt5a. Tumor cells proliferation can be inhibited by blocking the PI3K/AKT signaling pathway, and Wnt5a-mediated inactivation of the PI3K/AKT signaling pathway after B2 treatment. In vitro and in vivo experiments with Wnt5a overexpression, B2 significantly inhibited tumor growth, migration, and invasion. Moreover, B2 and Wnt5a also have a strong structural binding ability (binding energy of -7.567 ± 0.084 kcal/mol, binding values of 2.860 ± 0.434 µM), and three hydrogen bonds are generated at the docking positions of amino acids GLN286, ASN288, and ASN292.
In summary, our study confirmed for the first time that the growth of OS is related to abnormal overexpression of Wnt5a protein, and designed a novel small molecule inhibitor named B2 targeting Wnt5a protein, which inhibits OS growth by mediating PI3K/AKT signaling pathway by targeting Wnt5a protein. Our research laid the groundwork for the promotion of B2 as a new anticancer drug and revealed an innovative chemotherapeutic strategy for OS therapy.
Wang Y
，Hong J
，Ge S
，Wang T
，Mei Z
，He M
，Liu Y
，Fang J
，Liu C
，Yang L
，Yuan Y
... -
《-》
p-Coumaric Acid Inhibits Osteosarcoma Growth by Inhibiting PI3K/Akt Signaling Pathway.
P-coumaric acid (p-CA) is a kind of phenylpropionic acid derived from aromatic amino acids, which is widely distributed in many plants and human diets. It has strong pharmacological and inhibitory effects on a variety of tumors. However, the role of p-CA in osteosarcoma, a tumor with a poor prognosis, is still unknown. Therefore, we aimed to evaluate the effect of p-CA on osteosarcoma and explore its potential mechanism.
This study aimed to investigate whether p-CA has an inhibitory effect on the growth of osteosarcoma cells and explore its potential mechanism.
MTT assay and clonogenic assay were used to detect the effect of p-CA on the proliferation of osteosarcoma cells. The effect of p-CA on apoptosis of osteosarcoma cells was detected by the Hoechst staining and flow cytometry. The effects of p-CA on the migration and invasion of osteosarcoma cells were detected by scratch healing assay and Transwell invasion assay. Western blot and PI3K/Akt pathway activator 740Y-P were used to detect the anti-tumor mechanism of p-CA on osteosarcoma cells. The effect of p-CA on osteosarcoma cells in vivo was verified by an orthotopic osteosarcoma tumor animal model in nude mice.
MTT assay and clonogenic assay showed that p-CA inhibited the proliferation of osteosarcoma cells. Hoechst stain and flow cytometry showed that p-CA could induce apoptosis of osteosarcoma cells and lead to G2 phase arrest of osteosarcoma cells. Transwell assay and scratch healing assay found that p-CA could inhibit the migration and invasion of osteosarcoma cells. Western blot showed that p-CA could inhibit the activity of the PI3K/Akt signaling pathway in osteosarcoma cells, and 740Y-P could reverse its inhibitory effect. In vivo mouse models, p-CA has an antitumor effect on osteosarcoma cells in vivo, and at the same time, it has less toxic side effects on mice.
This study demonstrated that p-CA could effectively inhibit the proliferation, migration and invasion of osteosarcoma cells and promote apoptosis. p-CA may play an anti-osteosarcoma role by inhibiting PI3K/Akt signaling pathway.
Yang B
，Wang B
，Wang G
，Cao W
，Wang Q
，Pu H
，An W
... -
《-》
ResearchGate
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钛学术
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