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Cytotoxic and Pro-Apoptotic Effects of Cassane Diterpenoids from the Seeds of Caesalpinia sappan in Cancer Cells.

ABSTRACT: The chemical study on the seeds of Caesalpinia sappan led to the isolation of five new cassane diterpenoids, phanginins R?T (1-3) and caesalsappanins M and N (4 and 5), together with seven known compounds 6-12. Their structures were elucidated on the basis of NMR and HRESIMS analyses. The absolute configurations of compounds 1 and 4 were determined by the corresponding CD spectra. All the isolated compounds were tested for their cytotoxicity against ovarian cancer A2780 and HEY, gastric cancer AGS, and non-small cell lung cancer A549 cells. Compound 1 displayed significant toxicity against the four cell lines with the IC50 values of 9.9 ± 1.6 µM, 12.2 ± 6.5 µM, 5.3 ± 1.9 µM, and 12.3 ± 3.1 µM, respectively. Compound 1 induced G1 phase cell cycle arrest in A2780 cells. Furthermore, compound 1 dose-dependently induced A2780 cells apoptosis as evidenced by Hoechst 33342 staining, Annexin V positive cells, the up-regulated cleaved-PARP and the enhanced Bax/Bcl-2 ratio. What's more, compound 1 also promoted the expression of the tumor suppressor p53 protein. These findings indicate that cassane diterpenoids might have potential as anti-cancer agents, and further in vivo animal studies and structural modification investigation are needed.

SUBMITTER: Bao H

PROVIDER: S-EPMC6274183 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Cytotoxic and Pro-Apoptotic Effects of Cassane Diterpenoids from the Seeds of Caesalpinia sappan in Cancer Cells.

Bao Han H Zhang Le-Le LL Liu Qian-Yu QY Feng Lu L Ye Yang Y Lu Jin-Jian JJ Lin Li-Gen LG

Molecules (Basel, Switzerland) 20160618 6

The chemical study on the seeds of Caesalpinia sappan led to the isolation of five new cassane diterpenoids, phanginins R‒T (1-3) and caesalsappanins M and N (4 and 5), together with seven known compounds 6-12. Their structures were elucidated on the basis of NMR and HRESIMS analyses. The absolute configurations of compounds 1 and 4 were determined by the corresponding CD spectra. All the isolated compounds were tested for their cytotoxicity against ovarian cancer A2780 and HEY, gastric cancer A ...[more]

PMID: 27322234

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Project description:ObjectiveTo evaluate the anti-cancer properties of Caesalpinia sappan and Ficus septica in combination with doxorubicin on 4T1 cells, confirm their nephroprotective activities, and predict the molecular targets of the underlying mechanisms.MethodsThe cytotoxic activities of all extracts and doxorubicin were determined by MTT assay followed by cell cycle and apoptosis analysis using flow cytometry. Immunoblotting was used to determine the protein expressions. The proteins involved in the cell proliferation and migration were analyzed through bioinformatics approaches, whereas, the interaction between compounds and protein targets was observed through molecular docking. Furthermore, the effect of the extracts on cell migration was analyzed by scratch wound healing assay. The intracellular ROS after treatment with extracts was observed using DCFDA staining flow cytometry.ResultsBoth ECS and EFS performed cytotoxic properties and significantly enhanced doxorubicin's cytotoxic effects against 4T1 cells. However, these cytotoxic activities did not correlate with the cell cycle progression. On the contrary, the combination treatment caused apoptosis that may correlate with the decreasing of IκBα phosphorylation, indicating that all agents targeted the inhibition of NF-κB activation. The combination treatments also inhibited cell migration and decreased MMP-9 expression. TNBC proliferation and metastasis needed at least 54 proteins to be activated, some of them are related to NF-κB activation. The inhibitory effect of ECS correlated with the interaction of brazilin and brazilein to IKK, a kinase protein that plays a role in IκBα phosphorylation. In addition, ECS and EFS reduced ROS expression in Vero cells caused by doxorubicin.ConclusionIn conclusion, ECS and EFS effectively enhanced the cytotoxic effect of doxorubicin and inhibit cell migration on 4T1 cells and these activities may correlate to the inhibitory effect of NF-κB activation. ECS and EFS also exhibit ROS suppressing effect on Vero cells that may be beneficent to reduce nephrotoxicity of chemotherapeutic treatment.

Project description:Ethnopharmacological relevanceCaesalpinia sappan is a common remedy in Traditional Chinese Medicine and possesses diverse biological activities including anti-inflammatory properties. Osteoarthritis (OA) is a degenerative joint disease with an inflammatory component that drives the degradation of cartilage extracellular matrix. In order to provide a scientific basis for the applicability of Caesalpinia sappan in arthritic diseases, the present study aimed to assess the effects of an ethanolic Caesalpinia sappan extract (CSE) on human chondrocytes and macrophages.Materials and methodsPrimary human chondrocytes were isolated from cartilage specimens of OA patients. Primary cells, SW1353 chondrocytes and THP-1 macrophages were serum-starved and pretreated with different concentrations of CSE prior to stimulation with 10 ng/ml of interleukin-1beta (IL-1?) or lipopolysaccharide (LPS). Following viability tests, nitric oxide (NO) and tumor necrosis factor-alpha (TNF-?) were evaluated by Griess assay and ELISA, respectively. Using validated real-time PCR assays, mRNA levels of IL-1?, TNF-?, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were quantified. SW1353 cells were cotransfected with a COX-2 luciferase reporter plasmid and nuclear factor-kappa-B (NF-?B) p50 and p65 expression vectors in the presence or absence of CSE.ResultsCSE dose-dependently inhibited the expression of pro-inflammatory cytokines IL-1? and TNF-? in IL-1?-stimulated chondrocytes and LPS-stimulated THP-1 macrophages. CSE further suppressed the synthesis of NO in primary OA chondrocytes by blocking iNOS mRNA expression. The inhibition of COX-2 transcription was found to be related with the CSE inhibition of the p65/p50-driven transactivation of the COX-2 promoter.ConclusionsThe present report is first to demonstrate the anti-inflammatory activity of CSE in an in vitro cell model of joint inflammation. CSE can effectively abrogate the IL-1?-induced over-expression of inflammatory mediators at the transcriptional level in human chondrocytes and macrophages, most likely by inhibiting NF-?B (p65/p50) signaling. Blockade of IL-1?-induced NF-?B signaling and its downstream pro-inflammatory targets by CSE may be beneficial for reducing cartilage breakdown in arthritis.

Dataset Information

Cytotoxic and Pro-Apoptotic Effects of Cassane Diterpenoids from the Seeds of Caesalpinia sappan in Cancer Cells.

Publications

Cytotoxic and Pro-Apoptotic Effects of Cassane Diterpenoids from the Seeds of Caesalpinia sappan in Cancer Cells.

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