Stichoposide C Induces Apoptosis through the Generation of Ceramide in Leukemia and Colorectal Cancer Cells and Shows <i>In Vivo</i> Antitumor Activity

Yun, Seong-Hoon; Park, Eun-Seon; Shin, Sarah J.; Na, Yong-Woo; Han, Jin‐Yeong; Jeong, Jin–Sook; Shastina, Valeria V.; Stonik, Valentin A.; Park, Joo-In; Kwak, Jong‐Young

doi:10.1158/1078-0432.ccr-12-0655

Cited by 52 publications

(46 citation statements)

References 38 publications

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“…Moreover, under conditions where the classical apoptotic pathway fails, intracellular generation of ceramide may function as part of a backup system that enables caspase-independent programmed cell death (Taha et al, 2006). We demonstrated that STC induced apoptosis through the generation of ceramide by the activation of acid and neutral SMases (Yun et al, 2012). Therefore, the target of STC seems to be SMase leading to increases in ceramide and apoptosis.…”

Section: Stichoposidesmentioning

confidence: 97%

“…For example, glycosides from 19 species of the families Holothuriidae and Stichopodidae (the glycosides in majority belong to holothurin A and B series) inhibited the growth of Sarcoma-37 cells at in vitro concentrations ranging from 6.2 to 100 μg/ml (Kuznetsova et al, 1982). Although the anticancer mechanisms of the triterpene glycosides have not been investigated in detail, the biologic actions, structure-activity relationships, and molecular mechanisms of stichoposide C, frondoside A, and cucumariosides have been most intensively studied (Aminin et al, 2001; Jin et al, 2009; Yun et al, 2012; Yun, 2014) and are discussed in the following sections. In addition, the potential molecular mechanisms of other triterpene glycosides have been described.…”

Section: Anticancer Activities Of Marine Triterpene Glycosidesmentioning

confidence: 99%

“…The antitumor activity of STC appears to be related to its membranotropic effects (Kalinin et al, 2008). We previously reported that STC induced apoptosis of human leukemia and colorectal cancer cells through the activation of both intrinsic and extrinsic pathways (Yun et al, 2012). Anticancer agents increase ceramide levels, to variable extents, in all types of cancer cells (Taha et al, 2006).…”

Section: Stichoposidesmentioning

confidence: 99%

“…These results are consistent with the relative membranotropic activities of STC and STD, suggesting that their anticancer activities may be related to their membranotropic activities. More importantly, STC and STD did not have any toxicity in normal hematopoietic progenitor cells or in a mouse tumor model (Yun et al, 2012; Yun, 2014). …”

Section: Stichoposidesmentioning

confidence: 99%

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Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers

et al. 2014

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Many marine triterpene glycosides have in vitro and in vivo activities with very low toxicity, suggesting that they are suitable agents for the prevention and treatment of different diseases, particularly cancer. However, the molecular mechanisms of action of natural marine compounds in cancer, immune, and other various cells are not fully known. This review focuses on the structural characteristics of marine triterpene glycosides and how these affect their biological activities and molecular mechanisms. In particular, the membranotropic and membranolytic activities of frondoside A and cucumariosides from sea cucumbers and their ability to induce cytotoxicity and apoptosis have been discussed, with a focus on structure-activity relationships. In addition, the structural characteristics and antitumor effects of stichoposide C and stichoposide D have been reviewed along with underlying their molecular mechanisms.

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Section: Stichoposidesmentioning

confidence: 97%

Section: Anticancer Activities Of Marine Triterpene Glycosidesmentioning

confidence: 99%

Section: Stichoposidesmentioning

confidence: 99%

Section: Stichoposidesmentioning

confidence: 99%

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Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers

et al. 2014

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“…Treatment with stichoposide C from Thelenota anax induced apoptosis with activation of aSMase and nSMase in HL-60 cells (Yun et al, 2012). Resveratrol treatment increased expression of CerS and showed synergistic cytotoxicity with short chain ceramide, GCS inhibitor and SK1 inhibitor in K562 cells (Kartal et al, 2011).…”

Section: Role Of Sphingolipids and Metabolizing Enzymes In Hematologimentioning

confidence: 99%

Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies

Kitatani¹,

Taniguchi²,

Okazaki³

2015

Molecules and Cells

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Sphingolipids such as ceramide, sphingosine-1-phosphate and sphingomyelin have been emerging as bioactive lipids since ceramide was reported to play a role in human leukemia HL-60 cell differentiation and death. Recently, it is well-known that ceramide acts as an inducer of cell death, that sphingomyelin works as a regulator for microdomain function of the cell membrane, and that sphingosine-1-phosphate plays a role in cell survival/proliferation. The lipids are metabolized by the specific enzymes, and each metabolite could be again returned to the original form by the reverse action of the different enzyme or after a long journey of many metabolizing/synthesizing pathways. In addition, the metabolites may serve as reciprocal bio-modulators like the rheostat between ceramide and sphingosine-1-phosphate. Therefore, the change of lipid amount in the cells, the subcellular localization and the downstream signal in a specific subcellular organelle should be clarified to understand the pathobiological significance of sphingolipids when extracellular stimulation induces a diverse of cell functions such as cell death, proliferation and migration. In this review, we focus on how sphingolipids and their metabolizing enzymes cooperatively exert their function in proliferation, migration, autophagy and death of hematopoetic cells, and discuss the way developing a novel therapeutic device through the regulation of sphingolipids for effectively inhibiting cell proliferation and inducing cell death in hematological malignancies such as leukemia, malignant lymphoma and multiple myeloma.

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Sea cucumber extract TBL‐12 inhibits the proliferation, migration, and invasion of human prostate cancer cells through the p38 mitogen‐activated protein kinase and intrinsic caspase apoptosis pathway

et al. 2019

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Background: Sea cucumber is a kind of nutritious echinoderm that has multiple biological activities, including antioxidant, antibacterial, and antitumor activities.However, there is no extensive study on the antitumor effect of sea cucumber extract on prostate cancer (PCa). TBL-12 is a new sea cucumber extract. In this study, we investigated the in vivo anti-PCa effect of TBL-12 and its in vitro effects on the proliferation, apoptosis, migration, and invasion of the human PCa cell lines LNCaP, 22RV1, PC-3, and DU145, and evaluated its possible mechanisms. Methods: Cell proliferation was analyzed by cell counting kit-8 and colony formation assays. Scratch migration assay and transwell invasiveness assay were used to observe TBL-12 effect on the migration and invasion of PCa cells. Matrix metalloproteinase 2 (MMP-2) and MMP-9 expression and enzymatic activity was determined by Western blot analysis, quantitative reverse-transcription polymerase chain reaction, and gelatin zymography. Apoptosis level was detected by flow cytometry analysis. Western blot analysis was used to analyze p38 mitogen-activated protein kinase (MAPK) and apoptosis pathways. Angiogenic array analysis was used to explore autocrine and paracrine growth factors in PCa cell lines. Xenograft tumor model was built to observe the in vivo anticancer effect. Results: TBL-12 could significantly inhibit tumor growth in xenograft PCa mice in vivo, and dramatically inhibit the proliferation, colony formation, migration, and invasiveness of PCa cells in vitro (P < 0.05 and P < 0.001). The expression and enzyme activity of MMP-2 and MMP-9 were significantly suppressed by TBL-12 (P < 0.01), and decreased phosphorylation level of p38 in PCa cells was detected (P < 0.001). Furthermore, TBL-12 could reinforce the MMP-2/MMP-9 inhibitory effect of SB203580, a specific inhibitor of the p38 MAPK pathway (P < 0.05). Besides, TBL-12 could induce the apoptosis of PCa cells by activating caspase-9, caspase-7, and poly(ADP-ribose) polymerase and suppressing survivin, and inhibit The Prostate. 2019;79:826-839. wileyonlinelibrary.com/journal/pros 826 | 1 Yuan and Huang contributed equally to this study. the secretion of angiogenin, angiopoietin-2, and vascular endothelial growth factor in PCa cells. Conclusions: Sea cucumber extract TBL-12 could suppress the proliferation and metastasis of human PCa cells by inhibiting MMP-2 and MMP-9 via blocking the p38 MAPK pathway, inducing apoptosis through intrinsic caspase apoptosis pathway and inhibiting the secretion of angiogenic factors. Our findings may be of importance and significance for the research and clinical applications of sea cucumber extract in PCa treatment. K E Y W O R D S apoptosis, matrix metalloproteinases, prostate cancer, sea cucumber extract, tumor metastasis SUPPORTING INFORMATION Additional supporting information may be found online in the Supporting Information section at the end of the article. How to cite this article: Yuan L, Huang X, Zhou K, et al. Sea cucumber extract TBL-12 inhibits the proliferatio...

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Stichoposide C Induces Apoptosis through the Generation of Ceramide in Leukemia and Colorectal Cancer Cells and Shows In Vivo Antitumor Activity

Cited by 52 publications

References 38 publications

Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers

Relationships between chemical structures and functions of triterpene glycosides isolated from sea cucumbers

Role of Sphingolipids and Metabolizing Enzymes in Hematological Malignancies

Sea cucumber extract TBL‐12 inhibits the proliferation, migration, and invasion of human prostate cancer cells through the p38 mitogen‐activated protein kinase and intrinsic caspase apoptosis pathway

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