Category Archives: T24

Akt, Anti-cancer, anti-inflammatory, anti-proliferative, AP-1, apoptosis, Apoptotic, B16F10, BGC-803, Breast cancer, c-Jun, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, chemo-prevention, chemo-preventive, Chemo-preventive agent, chemo-sensitizing, Chemoprevention, Colon Cancer or Colorectal cancer, COX-2, COX-2 inhibitor, Cytostatic, cytostatic effect, cytotoxic, Esophageal cancer, FasL, G0/G1, G1, G2/M, Gastric cancer or Stomach cancer, H22, HL-60, HT-29, Hyptis capitata, IL-1, induces apoptosis, inhibits proliferation, JNK, Lung cancer, MCF-7, MDA-MB-231, MMP2, NAD(P)H, p65, PC3, Prostate cancer, Prunella vulgaris, Psychotria serpens, Rectal cancer, ROS, Rosmarinus officinalis, S, Salvia officinalis, T24, u-PA, YES-2

Ursolic acid

Cancer:
Glioblastoma, Lung, breast, colorectal, gastric, esophageal squamous carcinoma, prostate

Action:

Mitochondrial function, reactive oxygen species (ROS) generation.

Cytostatic, anti-inflammatory, chemo-prevention, COX-2 inhibitor, suppresses NF- κ B, induces IL-1 β , induces apoptosis

Ursolic acid, a pentacyclic triterpene acid found ubiquitously in the plant kingdom, including Rosmarinus officinalis (L.), Salvia officinalis (L.), Prunella vulgaris (L.), Psychotria serpens (L.) and Hyptis capitata (Jacq.). It has been shown to suppress the expression of several genes associated with tumorigenesis resulting in anti-inflammatory, anti-tumorigenic and chemo-sensitizing effects (Liu, 1995).

Glioblastoma Cancer

Ursolic acid, a natural pentacyclic triterpenic acid, possesses anticancer potential and diverse biological effects, but its correlation with glioblastoma multiforme cells and different modes of cell death is unclear. We studied the cellular actions of human GBM DBTRG-05MG cells after ursolic acid treatment and explored cell-selective killing effect of necrotic death as a cell fate.

Ursolic acid effectively reversed TMZ resistance and reduced DBTRG-05MG cell viability. Surprisingly, ursolic acid failed to stimulate the apoptotic and autophagic-related signaling networks. The necrotic death was characterized by annexin V/PI double-positive detection and release of HMGB1 and LDH. These ursolic acid-elicited responses were accompanied by ROS generation and glutathione depletion. Rapid mitochondrial dysfunction was paralleled by the preferential induction of necrosis, rather than apoptotic death. MPT is a phenomenon to provide the onset of mitochondrial depolarization during cellular necrosis. The opening of MPT pores that were mechanistically regulated by CypD, and ATP decline occurred in treated necrotic DBTRG-05MG cells. Cyclosporine A (an MPT pore inhibitor) prevented ursolic acid-provoked necrotic death and -involved key regulators.

The study by Lu et al., (2014) is the first to report that ursolic acid-modified mitochondrial function triggers defective death by necrosis in DBTRG-05MG cells rather than augmenting programmed death.

Gastric Cancer

Ursolic acid (UA) inhibits growth of BGC-803 cells in vitro in dose-dependent and time-dependent manner. Treated with UA in vivo, tumor cells can be arrested to G0/G1 stage. The apoptotic rate was significantly increased in tumor cells treated with UA both in vitro and in vivo. These results indicated that UA inhibits growth of tumor cells both in vitro and in vivo by decreasing proliferation of cells and inducing apoptosis (Wang et al., 2011).

Esophageal Squamous Carcinoma

The anti-neoplastic effects of combinations of anti-cancer drugs (5-fluorouracil, irinotecan and cisplatin) and triterpenes (ursolic acid, betulinic acid, oleanolic acid and a Japanese apricot extract (JAE) containing triterpenes) on esophageal squamous carcinoma cells were examined by the WST-8 (2-(2-methoxy- 4-nitrophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium, monosodium salt) assay in vitro and by an animal model in vivo. Triterpenes and JAE showed additive and synergistic cytotoxic effects, respectively, on esophageal squamous carcinoma cells (YES-2 cells) by combinational use of 5-fluorouracil. JAE and 5-fluorouracil induced cell-cycle arrest at G2/M phase and at S phase, respectively, and caused apoptosis in YES-2 cells.

These results suggest that triterpenes, especially JAE, are effective supplements for enhancing the chemotherapeutic effect of 5-fluorouracil on esophageal cancer (Yamai et al., 2009).

COX-2 Inhibitor

Subbaramaiah et al. (2000) studied the effects of ursolic acid, a chemo-preventive agent, on the expression of cyclooxygenase-2 (COX-2). Treatment with ursolic acid suppressed phorbol 12-myristate 13-acetate (PMA)-mediated induction of COX-2 protein and synthesis of prostaglandin E2. Ursolic acid also suppressed the induction of COX-2 mRNA by PMA. Increased activator protein-1 activity and the binding of c-Jun to the cyclic AMP response element of the COX-2 promoter, effects were blocked by ursolic acid (Subbaramaiah et al., 2000).

Lung Cancer, Suppresses NF- κB

In terms of general anti-cancer mechanism, ursolic acid has also been found to suppress NF-κB activation induced by various carcinogens through the inhibition of the DNA binding of NF-κB. Ursolic acid also inhibits IκBα kinase and p65 phosphorylation (Shishodia et al., 2003). In particular, ursolic acid has been found to block cell-cycle progression and trigger apoptosis in lung cancer and may hence act as a chemoprevention agent for lung cancer (Hsu et al., 2004).

Breast Cancer

Ursolic acid is a potent inhibitor of MCF-7 cell proliferation. This triterpene exhibits both cytostatic and cytotoxic activity. It exerts an early cytostatic effect at G1 followed by cell death. Results suggest that alterations in cell-cycle phase redistribution of MCF-7 human breast cancer, by ursolic acid, may significantly influence MTT (colorimetric assays) reduction to formazan (Es-Saady et al., 1996).

Induces IL-1 β

Interleukin (IL)-1beta is a pro-inflammatory cytokine responsible for the onset of a broad range of diseases, such as inflammatory bowel disease and rheumatoid arthritis. It has recently been found that aggregated ursolic acid (UA), a triterpene carboxylic acid, is recognized by CD36 for generating reactive oxygen species (ROS) via NADPH oxidase (NOX) activation, thereby releasing IL-1beta protein from murine peritoneal macrophages (pMphi) in female ICR mice. In the present study, Ikeda et al. (2008) investigated the ability of UA to induce IL-1beta production in pMphi from 4 different strains of female mice as well as an established macrophage line. In addition, the different susceptibilities to UA-induced IL-1beta release were suggested to be correlated with the amount of superoxide anion (O2-) generated from the 5 different types of Mphi.

Notably, intracellular, but not extracellular, O2- generation was indicated to play a major role in UA-induced IL-1beta release. Together, these results indicate that the UA-induced IL-1beta release was strain-dependent, and the expression status of CD36 and gp91phox is strongly associated with inducibility.

Induces Apoptosis: Breast Cancer, Prostate Cancer

Ursolic acid (UA) induced apoptosis and modulated glucocorticoid receptor (GR) and Activator Protein-1 (AP-1) in MCF-7 breast cancer cells. UA is a GR modulator and may be considered as a potential anti-cancer agent in breast cancer (Kassi et al., 2009).

UA induces apoptosis via both extrinsic and intrinsic signaling pathways in cancer cells (Kwon et al., 2010). In PC-3 cells, UA inhibits proliferation by activating caspase-9 and JNK as well as FasL activation and Akt inhibition (Zhang et al., 2010). A significant proliferation inhibition and invasion suppression in both a dose- and time-dependent manner is observed in highly metastatic breast cancer MDA-MB-231 cells; this inhibition is related to the down-regulation of MMP2 and u-PA expression (Yeh et al., 2010).

Ursolic acid additionally stimulates the release of cytochrome C in HL-60 cells and breast cancer MCF-7 cells. The activation of caspase-3 in a cytochrome C-dependent manner induces apoptosis via the mitochondrial pathway (Qian et al., 2011).

Colorectal Cancer

Ursolic acid (UA) has strong anti-proliferative and apoptotic effects on human colon cancer HT-29 cells. UA dose-dependently decreased cell proliferation and induced apoptosis, accompanied by activation of caspase 3, 8 and 9. The effects may be mediated by alkaline sphingomyelinase activation (Andersson et al., 2003).

Ursolic acid (UA), using the colorectal cancer (CRC) mouse xenograft model and the HT-29 human colon carcinoma cell line, was evaluated for its efficacy against tumor growth in vivo and in vitro, and its molecular mechanisms were investigated. It was found that UA inhibits cancer growth without apparent toxicity. Furthermore, UA significantly suppresses the activation of several CRC-related signaling pathways and alters the expression of critical target genes. These molecular effects lead to the induction of apoptosis and inhibition of cellular proliferation.

These data demonstrate that UA possesses a broad range of anti-cancer activities due to its ability to affect multiple intracellular targets, suggesting that UA could be a novel multipotent therapeutic agent for cancer treatment (Lin et al., 2013).

Action: Anti-tumor, inhibits tumor cell migration and invasion

Ursolic acid (UA) is a sort of pentacyclic triterpenoid carboxylic acid purified from natural plant. UA has a series of biological effects such as sedative, anti-inflammatory, anti-bacterial, anti-diabetic, antiulcer, etc. It is discovered that UA has a broad-spectrum anti-tumor effect in recent years, which has attracted more and more scholars’ attention. This review explained anti-tumor actions of UA, including (1) the protection of cells’ DNA from different damages; (2) the anti-tumor cell proliferation by the inhibition of epidermal growth factor receptor mitogen-activated protein kinase signal or of FoxM1 transcription factors, respectively; (3) antiangiogenesis, (4) the immunological surveillance to tumors; (5) the inhibition of tumor cell migration and invasion; (6) the effect of UA on caspase, cytochromes C, nuclear factor kappa B, cyclooxygenase, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or mammalian target of rapamycin signal to induce tumor cell apoptosis respectively, and etc. Moreover, UA has selective toxicity to tumor cells, basically no effect on normal cells.

Inhibition of Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Pathway
Activation of mitogen-activated protein kinase (MAPK) allows cell excessive proliferation involved in the carcinogenic process (Park et al., 1999). Subfamilies of MAPK, metastasis.(24) Otherwise, UA suppresses the activation of NF-κB and down-regulation of the MMP-9 protein, which in turn contributes to its inhibitory effects on IL-1β or tumor necrosis factor α (TNF-α)-induced C6 glioma cell invasion (Huang et al., 2009).

U A suppresses inter cellular adhesion molecules-1 (ICAM-1) expression of non-small cell lung cancer (NSCLC) H3255, A549, Calu-6 cells, and significantly inhibits fibronectin expression in a concentration-dependent way. UA significantly suppresses the expression of MMP-9 and MMP-2 and inhibits protein kinase C activity in test cell lines, at the same time, UA reduces cell invasion in a concentration-dependent manner (Huang et al., 2011).

Cancer: Multiple myeloma

Action: Anti-inflammatory, down-regulates STAT3

When dealing with the multiple myeloma, by the way of activating the proto-oncogene-mediated c-Src, JAK1, JAK2, and ERKs, ursolic acid (UA) can not only inhibit the expression of IL-6-induced STAT3 but also downregulates the STAT3 by regulating gene products, such as cyclin D1, Bcl-2, Bcl-xL, surviving, Mcl-1 and VEGF. Above all, UA can inhibit the proliferation of multiple myeloma cells and induce apoptosis, to arrest cells at G1 phase and G0 phase of cell cycle (Pathak et al., 2007).

The essential oils of ginger (Zingiber officinale) and turmeric (Curcuma longa) contain a large variety of terpenoids, some of which possess anticancer, anti-ulcer, and antioxidant properties. Despite their importance, only four terpene synthases have been identified from the Zingiberaceae family: (+)-germacrene D synthase and (S)-β-bisabolene synthase from ginger rhizome, and α-humulene synthase and β-eudesmol synthase from shampoo ginger (Zingiber zerumbet) rhizome (Koo et al., 2012).

Cancer: Colorectal

Wong et al., have previously reported Signal Transducer and Activator of Transcription 3 (STAT3) to be constitutively activated in aldehyde dehydrogenase (ALDH)(+)/cluster of differentiation-133 (CD133)(+) colon cancer-initiating cells. In the present study they tested the efficacy of inhibiting STAT3 signaling in human colon cancer-initiating cells by ursolic acid (UA), which exists widely in fruits and herbs.

ALDH(+)/CD133(+) colon cancer-initiating cells. UA also reduced cell viability and inhibited tumor sphere formation of colon cancer-initiating cells, more potently than two other natural compounds, resveratrol and capsaicin. UA also inhibited the activation of STAT3 induced by interleukin-6 in DLD-1 colon cancer cells. Furthermore, daily administration of UA suppressed HCT116 tumor growth in mice in vivo.

Their results suggest STAT3 to be a target for colon cancer prevention. UA, a dietary agent, might offer an effective approach for colorectal carcinoma prevention by inhibiting persistently activated STAT3 in cancer stem cells.

References

 

Andersson D, Liu JJ, Nilsson A, Duan RD. (2003). Ursolic acid inhibits proliferation and stimulates apoptosis in HT29 cells following activation of alkaline sphingomyelinase. Anti-cancer Research, 23(4):3317-22.

 

Es-Saady D, Simon A, Jayat-Vignoles C, Chulia AJ, Delage C. (1996). MCF-7 cell-cycle arrested at G1 through ursolic acid, and increased reduction of tetrazolium salts. Anti-cancer Research, 16(1):481-6.

 

Hsu YL, Kuo PL, Lin CC. (2004). Proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small-cell lung cancer A549 cells. Life Sciences, 75(19), 2303-2316.

 

Ikeda Y, Murakami A, Ohigashi H. (2008). Strain differences regarding susceptibility to ursolic acid-induced interleukin-1beta release in murine macrophages. Life Sci, 83(1-2):43-9. doi: 10.1016/j.lfs.2008.05.001.

 

Kassi E, Sourlingas TG, Spiliotaki M, et al. (2009). Ursolic Acid Triggers Apoptosis and Bcl-2 Down-regulation in MCF-7 Breast Cancer Cells. Cancer Investigation, 27(7):723-733. doi:10.1080/07357900802672712.

 

Kwon SH, Park HY, Kim JY, et al. (2010). Apoptotic action of ursolic acid isolated from Corni fructus in RC-58T/h/SA#4 primary human prostate cancer cells. Bioorg Med Chem Lett, 20:6435–6438. doi: 10.1016/j.bmcl.2010.09.073.

 

Lin J, Chen Y, Wei L, et al. (2013). Ursolic acid promotes colorectal cancer cell apoptosis and inhibits cell proliferation via modulation of multiple signaling pathways. Int J Oncol, (4):1235-43. doi: 10.3892/ijo.2013.2040.

 

Liu J. (1995). Pharmacology of oleanolic acid and ursolic acid. Journal of Ethnopharmacology, 49(2), 57-68.

 

Shishodia S, Majumdar S, Banerjee S, Aggarwal BB. (2003). Ursolic Acid Inhibits Nuclear Factor-OE ∫ B Activation Induced by Carcinogenic Agents through Suppression of IOE ∫ BOE± Kinase and p65 Phosphorylation. Cancer Research, 63(15), 4375-4383.

 

Subbaramaiah K, Michaluart P, Sporn MB, Dannenberg AJ. (2000). Ursolic Acid Inhibits Cyclooxygenase-2 Transcription in Human Mammary Epithelial Cells. Cancer Res, 60:2399

 

Qian J, Li X, Guo GY, et al. (2011). Potent anti-tumor activity of emodin on CNE cells in vitro through apoptosis. J Zhejiang Sci-Tech Univ (Chin), 42:756-759

 

Wang X, Zhang F, Yang L, et al. (2011). Ursolic Acid Inhibits Proliferation and Induces Apoptosis of Cancer Cells In Vitro and In Vivo. J Biomed Biotechnol, 2011:419343. doi: 10.1155/2011/419343.

 

Yamai H, et al. (2009). Triterpenes augment the inhibitory effects of anti-cancer drugs on growth of human esophageal carcinoma cells in vitro and suppress experimental metastasis in vivo. Int J Cancer, 125(4):952-60. doi: 10.1002/ijc.24433.

 

Yeh CT, Wu CH, Yen GC. (2010). Ursolic acid, a naturally occurring triterpenoid, suppresses migration and invasion of human breast cancer cells by modulating c-Jun N-terminal kinase, Akt and mammalian target of rapamycin signaling. Mol Nutr Food Res, 54:1285–1295. doi: 10.1002/mnfr.200900414.

 

Zhang Y, Kong C, Zeng Y, et al. (2010). Ursolic acid induces PC-3 cell apoptosis via activation of JNK and inhibition of Akt pathways in vitro. Mol Carcinog, 49:374–385.

 

Zhang LL, Wu BN, Lin Y et al. (2014) Research Progress of Ursolic Acid’s Anti-Tumor Actions. Chin J Integr Med 2014 Jan;20(1):72-79

 

Reference

 

Huang HC, Huang CY, Lin-Shiau SY, Lin JK. Ursolic acid inhibits IL-1beta or TNF-alpha-induced C6 glioma invasion through suppressing the association ZIP/p62 with PKC-zeta and downregulating the MMP-9 expression. Mol Carcinog 2009;48:517-531

 

Huang CY, Lin CY, Tsai CW, Yin MC. Inhibition of cell proliferation, invasion and migration by ursolic acid in human lung cancer cell lines. Toxicol In Vitro 2011;25:1274-1280.

 

Park KS, Kim NG, Kim JJ, Kim H, Ahn YH, Choi KY. Differential regulation of MAP kinase cascade in human colorectal tumorigenesis. Br J Cancer 1999;81:1116-1121.

 

 

Pathak AK, Bhutani M, Nair AS, Ahn KS, Chakraborty A, Kadara H, et al. Ursolic acid inhibits STAT3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells. Mol Cancer Res 2007;5:943-595

 

 

Koo HJ, Gang DR. (2012) Suites of terpene synthases explain differential terpenoid production in ginger and turmeric tissues. PLoS One. 2012;7(12):e51481. doi: 10.1371/journal.pone.0051481.

 

 

Wang W, Zhao C, Jou D, Lü J, Zhang C, Lin L, Lin J. (2013) Ursolic acid inhibits the growth of colon cancer-initiating cells by targeting STAT3. Anticancer Res. 2013 Oct;33(10):4279-84.

 
Lu C-C, Huang B-R, Liao P-J, Yen G-C. Ursolic acid triggers a non-programmed death (necrosis) in human glioblastoma multiforme DBTRG-05MG cells through MPT pore opening and ATP decline. Molecular Nutrition & Food Research. 2014 DOI: 10.1002/mnfr.201400051

 

 

 

A549, LL/2, Akt, angiogenesis, Anti-cancer, anti-tumor, anti-tumor activity, apoptosis, apoptosis-inducing, Apoptotic, BAX, Bcl-2, c-Myc, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Cortex periplocae, Cytostatic, cytostatic effect, cytotoxic, ERK, G0/G1, G1, HeLa, K562, Lung cancer, MCF-7, PC3, Pro-apoptotic, QG-56, SMMC-7721, SW480, T24, TE-13, Eca-109, TRAIL, U937

Periplocin

Cancer: Lung, colorectal, leukemia

Action: Apoptosis-inducing, cytostatic effect

Apoptosis

The anti-tumor component of Cortex periplocae is periplocin. Periplocin is one of the cardenolides isolated from cortex periplocae which is used for treatment of rheumatoid arthritis and reinforcement of bones and tendons in traditional medicine.

Periplocin has been reported to inhibit many cell lines, including MCF-7, TE-13, QG-56, SMMC-7721, T24, Hela, K562, TE-13 and Eca-109 cells. Studies have shown that periplocin reduces the expression of survivin, an inhibitor of apoptosis. It also releases caspases-3 and -7 from complexes and thereby increases their activities, ultimately inducing tumor cell apoptosis (Zhao et al., 2009).

Lung Cancer

The anti-tumor activity of periplocin was investigated in lung cancer cells both in vitro and in vivo, and its anti-cancer mechanism was explored. Periplocin inhibited the growth of lung cancer cells and induced their apoptosis in a time- and dose-dependent manner by cell-cycle arrest in G0/G1 phase. Periplocin exhibited anti-tumor activity both in human (A549) and mouse (LL/2) lung cancer xenograft models. Immunohistochemical analysis revealed that intratumoral angiogenesis was significantly suppressed.

Furthermore, anti-cancer activity mediated by periplocin was associated with decreased level of phosphorylated AKT and ERK both in vitro and in vivo, which are important for cell growth and survival. Moreover, periplocin induced apoptosis by down-regulating Bcl-2 and up-regulating Bax, leading to activation of caspase-3 and caspase-9.

These findings suggest that periplocin could inhibit the growth of lung cancer both in vitro and in vivo, which could be attributed to the inhibition of proliferation and the induction of apoptosis signaling pathways, such as AKT and ERK. These observations provide further evidence on the anti-tumor effect of periplocin, and it may be of importance to further explore its potential role as a therapeutic agent for cancer (Lu et al., 2010).

Colorectal Carcinomas

The Wnt/beta-catenin signaling pathway plays an important role in the development and progression of human cancers, especially in colorectal carcinomas. Periplocin extracted from cortex periplocae (CPP) significantly inhibited the proliferation of SW480 cells in a time-and dose-dependent manner (P<0.01). CPP (0.5 microg/mL) also caused G0/G1 cell-cycle arrest of SW480 cells and induced cell apoptosis (P<0.05). Compared to untreated control cells, after the treatment with CPP, the protein levels of beta-catenin in total cell lysates, cytosolic extracts, and nuclear extracts were reduced (P<0.01); the binding activity of the TCF complex in nucleus to its specific DNA binding site was suppressed; mRNAs of the downstream target genes survivin, c-myc and cyclin D1 were decreased (P<0.01) while beta-catenin mRNA remained unchanged.

CPP could significantly inhibit the proliferation of SW480 cells, which may be through down-regulating the Wnt/beta-catenin signaling pathway (Du et al., 2009).

Pro-apoptotic and Cytostatic Effect/Leukemia

Cardenoliddes are steroid glycosides which are known to exert cardiotonic effects by inhibiting the Na(+)/K(+)-ATPase. Several of these compounds have been shown also to possess anti-tumor potential. The aim of the present work was the characterization of the tumor cell growth inhibition activity of four cardenolides, isolated from Periploca graeca L., and the mechanisms underlying such an effect.

The pro-apoptotic and cytostatic effect of the compounds was tested in U937 (monocytic leukemia) and PC3 (prostate adenocarcinoma). Characterization of apoptosis and cell-cycle impairment was obtained by cytofluorimetry and WB. Periplocymarin and periplocin were the most active compounds, periplocymarin being more effective than the reference compound ouabain. The reduction of cell number by these two cardenolides was due in PC3 cells mainly to the activation of caspase-dependent apoptotic pathways, while in U937 cells to the induction of cell-cycle impairment without extensive cell death. Interestingly, periplocymarin, at cytostatic but non-cytotoxic doses, was shown to sensitize U937 cells to TRAIL. Taken together, these data outline that cardiac glycosides are promising anti-cancer drugs and contribute to the identification of new natural cardiac glycosides to obtain chemically modified non-cardioactive/low toxic derivatives with enhanced anti-cancer potency (Bloise et al., 2009).

References

Bloise E, Braca A, De Tommasi N, Belisario MA. (2009). Pro-apoptotic and cytostatic activity of naturally occurring cardenolides. Cancer Chemother Pharmacol, 64(4):793-802. doi: 10.1007/s00280-009-0929-5.


Du YY, Liu X, Shan BE. (2009). Periplocin extracted from cortex periplocae induces apoptosis of SW480 cells through inhibiting the Wnt/beta-catenin signaling pathway. Ai Zheng, 28(5):456-60.


Lu ZJ, Zhou Y, Song Q, et al. (2010). Periplocin inhibits growth of lung cancer in vitro and in vivo by blocking AKT/ERK signaling pathways. Cell Physiol Biochem, 26(4-5):609-18. doi: 10.1159/000322328.


Zhao LM, Ai J, Zhang Q, et al. (2009). Periplocin (a sort of ethanol from Cortex periplocae) induces apoptosis of esophageal carcinoma cells by influencing expression of related genes. Tumor (Chin), 29:1025-1030.

ABC, Anti-cancer, anti-inflammatory, anti-metastasis, Anti-metastatic, anti-oxidant, anti-proliferative, apoptosis, apoptosis induction, apoptosis-inducing, Apoptotic, BAX, Bcl-2, Bladder cancer, Breast cancer, c-Fos, c-Jun, CDC2, CDC25A, CDC25C, cell-cycle arrest, Chapter 7 Isolates and Cancer Research, Chemoprevention, ER, ERK1, G1, G2/M, hTERT, JNK, Lung cancer, lymphangiogenesis inhibitor, lymphangiogenesis inhibitors, MCF-7, MCF-7, MDA-MB-231, MDA-MB-231, MDR, metastasis, MPSC1 (PT), A2780 (PT) and SKOV3 (PT), Nausea and Vomiting, NFATc1, Ovarian cancer, p21, p38, p53, PARP, Pro-apoptotic, pro-oxidative, Prostate cancer, ROS, S, Sarcoma, T24, TIMP-2, TNF

Costunolide and Dehydrocostus Lactone

Cancers:
Breast, cervical., lung, ovarian, bladder, leukemia, prostate, gastric

Action: Anti-inflammatory, pro-oxidative, MDR, lymphangiogenesis inhibitor, anti-metastasis, mediates apoptosis, anti-metastatic

Components of Saussurea lappa Clarke, Vladimiria souliei (Franchet) Lingelsheim (Compositae)

Breast cancer; Anti-metastatic

It was found that costunolide inhibited the growth and telomerase activity of MCF-7 and MDA-MB-231 cells in a concentration- and time-dependent manner. The expression of hTERT mRNA was also inhibited but hTR mRNA was not. In addition, the bindings of transcription factors in hTERT promoters were significantly decreased in both cells by the treatment of costunolide. These results suggest that costunolide inhibited the growth of both MCF-7 and MDA-MB-231 cells and this effect was mediated at least in part by a significant reduction in telomerase activity (Choi et al., 2005).

Breast Cancer

Costunolide has been demonstrated to suppress tumor growth and metastases of MDA-MB-231 highly metastatic human breast cancer cells via inhibiting TNF-α induced NF-kB activation. Costunolide also inhibited MDA-MB-231 tumor growth and metastases without affecting body weights in the in vivo mouse orthotopic tumor growth assays.

In addition, costunolide inhibited in vitro TNF-α induced invasion and migration of MDA-MB-231 cells. Costunolide further suppressed TNF-α induced NF-kB signaling activation, resulting in a reduced expression of MMP-9, a well-known NF-kB-dependent gene to mediate breast cancer cell growth and metastases. Taken together, these results suggest that SLC and its derivative costunolide suppress breast cancer growth and metastases by inhibiting TNF-α induced NF-k B activation, suggesting that costunolide as well as SLC may be promising anti-cancer drugs, especially for metastatic breast cancer (Choi et al., 2013).

Several Chinese herbs, namely, Herba Taraxaci Mongolici (Pu Gong Ying), Radix Glycyrrhizae Uralensis (Gan Cao), Radix Bupleuri (Chai Hu), Radix Aucklandiae Lappae/ Radix Aucklandiae Lappae (Mu Xiang), Fructus Trichosanthis (Gua Lou) and Rhizoma Dioscoreae Bulbiferae (Huang Yao Zi) are frequently used in complex traditional Chinese medicine formulas for breast hyperplasia and breast tumor therapy.

The pharmacological effects of these Chinese herbs are all described as 'clearing heat-toxin and resolving masses' in traditional use. A bioactivity-oriented screening platform, which was based on a human breast cancer MCF-7 cellular model was developed to rapidly screen the 6 Chinese herbs. Two potential anti-breast cancer compounds, which were costunolide (Cos) and dehydrocostus lactone (Dehy), were identified in Radix Aucklandiae Lappae.

Combination of the two compounds showed a synergism on inhibiting the proliferation of MCF-7 cells in vitro, which exhibits a potential application prospect for breast cancer therapy. This bioactivity-oriented screening strategy is rapid, economical., reliable and specific for screening potential anti-breast cancer compounds in traditional Chinese medicines (Peng et al., 2013).

Dehydrocostuslactone (DHE) suppresses the expression of cyclin D, cyclin A, cyclin-dependent kinase 2, and cdc25A and increases the amount of p53 and p21, resulting in G(0)/G(1)-S phase arrest in MCF-7 cells. In contrast, DHE caused S-G(2)/M arrest by increasing p21 expression and chk1 activation and inhibiting cyclin A, cyclin B, cdc25A, and cdc25C expression in MDA-MB-231 cells. Reduction of SOCS-1 and SOCS-3 expression by small interfering RNA inhibits DHE-mediated signal transducer and activator of transcription-3 inhibition, p21 up-regulation, and cyclin-dependent kinase 2 blockade, supporting the hypothesis that DHE inhibits cell-cycle progression and cell death through SOCS-1 and SOCS-3.

Significantly, animal studies have revealed a 50% reduction in tumor volume after a 45-day treatment period. Taken together, this study provides new insights into the molecular mechanism of the DHE action that may contribute to the chemoprevention of breast cancer (Kuo et al., 2009).

ER- Breast Cancer

Costunolide induced apoptosis through the extrinsic pathway, including the activation of Fas, caspase-8, caspase-3, and degradation of PARP. However, it did not have the same effect on the intrinsic pathway as revealed by analysis of mitochondrial membrane potential (Δψ m) with JC-1 dye and expression of Bcl2 and Bax proteins level.

Furthermore, costunolide induced cell-cycle arrest in the G2/M phase via decrease in Cdc2, cyclin B1 and increase in p21WAF1 expression, independent of p53 pathway in p53-mutant MDA-MB-231 cells, and increases Cdc2-p21WAF1 binding/

Through this study it was confirmed that costunolide induces G2/M cell-cycle arrest and apoptotic cell death via extrinsic pathway in MDA-MB-231 cells, suggesting that it could be a promising anti-cancer drug especially for ER negative breast cancer (Choi et al., 2012).

Bladder Cancer

Costunolide, a member of sesquiterpene lactone family, possesses potent anti-cancer properties. The effects of costunolide were investigated on the cell viability and apoptosis in human bladder cancer T24 cells. Treatment of T24 cells with costunolide resulted in a dose-dependent inhibition of cell viability and induction of apoptosis, which was associated with the generation of ROS and disruption of mitochondrial membrane potential (Δψm).

These effects were significantly blocked when the cells were pre-treated with N-acetyl- cysteine (NAC), a specific ROS inhibitor. Exposure of T24 cells to costunolide was also associated with increased expression of Bax, down-regulation of Bcl-2, and of   survivin and significant activation of caspase-3, and its downstream target PARP. These findings provide the rationale for further in vivo and clinical investigation of costunolide against human bladder cancer (Rasul et al., 2013).

Sarcomas; MDR

Human soft tissue sarcomas represent a rare group of malignant tumors that frequently exhibit chemotherapeutic resistance and increased metastatic potential following unsuccessful treatment.

The effects on cell proliferation, cell-cycle distribution, apoptosis induction, and ABC transporter expression were analyzed. Cells treated with costunolide showed no changes in cell-cycle, little in caspase 3/7 activity, and low levels of cleaved caspase-3 after 24 and 48 hours. Dehydrocostus lactone caused a significant reduction of cells in the G1 phase and an increase of cells in the S and G2/M phase. Moreover, it led to enhanced caspase 3/7 activity, cleaved caspase-3, and cleaved PARP indicating apoptosis induction.

These data demonstrate that dehydrocostus lactone affects cell viability, cell-cycle distribution and ABC transporter expression in soft tissue sarcoma cell lines. Furthermore, it led to caspase 3/7 activity as well as caspase-3 and PARP cleavage, which are indicators of apoptosis. Therefore, this compound may be a promising lead candidate for the development of therapeutic agents against drug-resistant tumors (Kretschmer et al., 2013).

Leukemia, Lung Cancer

Costunolide, an active compound isolated from the stem bark of Magnolia sieboldii, has been found to induce apoptosis via reactive oxygen species (ROS) and Bcl-2-dependent mitochondrial permeability transition in human leukemia cells. Mitogen-activated protein kinases (MAPKs) were investigated for their involvement in the costunolide-induced apoptosis in human promonocytic leukemia U937 cells.

Treatment with costunolide resulted in the significant activation of c-Jun N-terminal kinase (JNK), but not of extracellular-signal-related kinase (ERK1/2) or p38. In vitro kinase assays showed that JNK activity was low in untreated cells but increased dramatically after 30 minutes of costunolide treatment. U937 cells co-treated with costunolide and sorbitol, a JNK activator, exhibited higher levels of cell death. In addition, inhibition of the JNK pathway using a dominant-negative mutation of c-jun and JNK inhibitor SP600125, significantly prevented costunolide-induced apoptosis.

Furthermore, pre-treatment with the anti-oxidant NAC (N-acetyl-L-cysteine) blocked the costunolide-stimulated activation of JNK while the overexpression of Bcl-2 failed to reverse JNK activation. These results indicate that costunolide-induced JNK activation acts downstream of ROS but upstream of Bcl-2, and suggest that ROS-mediated JNK activation plays a key role in costunolide-induced apoptosis. Moreover, the administration of costunolide (intraperitoneally once a day for 7 days) significantly suppressed tumor growth and increased survival in 3LL Lewis lung carcinoma-bearing model (Choi et al., 2009).

Prostate Cancer

Several pharmacological and biochemical assays were used to characterize the apoptotic-signaling pathways of costunolide in prostate cancer cells. Costunolide showed effective anti-proliferative activity against hormone dependent (LNCaP) and independent (PC-3 and DU-145) prostate cancer cells (ATCC¨) by sulforhodamine B assay, clonogenic test and flow cytometric analysis of carboxyfluorescein succinimidyl ester labeling. In PC-3 cells data showed that costunolide induced a rapid overload of nuclear Ca(2+), DNA damage response and ATR phosphorylation.

This indicated the crucial role of intracellular Ca(2+) mobilization and thiol depletion but not of reactive oxygen species production in apoptotic signaling. Data suggest that costunolide induces the depletion of intracellular thiols and overload of nuclear Ca(2+) that cause DNA damage and p21 up-regulation. The association of p21 with the cyclin dependent kinase 2/cyclin E complex blocks cyclin dependent kinase 2 activity and inhibits Rb phosphorylation, leading to G1 arrest of the cell-cycle and subsequent apoptotic cell death in human prostate cancer cells (Hsu et al., 2011).

Gastric Cancer, Prostate Cancer

Radix Aucklandiae Lappae/Saussurea lappa has been used in Chinese traditional medicine for the treatment of abdominal pain, tenesmus, nausea, and cancer; previous studies have shown that S. lappa also induces G(2) growth arrest and apoptosis in gastric cancer cells. The effects of hexane extracts of S. lappa (HESLs) on the migration of DU145 and TRAMP-C2 prostate cancer cells were investigated.

The active compound, dehydrocostus lactone (DHCL), in fraction 7 dose-dependently inhibited the basal and EGF-induced migration of prostate cancer cells. HESL and DHCL reduced matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 secretion but increased TIMP-2 levels in both the absence and presence of EGF. These results demonstrate that the inhibition of MMP-9 secretion and the stimulation of TIMP-2 secretion contribute to reduced migration of DU145 cells treated with HESL and DHCL.

This indicates that HESL containing its active principle, DHCL, has potential as an anti-metastatic agent for the treatment of prostate cancer (Kim et al., 2012).

Anti-metastatic

Lymphangiogenesis inhibitors from crude drugs used in Japan and Korea were investigated for their impact on metastasis. The three crude drugs Saussureae Radix, Psoraleae Semen and Aurantti Fructus Immaturus significantly inhibited the proliferation of temperature-sensitive rat lymphatic endothelial (TR-LE) cells in vitro.

Among isolated compounds, several compounds; costunolide, dehydrocostus lactone, psoracorylifol D, bavachinin, bakuchiol, showed an inhibitory effect on the proliferation and the capillary-like tube formation of TR-LE cells. In addition, all compounds showed selective inhibition of the proliferation of TR-LE cells compared to Hela and Lewis lung carcinoma (LLC) cells.

These compounds might offer clinical benefits as lymphangiogenesis inhibitors and may be good candidates for novel anti-cancer and anti-metastatic agents (Jeong et al., 2013).

Ovarian Cancer, MDR

The apoptosis-inducing effect of costunolide, a natural sesquiterpene lactone, was studied in platinum-resistant human ovarian cancer cells relative to cisplatin.

The MTT assay for cell viability, PI staining for cell-cycle profiling, and annexin V assay for apoptosis analysis were performed. Costunolide induced apoptosis of platinum-resistant cells in a time and dose-dependent manner and suppressed tumor growth in the SKOV3 (PT)-bearing mouse model. In addition, costunolide triggered the activation of caspase-3, caspase-8, and caspase-9. Pre-treatment with caspase inhibitors neutralized the pro-apoptotic activity of costunolide. We further demonstrated that costunolide induced a significant increase in intracellular reactive oxygen species (ROS). Moreover, costunolide synergized with cisplatin to induce cell death in platinum-resistant ovarian cancer cells.

Data suggests that costunolide, alone or in combination with cisplatin, may be of therapeutic potential in platinum-resistant ovarian cancers (Yang, Kim, Lee, & Choi, 2011).

Anti-inflammatory, Anti-oxidant, Mediates Apoptosis

Cheon et al. (2013) found that costunolide significantly inhibited RANKL-induced BMM differentiation into osteoclasts in a dose-dependent manner without causing cytotoxicity. Costunolide did not regulate the early signaling pathways of RANKL, including the mitogen-activated protein kinase and NF-κB pathways.

However, costunolide suppressed nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1) expression via inhibition of c-Fos transcriptional activity without affecting RANKL-induced c-Fos expression. The inhibitory effects of costunolide were rescued by overexpression of constitutively active (CA)-NFATc1. Taken together, these results suggest that costunolide inhibited RANKL-induced osteoclast differentiation by suppressing RANKL-mediated c-Fos transcriptional activity.

References

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Kim EJ, Hong JE, Lim SS, et al. (2012). The hexane extract of Saussurea lappa and its active principle, dehydrocostus lactone, inhibit prostate cancer cell migration. J Med Food, 15(1):24-32. doi: 10.1089/jmf.2011.1735.


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