Escin’s Relevant Biological Activities in Cancer Therapy

Version	Summary	Created by	Modification	Content Size	Created at	Operation
1		Jamoliddin Razzokov	--	2303	2023-02-27 08:33:43	\|
2	format correct	Conner Chen	-50 word(s)	2253	2023-02-27 09:18:57	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom13020315

Although modern medicine is advancing at an unprecedented rate, basic challenges in cancer treatment and drug resistance remain. Exploiting natural-product-based drugs is a strategy that has been proven over time to provide diverse and efficient approaches in patient care during treatment and post-treatment periods of various diseases, including cancer. Escin—a plant-derived triterpenoid saponin—is one example of natural products with a broad therapeutic scope. Initially, escin was proven to manifest potent anti-inflammatory and anti-oedematous effects. However, later, other novel activities of escin relevant to cancer treatment have been reported. It can be demonstrated escin’s efficacy in compositions with other approved drugs to accomplish synergy and increased bioavailability to broaden their apoptotic, anti-metastasis, and anti-angiogenetic effects.

angiogenesis apoptosis cancer Escin

1. Anti-Cancer Effects

It has long been known that escin has potential anti-cancer effects. Escin’s anti-cancer mechanisms can be grouped into three categories: (i) inducing apoptosis, (ii) reducing cell proliferation and (iii) inhibiting metastasis. Over the past two decades, the results of numerous in vitro and in vivo studies revealed the efficacy of escin in suppressing and/or preventing over 15 cancer types, which are summarised in Table 1.

Table 1. Anti-cancer effects of escin revealed by in vitro or in vivo studies.

Cancer Type	Model System	Anti-Cancer Effects and Mechanisms of Escin by			Ref.
Cancer Type	Model System	Inducing Cell Apoptosis	Decreasing Cell Proliferation	Inhibiting Metastasis and Invasion
Bladder cancer	T24, J82, TCCSUP, and RT-4 cell lines	Through death receptor and mitochondria mediated pathways	↓ NF–κB p65, partially affects STAT3 expression		^[1]
Breast cancer	MDA-MB-231 cell line			↓ LOXL2, ↓ c-Myc, ↓ GSL1, ↑ASCT2	^[2]^[3]
Breast cancer	Mice and MCF-7 cell line	Yes	Yes	↑ p53, ↓ Bcl-2	^[4]^[5]^[6]^[7]
Colon cancer	HT-29 cell line		Cell cycle arrest at G1/S phase mediated by induction of p21^WAF1/CIP1		^[8]
Colon cancer	LoVo cell line		Yes		^[9]
Colorectal cancer	Mice and HCT116, HCT8 cell lines	Through DNA damage	Yes		^[10]
Colorectal cancer	Mice and HCT116, HCT8 cell lines	Through DNA damage ↑ TIGAR ↑ ROS	Yes		^[11]
Cholangiocarcinoma	QBC939, MZ-ChA-1 Sk-ChA-1 cell lines	↑ caspase-3, ↓ Bcl-2	Cell cycle arrest at G1 and G2/M phases		^[12]
Cholangiocarcinoma	QBC939 cell line	Sensitised to 5-FU and VCR	↓ P-glycoprotein, ↓ GSK3b/ catenin		^[13]
Gastric cancer	AGS cell lines			Through Akt signalling pathway	^[14]
Glioblastoma multiforme	Classical and mesenchymal glioblastoma-initiating cells	Through mitochondria-mediated pathway	Yes		^[15]
Hepatocellular carcinoma	SMMC-7721 cell line	↑ caspases 3, 8, 9; ↓ Bcl-2 with 5-FU	Cell cycle arrest at G0/G1 with 5-FU		^[16]
	HepG2 cell line	↑ PARP, AIF, BAX, and Bcl-2	Cell cycle arrest at G1/S phase		^[17]
	HepG2 cell line		↓ Akt/JAK/STAT, ↓ cyclin D1, ↓ Bcl-2, ↓ Bcl-xL, ↓ survivin, ↓ Mcl-1, ↓ VEGF; sensitised to Dx, PTX		^[18]
Leukaemia	Jurkat T-cell line	↑ Caspases-3, 8, 9, ↓ PARP, ↓ Bcl-2, ↑ ROS	Yes		^[5]^[19]
	CEM cell line		Yes		^[5]
	KBM-5 cell line	TNF-induced apoptosis	↓ TNF ↓ NF–κB	↓ TNF ↓ NF–κB	^[20]
Lung cancer	A549 cell line		Through JAK/STAT signalling pathway	↓ iNOS	^[21]
	Mice and H460 cell line		↓ ALDH1A1 ↓ p-Akt, ↑ p21	↓ RhoA and Rock	^[22]
	A549 cell line	↑ BAX, ↑ caspase-3	Cell cycle arrest at G0/G1phase		^[23]
Melanoma	SK-MEL5 and B16F10 cell lines		↓ NF–κB, ↓ IκB	Through ERK1/2 signalling	^[24]
Osteosarcoma	Mice and MNNG/HOS, Saos-2, MG-63, U-2OS, HUVEC cell lines	Through ROS/p38 MAPK signalling pathway			^[25]
Osteosarcoma	Mice and MG-63, OS732 cell lines	↑ Caspases-3, 8, 9	↓ PI3K/Akt pathway		^[26]
Ovarian cancer	HeyA8, SNU-119, Kuramochi, Ovcar4, and Ovcar5 cell lines			↓ Autophagy-dependent CSC differentiation, ↓ Stromal ECM production driven by HIF1α	^[27]
Pancreatic cancer	Mice and BxPC-3, PANC-1 cell lines	↓ NF–κB, ↓ c-Myc, ↓ COX-2, ↓ cyclin D1, ↓ survivin, ↓ Bcl-xL, ↓ Bcl-2, ↑ caspase-3			^[28]
	COLO357, MIA-Paca, Panc-1, cell lines	Yes	↓ NF–κB, ↓ cyclin D, sensitised cells to cisplatin		^[29]
	BxPC-3, AsPC-1, SW1990 cell lines		↓ NF-κB	↓ IL-8, ↓ VEGF	^[30]
Prostate cancer	Mice and CRPC, PC-3, DU-145 cell lines	↑ c-caspase-3, ↑ BAX, ↓ Bcl-2, ↓ cIAP-1, ↓ cIAP-2 ↓ xIAP, ↑ PARP	Cell cycle arrest at G2/M-phase		^[31]
Renal cancer	786-O and Caki-1 cell lines	↓ Bcl-2, ↑ ROS	Cell cycle arrest at G2/M arrest		^[32]

Abbreviations: Dx—doxorubicin, IL—interleukin, PTX—paclitaxel, VCR—Vincristine, LOXL2—lysyl oxidase-like 2, EMT—epithelial-mesenchymal transition, 5-FU—5-Fluorouracil, CSC—cancer stem cell, GLS1—kidney type glutaminase, ASCT2—alanine-serine-cysteine 2 protein, MAPKs—p38 mitogen-activated protein kinases, NF-κB—Nuclear factor kappa B, ROS—reactive oxygen species, TIGAR—TP53-induced glycolysis and apoptosis regulator, CXCL16—chemokine (C-X-C motif) ligand, iNOS—inducible nitric oxide synthase, ERK1/2—extracellular signal-regulated kinase 1/2, PARP (c)—poly (adenosine diphosphateribose) polymerase, Bcl-2—B-cell lymphoma 2 proteins, BAX—BCL2-associated X, Bcl-xL—X-linked inhibitor of apoptosis protein (xIAP), ALDH—aldehyde dehydrogenase, p-Akt—phospho-Akt, HUVECs—human umbilical vein endothelial cells, VEGF—vascular epidermal growth factor, ECM—extracellular matrix, and HIF1α—Hypoxia-inducible factor 1-alpha.

Regarding the molecular mechanisms of escin-induced apoptosis of cancer cells, ample evidence has been compiled to support the mitochondria-mediated (intrinsic) apoptosis pathway and reactive oxygen species (ROS)-induced DNA damage (Figure 1). Nevertheless, there are reports of death-receptor-induced (extrinsic) apoptosis induced by escin ^[2]^[21].

Figure 1. Possible molecular targets of escin’s anti-cancer mechanisms. Abbreviations: BS—binding site, NF-κB—Nuclear factor kappa B, ERK1/2—extracellular signal-regulated kinase 1/2, Bcl-2—B-cell lymphoma 2 proteins, BAX—BCL2-associated X, Bcl-xL—X-linked inhibitor of apoptosis protein (xIAP), VEGF—vascular epidermal growth factor, MAPKs—p38 mitogen-activated protein kinases, IκBα—cytoplasmic inhibitory protein of NF-κB, STAT3—signal transducer and activator of transcription protein 3.

The intrinsic apoptosis pathway is a mitochondria-actuated event at which various stimuli decrease membrane potential and hence increase the permeability of the mitochondrial membrane ^[33]. Consequently, several enzymes and molecules are released from mitochondria to activate the caspase-dependent mitochondrial apoptosis. It is believed that escin disrupts several pathways leading to the mitochondrial depolarisation. This includes the inhibition of NF–κB, which results in the downregulation of anti-apoptotic Bcl family proteins ^[28]^[31]^[34] and ROS/p38 MAPK pathway ^[25] (Figure 1). Elevated caspase protein levels corroborate this mechanistic explanation (Table 1). Meanwhile, ROS can give rise to cancer cell death through DNA damage ^[5]^[10]^[11].

Molecular mechanisms of the anti-proliferative effects of escin mostly depend upon the inhibition of the NF–κB, JAK/STAT and ERK1/2 pathways. Here, the NF–κB pathway, which is the central target of escin’s anti-inflammatory effects, is believed to be one of the key linkages between inflammation and cancer ^[35]. Apart from mediating the proinflammatory ^[36] and anti-apoptotic ^[34] genes, NF–κB also targets the genes of cell proliferation regulators such as cyclins and cytokines ^[37] (Figure 1). Moreover, NF–κB contributes to cancer metastasis and invasion through the upregulation of adhesion molecules ^[37] and chemokines ^[20]^[30]. Therefore, NF–κB inhibition is the main contribution to the anti-cancer, as well as anti-inflammatory effects of escin. In addition, ERK1/2, JAK/STAT and Akt proteins and their signalling pathways were also shown to be affected by escin to inhibit cell proliferation. At a cellular level and depending on cancer type, escin-treated cancer cells were caught in cell cycle arrests at the G0/G1, G1/S and G2/M cell cycle phases (Table 1).

Anti-metastasis effects of escin, albeit being less investigated, seem to encompass a wide variety of mechanisms. Many reported the downregulation of NF–κB and downstream molecules of NF–κB signalling pathways, like vascular epidermal growth factor (VEGF), IL-8 ^[30], TNF ^[20] and Bcl family proteins ^[38]. Others advocated contributions from Akt and ERK1/2 ^[14]^[24]. Meanwhile, more recent studies communicated that escin inhibits metastasis by regulating the tumour microenvironment, for instance, by blocking ECM production, inhibiting hypoxia-inducible factor 1-alpha (HIF1α) targeted protein expression ^[27] and downregulating inducible nitric oxide synthase (iNOS) ^[21], RhoA and Rock proteins ^[22]. Escin’s regulation of the tumour microenvironment is evidenced by the downregulation of several matrix metalloproteinases (MMPs) ^[4]^[39]. Escin also displays potent anti-angiogenetic effects to prevent tumour metastasis, which will be discussed next.

2. Anti-Angiogenetic Effects

Escin’s anti-angiogenetic effects are also of interest, especially in the context of cancer treatment. Several in vitro and in vivo studies have indicated escin’s efficacy in the inhibition of tumour invasion, migration and metastasis (Table 1). It was demonstrated that escin inhibits proliferation ^[40] and migration of HUVECs ^[41]. The exact mechanisms by which escin alters HUVECs proliferation and migration remain elusive, but it was suggested that escin acts on HUVECs through Akt, p38/MAPK and ERK signalling pathways and by inhibition of PKC-α, EFNB2 and growth factor expression ^[40]^[41]. Escin’s anti-angiogenic effects are also facilitated by disrupting the extracellular matrix (ECM) modelling and adhesion. Reports showed escin to inhibit the secretion of vascular epidermal growth factor (VEGF) in HUVECs ^[4], matrix metalloproteinases (MMP-3 and MMP-9) in rats ^[42] and ECM production in mesothelial cells and fibroblasts ^[27]. Because of the anti-inflammatory, anti-oedematous and venotonic effects, scientists were quick to consider escin for the treatment of widespread chronic venous insufficiency (CVI). Escin’s efficacy against CVI has been tested by numerous in vitro, in vivo and clinical trials ^[43]^[44]. Nowadays, standardised horse-chestnut dry extract is used at various stages of CVI, varicose and other venous disorders associated with oedema ^[45].

3. Anti-Inflammatory Effects

Inflammation is a basic immune response to infection and injury that sets complex defence signalling pathways on “fire”. When out of control, inflammation can be chronic, which is also associated with tumour development ^[37]. Escin’s potential effect in reducing inflammation was already shown in the 1960s ^[46]. Extensive research on this topic proposed several key players of inflammatory networks as the targets of escin’s anti-inflammatory properties. There are numerous reports indicating that escin supresses the activation of nuclear factor kappa B (NF–κB) and inflammation processes initiated by this protein. This is substantiated by in vitro and in vivo studies where escin decreases the level of proinflammatory cytokines ^[47]^[48]^[49]^[50]^[51]^[52], tumour necrosis factor α (TNF-α), and interleukins IL-1β and IL-6, whose production is directly regulated by NF–κB as a transcription factor. Results of many studies with proinflammatory factors (TNFα, IL-1β), Toll-receptor ligands (lipopolysaccharides) and 11-β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) put forward a glucocorticoid-like (GC) mechanism of escin in the regulation of inflammation (Figure 2).

Figure 2. Overview of anti-inflammatory mechanisms of escin at the molecular level.

Initially, it was shown that escin upregulates adrenocorticotropin and corticosterone levels ^[53]. Hence, anti-inflammatory effects of escin were accredited to increased levels of GCs ^[54]. However, following results indicated that escin’s anti-inflammatory effects are realised through upregulation of glucocorticoid receptor (GR) and induction of the conformation change in the receptor to facilitate GC binding ^[50]^[52]^[55]^[56]. This conformational change is necessary to expose GR to nucleoporins and importins that transfer the GC-bound GR into the nucleus. After, the GR can be recruited to indirect binding sites in DNA by interacting with DNA-TF complexes ^[57]. These interactions between GR and DNA-TF complexes directly influence gene transcription by changing DNA–TF interactions and/or by recruiting other TFs and cofactors that can result in suppression of proinflammatory factors like TNFα, IL-1β, and IL-6 (Figure 2).

Meanwhile, GC-bound GRs can inhibit the activation of NF–κB in the cytosol. Studies indicate that escin itself can inhibit the activation of NF–κB by downregulating the expression of p65 ^[30]^[50] and by inhibiting the IKK complex (comprised of the IKKα and IKKβ catalytic subunits and the IKKγ regulatory subunit) activation ^[20]. P65 is a necessary component of the p50/p65 dimer that is a primary target of the canonical NF–κB activation pathway ^[37]. There are other findings that report the inhibition of NF–κB by escin in mice ^[58]^[59], rats ^[50]^[60], human bladder cancer cells ^[1], human endothelial cells ^[61], and human pancreatic cancer cells (BxPC-3, PANC-1) ^[28]^[30]. However, the exact mechanisms of direct NF–κB inhibition by escin still remain unresolved. Decreased TNF-α, IL-1β, IL-6, and NO levels and increased antioxidant factors are ascribed as plausible explanations for escin-induced NF–κB inhibition ^[47]^[49]^[54]^[62].

4. Antioxidant, Protective and Ameliorative Effects

In general, escin’s potent anti-inflammatory and antioxidant activities prompted its evaluation for alleviating pain and complications in several diseases and might be very useful in chemotherapy and surgical treatment of cancer diseases. This is very crucial for healthy cells to survive detrimental conditions of cancer chemotherapies and act as a scavenger of ROS whose levels are elevated in tumour microenvironments. For instance, escin increased glutathione, catalase and SOD activities, decreased MMP-9 levels and mitigated cardiac autonomic neuropathy in rats with diabetes induced by streptozotocin ^[63]. The same antioxidant effects of escin (increased catalase and SOD activities) appear to be useful against cyclophosphamide-induced cardiotoxicity ^[64]. Escin’s antioxidant mechanisms can also be realised via the AKT-Nrf2 signalling pathway, as shown in studies of H₂O₂-induced cytotoxicity in established retinal pigment epithelium (ARPE-19) and primary murine RPE cells ^[65].

Escin also displays promising effects in brain injuries and neurodegenerative diseases - a hot topic of contemporary medicine. Escin attenuated cerebral ischemia-reperfusion injury in rats by reducing the volume of cerebral infarct and water content, and by ameliorating the neurological deficit ^[66]. Likewise, escin was effective in inhibiting inflammation, attenuating cognitive deficit and protecting hippocampal neurons in ischemic brain injury ^[67]. There is a growing interest in escin’s potential role in neurodegenerative diseases. I is reported that oral treatment with escin diminished behavioural impairments, oxidative stress and inflammation in the chronic MPTP/probenecid mouse model of Parkinson’s disease (PD) by reducing the levels of TNF-α, IL-6, IL-4, IL-10, SOD and catalase ^[62]. Later, escin’s positive effects on mitochondrial dysfunction, oxidative stress and apoptosis in a mouse PD model was demonstrated ^[68]. Meanwhile, escin was proven to be an autophagy inducer that degrades mutant huntingtin protein (mHtt) and inhibits mHtt-induced apoptosis in vitro and in vivo ^[69]. Escin’s autophagy induction mechanisms in HT22 cells were attributed to the regulation of mTOR and ERK pathways ^[69].

Ameliorative effects of escin also rely on intervening inflammatory processes, mostly through the NF–κB pathway. For instance, Zhang et al. recently reported the ameliorative effects of escin on neuropathic pain in chronic constriction injury of the sciatic nerve by suppressing the NF–κB pathway and its targets: pro-inflammatory cytokines, TNF-α, glial fibrillary acidic protein and nerve growth factor ^[70]. Escin was found to be a useful analgesic in bone cancer pain by suppressing inflammation and microglial activation, possibly through the suppression of the p38 MAPK/c-Fos signalling pathway ^[71]. Moreover, escin can contribute to muscle regeneration and prevention of muscle atrophy by reducing inflammatory infiltration, fibrosis and by increasing the number of muscle fibres ^[72]^[73].

References

Huang, S.; Wang, X.; Liu, M.; Lin, Z.; Gu, W.; Zhao, H.; Zhang, Y.; Ding, B.; Liu, J.; Wu, X.; et al. Modification of sodium aescinate into a safer, more stable and effective water-soluble drug by liposome-encapsulation: An in vitro and in vivo study. Drug Deliv. 2022, 29, 1132–1141.
Cheng, C.L.; Chao, W.T.; Li, Y.H.; Ou, Y.C.; Wang, S.S.; Chiu, K.Y.; Yuan, S.Y. Escin induces apoptosis in human bladder cancer cells: An in vitro and in vivo study. Eur. J Pharm. 2018, 840, 79–88.
Wang, Y.; Xu, X.; Zhao, P.; Tong, B.; Wei, Z.; Dai, Y. Escin Ia suppresses the metastasis of triple-negative breast cancer by inhibiting epithelial-mesenchymal transition via down-regulating LOXL2 expression. Oncotarget 2016, 7, 23684–23699.
Akar, S.; Donmez-Altuntas, H.; Hamurcu, Z. β-Escin reduces cancer progression in aggressive MDA-MB-231 cells by inhibiting glutamine metabolism through downregulation of c-myc oncogene. Mol. Biol. Rep. 2022, 49, 7409–7415.
Mojzisova, G.; Mojzis, J.; Pilatova, M.; Varinska, L.; Ivanova, L.; Strojny, L.; Richnavsky, J. Antiproliferative and antiangiogenic properties of horse chestnut extract. Phytother. Res. 2013, 27, 159–165.
Mojzisova, G.; Kello, M.; Pilatova, M.; Tomeckova, V.; Vaskova, J.; Vasko, L.; Bernatova, S.; Mirossay, L.; Mojzis, J. Antiproliferative effect of beta-escin—An in vitro study. Acta Biochim. Pol. 2016, 63, 79–87.
Mazrouei, R.; Raeisi, E.; Lemoigne, Y.; Heidarian, E. Activation of p53 Gene Expression and Synergistic Antiproliferative Effects of 5-Fluorouracil and beta-escin on MCF7 Cells. J. Med. Signals Sens. 2019, 9, 196–203.
Yang, Y.; Long, L.; Zhang, X.; Song, K.; Wang, D.; Xiong, X.; Gao, H.; Sha, L. 16-Tigloyl linked barrigenol-like triterpenoid from Semen Aesculi and its anti-tumor activity in vivo and in vitro. RSC Adv. 2019, 9, 31758–31772.
Patlolla, J.M.; Raju, J.; Swamy, M.V.; Rao, C.V. Beta-escin inhibits colonic aberrant crypt foci formation in rats and regulates the cell cycle growth by inducing p21(waf1/cip1) in colon cancer cells. Mol. Cancer 2006, 5, 1459–1466.
Seweryn, E.; Glehsk, M.; Środa-Pomianek, K.; Ceremuga, I.; Włodarczyk, M.; Gamian, A. Cytotoxic Effects of Four Aescin Types on Human Colon Adenocarcinoma Cell Lines. Nat. Prod. Commun. 2014, 9, 387–390.
Wang, Z.; Chen, Q.; Li, B.; Xie, J.-M.; Yang, X.-D.; Zhao, K.; Wu, Y.; Ye, Z.-Y.; Chen, Z.-R.; Qin, Z.-H.; et al. Escin-induced DNA damage promotes escin-induced apoptosis in human colorectal cancer cells via p62 regulation of the ATM/γH2AX pathway. Acta Pharmacol. Sin. 2018, 39, 1645–1660.
Li, B.; Wang, Z.; Xie, J.M.; Wang, G.; Qian, L.Q.; Guan, X.M.; Shen, X.P.; Qin, Z.H.; Shen, G.H.; Li, X.Q.; et al. TIGAR knockdown enhanced the anticancer effect of aescin via regulating autophagy and apoptosis in colorectal cancer cells. Acta Pharm. Sin. 2019, 40, 111–121.
Shen, D.Y.; Kang, J.H.; Song, W.; Zhang, W.Q.; Li, W.G.; Zhao, Y.; Chen, Q.X. Apoptosis of human cholangiocarcinoma cell lines induced by beta-escin through mitochondrial caspase-dependent pathway. Phytother. Res. 2011, 25, 1519–1526.
Huang, G.L.; Shen, D.Y.; Cai, C.F.; Zhang, Q.Y.; Ren, H.Y.; Chen, Q.X. beta-escin reverses multidrug resistance through inhibition of the GSK3beta/beta-catenin pathway in cholangiocarcinoma. World J. Gastroenterol. 2015, 21, 1148–1157.
Lee, H.S.; Hong, J.E.; Kim, E.J.; Kim, S.H. Escin suppresses migration and invasion involving the alteration of CXCL16/CXCR6 axis in human gastric adenocarcinoma AGS cells. Nutr. Cancer 2014, 66, 938–945.
Harford-Wright, E.; Bidère, N.; Gavard, J. β-escin selectively targets the glioblastoma-initiating cell population and reduces cell viability. Oncotarget 2016, 7, 66865–66879.
Ming, Z.J.; Hu, Y.; Qiu, Y.H.; Cao, L.; Zhang, X.G. Synergistic effects of β-aescin and 5-fluorouracil in human hepatocellular carcinoma SMMC-7721 cells. Phytomedicine 2010, 17, 575–580.
Zhou, X.Y.; Fu, F.H.; Li, Z.; Dong, Q.J.; He, J.; Wang, C.H. Escin, a natural mixture of triterpene saponins, exhibits antitumor activity against hepatocellular carcinoma. Planta Med. 2009, 75, 1580–1585.
Tan, S.M.-L.; Li, F.; Rajendran, P.; Kumar, A.P.; Hui, K.M.; Sethi, G. Identification of β-Escin as a Novel Inhibitor of Signal Transducer and Activator of Transcription 3/Janus-Activated Kinase 2 Signaling Pathway that Suppresses Proliferation and Induces Apoptosis in Human Hepatocellular Carcinoma Cells. J. Pharmacol. Exp. Ther. 2010, 334, 285.
Zhang, Z.; Gao, J.; Cai, X.; Zhao, Y.; Wang, Y.; Lu, W.; Gu, Z.; Zhang, S.; Cao, P. Escin sodium induces apoptosis of human acute leukemia Jurkat T cells. Phytother. Res. 2011, 25, 1747–1755.
Harikumar, K.B.; Sung, B.; Pandey, M.K.; Guha, S.; Krishnan, S.; Aggarwal, B.B. Escin, a Pentacyclic Triterpene, Chemosensitizes Human Tumor Cells through Inhibition of Nuclear Factor-κB Signaling Pathway. Mol. Pharmacol. 2010, 77, 818.
Ji, D.B.; Xu, B.; Liu, J.T.; Ran, F.X.; Cui, J.R. beta-Escin sodium inhibits inducible nitric oxide synthase expression via downregulation of the JAK/STAT pathway in A549 cells. Mol. Carcinog. 2011, 50, 945–960.
Patlolla, J.M.; Qian, L.; Biddick, L.; Zhang, Y.; Desai, D.; Amin, S.; Lightfoot, S.; Rao, C.V. beta-Escin inhibits NNK-induced lung adenocarcinoma and ALDH1A1 and RhoA/Rock expression in A/J mice and growth of H460 human lung cancer cells. Cancer Prev. Res. 2013, 6, 1140–1149.
Ciftci, G.A.; Iscan, A.; Kutlu, M. Escin reduces cell proliferation and induces apoptosis on glioma and lung adenocarcinoma cell lines. Cytotechnology 2015, 67, 893–904.
Kwak, H.; An, H.; Alam, M.B.; Choi, W.-S.; Lee, S.Y.; Lee, S.-H. Inhibition of Migration and Invasion in Melanoma Cells by β-Escin via the ERK/NF-κB Signaling Pathway. Biol. Pharm. Bull. 2018, 41, 1606–1610.
Zhu, J.; Yu, W.; Liu, B.; Wang, Y.; Shao, J.; Wang, J.; Xia, K.; Liang, C.; Fang, W.; Zhou, C.; et al. Escin induces caspase-dependent apoptosis and autophagy through the ROS/p38 MAPK signalling pathway in human osteosarcoma cells in vitro and in vivo. Cell Death Dis. 2017, 8, e3113.
Zhu, M.; Ying, J.; Lin, C.; Wang, Y.; Huang, K.; Zhou, Y.; Teng, H. beta-Escin inhibits the proliferation of osteosarcoma cells via blocking the PI3K/Akt pathway. RSC Adv. 2018, 8, 29637–29644.
Kenny, H.A.; Hart, P.C.; Kordylewicz, K.; Lal, M.; Shen, M.; Kara, B.; Chen, Y.J.; Grassl, N.; Alharbi, Y.; Pattnaik, B.R.; et al. The Natural Product beta-Escin Targets Cancer and Stromal Cells of the Tumor Microenvironment to Inhibit Ovarian Cancer Metastasis. Cancers 2021, 13, 3931.
Wang, Y.W.; Wang, S.J.; Zhou, Y.N.; Pan, S.H.; Sun, B. Escin augments the efficacy of gemcitabine through down-regulation of nuclear factor-kappaB and nuclear factor-kappaB-regulated gene products in pancreatic cancer both in vitro and in vivo. J Cancer Res. Clin. Oncol. 2012, 138, 785–797.
Rimmon, A.; Vexler, A.; Berkovich, L.; Earon, G.; Ron, I.; Lev-Ari, S. Escin Chemosensitizes Human Pancreatic Cancer Cells and Inhibits the Nuclear Factor-kappaB Signaling Pathway. Biochem. Res. Int. 2013, 2013, 251752.
Omi, K.; Matsuo, Y.; Ueda, G.; Aoyama, Y.; Kato, T.; Hayashi, Y.; Imafuji, H.; Saito, K.; Tsuboi, K.; Morimoto, M.; et al. Escin inhibits angiogenesis by suppressing interleukin8 and vascular endothelial growth factor production by blocking nuclear factorkappaB activation in pancreatic cancer cell lines. Oncol. Rep. 2021, 45, 55.
Piao, S.; Kang, M.; Lee, Y.J.; Choi, W.S.; Chun, Y.S.; Kwak, C.; Kim, H.H. Cytotoxic effects of escin on human castration-resistant prostate cancer cells through the induction of apoptosis and G2/M cell cycle arrest. Urology 2014, 84, 982.e1–982.e7.
Yuan, S.Y.; Cheng, C.L.; Wang, S.S.; Ho, H.C.; Chiu, K.Y.; Chen, C.S.; Chen, C.C.; Shiau, M.Y.; Ou, Y.C. Escin induces apoptosis in human renal cancer cells through G2/M arrest and reactive oxygen species-modulated mitochondrial pathways. Oncol. Rep. 2017, 37, 1002–1010.
Elmore, S. Apoptosis: A Review of Programmed Cell Death. Toxicol. Pathol. 2007, 35, 495–516.
Luo, J.-L.; Kamata, H.; Karin, M. IKK/NF-κB signaling: Balancing life and death—A new approach to cancer therapy. J. Clin. Investig. 2005, 115, 2625–2632.
Taniguchi, K.; Karin, M. NF-kappaB, inflammation, immunity and cancer: Coming of age. Nat. Rev. Immunol. 2018, 18, 309–324.
Li, Q.; Verma, I.M. NF-kappaB regulation in the immune system. Nat. Rev. Immunol. 2002, 2, 725–734.
Zhang, X.; Zhang, S.; Yang, Y.; Wang, D.; Gao, H. Natural barrigenol-like triterpenoids: A comprehensive review of their contributions to medicinal chemistry. Phytochemistry 2019, 161, 41–74.
Liu, T.; Zhang, L.; Joo, D.; Sun, S.C. NF-kappaB signaling in inflammation. Signal Transduct. Target 2017, 2, 17023.
Paneerselvam, C.; Ganapasam, S. beta-Escin alleviates cobalt chloride-induced hypoxia-mediated apoptotic resistance and invasion via ROS-dependent HIF-1alpha/TGF-beta/MMPs in A549 cells. Toxicol. Res. 2020, 9, 191–201.
Varinska, L.; Faber, L.; Kello, M.; Petrovova, E.; Balazova, L.; Solar, P.; Coma, M.; Urdzik, P.; Mojzis, J.; Svajdlenka, E.; et al. beta-Escin Effectively Modulates HUVECS Proliferation and Tube Formation. Molecules 2018, 23, 197.
Wang, X.H.; Xu, B.; Liu, J.T.; Cui, J.R. Effect of beta-escin sodium on endothelial cells proliferation, migration and apoptosis. Vasc. Pharm. 2008, 49, 158–165.
Cheng, P.; Kuang, F.; Ju, G. Aescin reduces oxidative stress and provides neuroprotection in experimental traumatic spinal cord injury. Free Radic. Biol. Med. 2016, 99, 405–417.
Diehm, C.; Trampisch, H.J.; Lange, S.; Schmidt, C. Comparison of leg compression stocking and oral horse-chestnut seed extract therapy in patients with chronic venous insufficiency. Lancet 1996, 347, 292–294.
Assessment Report on Aesculus hippocastanum L., semen; European Medicines Agency: Amsterdam, The Netherlands, 2020.
Dudek-Makuch, M.; Studzińska-Sroka, E. Horse chestnut—Efficacy and safety in chronic venous insufficiency: An overview. Rev. Bras. Farmacogn. 2015, 25, 533–541.
Vogel, G.; Marek, M.L.; Stoeckert, I. Weitere Untersuchengen zun Wirkungsmechanismus des Rosskastanien-Saponins Aescin. Arzneim. Forsch. 1963, 13, 59–64.
Xin, W.; Zhang, L.; Fan, H.; Jiang, N.; Wang, T.; Fu, F. Escin attenuates acute lung injury induced by endotoxin in mice. Eur. J. Pharm. Sci. 2011, 42, 73–80.
Xin, W.; Zhang, L.; Sun, F.; Jiang, N.; Fan, H.; Wang, T.; Li, Z.; He, J.; Fu, F. Escin exerts synergistic anti-inflammatory effects with low doses of glucocorticoids in vivo and in vitro. Phytomedicine 2011, 18, 272–277.
Liu, S.; Wang, H.; Qiu, C.; Zhang, J.; Zhang, T.; Zhou, W.; Lu, Z.; Rausch-Fan, X.; Liu, Z. Escin inhibits lipopolysaccharide-induced inflammation in human periodontal ligament cells. Mol. Med. Rep. 2012, 6, 1150–1154.
Wang, H.; Zhang, L.; Jiang, N.; Wang, Z.; Chong, Y.; Fu, F. Anti-inflammatory effects of escin are correlated with the glucocorticoid receptor/NF-kappaB signaling pathway, but not the COX/PGF2alpha signaling pathway. Exp. Med. 2013, 6, 419–422.
Gupta, S.C.; Tyagi, A.K.; Deshmukh-Taskar, P.; Hinojosa, M.; Prasad, S.; Aggarwal, B.B. Downregulation of tumor necrosis factor and other proinflammatory biomarkers by polyphenols. Arch Biochem Biophys 2014, 559, 91–99.
Zhao, S.-Q.; Xu, S.-Q.; Cheng, J.; Cao, X.-L.; Zhang, Y.; Zhou, W.-P.; Huang, Y.-J.; Wang, J.; Hu, X.-M. Anti-inflammatory effect of external use of escin on cutaneous inflammation: Possible involvement of glucocorticoids receptor. Chin. J. Nat. Med. 2018, 16, 105–112.
Yang, Y.; Wang, L.; Yuan, M.; Yu, Q.; Fu, F. Anti-Inflammatory and Gastroprotective Effects of Escin. Nat. Prod. Commun. 2020, 15, 1–10.
Hiai, S.; Yokoyama, H.; Oura, H. Effect of escin on adrenocorticotropin and corticosterone levels in rat plasma. Chem. Pharm. Bull. 1981, 29, 490–494.
Zhang, L.; Wang, H.; Fan, H.; Wang, T.; Jiang, N.; Yu, P.; Fu, F. The potent anti-inflammatory agent escin does not increase corticosterone secretion and immune cell apoptosis in mice. Fitoterapia 2011, 82, 861–867.
Zhang, F.; Li, Y.; Zhang, L.; Mu, G. Synergistic protective effects of escin and lowdose glucocorticoids on bloodretinal barrier breakdown in a rat model of retinal ischemia. Mol. Med. Rep. 2013, 7, 1511–1515.
Timmermans, S.; Souffriau, J.; Libert, C. A General Introduction to Glucocorticoid Biology. Front. Immunol. 2019, 10, 1545.
Cheng, Y.; Wang, H.; Mao, M.; Liang, C.; Zhang, Y.; Yang, D.; Wei, Z.; Gao, S.; Hu, B.; Wang, L.; et al. Escin Increases the Survival Rate of LPS-Induced Septic Mice Through Inhibition of HMGB1 Release from Macrophages. Cell Physiol. Biochem. 2015, 36, 1577–1586.
Ding, Y.X.; Eerduna, G.W.; Duan, S.J.; Li, T.; Liu, R.X.; Zhang, L.M.; Wang, T.; Fu, F.H. Escin ameliorates the impairments of neurological function and blood brain barrier by inhibiting systemic inflammation in intracerebral hemorrhagic mice. Exp. Neurol. 2021, 337, 113554.
Ali, F.E.M.; Ahmed, S.F.; Eltrawy, A.H.; Yousef, R.S.; Ali, H.S.; Mahmoud, A.R.; Abd-Elhamid, T.H. Pretreatment with Coenzyme Q10 Combined with Aescin Protects against Sepsis-Induced Acute Lung Injury. Cells Tissues Organs 2021, 210, 195–217.
Domanski, D.; Zegrocka-Stendel, O.; Perzanowska, A.; Dutkiewicz, M.; Kowalewska, M.; Grabowska, I.; Maciejko, D.; Fogtman, A.; Dadlez, M.; Koziak, K. Molecular Mechanism for Cellular Response to beta-Escin and Its Therapeutic Implications. PLoS ONE 2016, 11, e0164365.
Selvakumar, G.P.; Janakiraman, U.; Essa, M.M.; Justin Thenmozhi, A.; Manivasagam, T. Escin attenuates behavioral impairments, oxidative stress and inflammation in a chronic MPTP/probenecid mouse model of Parkinson’s disease. Brain Res. 2014, 1585, 23–36.
Suryavanshi, S.V.; Kulkarni, Y.A. Attenuation of Cardiac Autonomic Neuropathy by Escin in Diabetic Rats. Pharmacology 2021, 106, 211–217.
Gur, F.; Cengiz, M.; Kutlu, H.M.; Cengiz, B.P.; Ayhanci, A. Molecular docking analyses of Escin as regards cyclophosphamide-induced cardiotoxicity: In vivo and in Silico studies. Toxicol. Appl. Pharm. 2021, 411, 115386.
Wang, K.; Jiang, Y.; Wang, W.; Ma, J.; Chen, M. Escin activates AKT-Nrf2 signaling to protect retinal pigment epithelium cells from oxidative stress. Biochem. Biophys. Res. Commun. 2015, 468, 541–547.
Hu, X.M.; Zeng, F.D. Protective effects of sodium beta-aescin on ischemia-reperfusion injury in rat brain. Yao Xue Xue Bao 2004, 39, 419–423.
Zhang, L.; Fu, F.; Zhang, X.; Zhu, M.; Wang, T.; Fan, H. Escin attenuates cognitive deficits and hippocampal injury after transient global cerebral ischemia in mice via regulating certain inflammatory genes. Neurochem. Int. 2010, 57, 119–127.
Selvakumar, G.P.; Manivasagam, T.; Rekha, K.R.; Jayaraj, R.L.; Elangovan, N. Escin, a novel triterpene, mitigates chronic MPTP/p-induced dopaminergic toxicity by attenuating mitochondrial dysfunction, oxidative stress, and apoptosis. J. Mol. Neurosci. 2015, 55, 184–197.
Sun, Y.; Jiang, X.; Pan, R.; Zhou, X.; Qin, D.; Xiong, R.; Wang, Y.; Qiu, W.; Wu, A.; Wu, J. Escins Isolated from Aesculus chinensis Bge. Promote the Autophagic Degradation of Mutant Huntingtin and Inhibit its Induced Apoptosis in HT22 cells. Front. Pharm. 2020, 11, 116.
Zhang, L.; Chen, X.; Wu, L.; Li, Y.; Wang, L.; Zhao, X.; Zhao, T.; Zhang, L.; Yan, Z.; Wei, G. Ameliorative effects of escin on neuropathic pain induced by chronic constriction injury of sciatic nerve. J. Ethnopharmacol. 2021, 267, 113503.
Yang, G.; Li, J.; Xu, Q.; Xie, H.; Wang, L.; Zhang, M. Sodium aescinate alleviates bone cancer pain in rats by suppressing microglial activation via p38 MAPK/c-Fos signaling. Mol. Cell. Toxicol. 2022, 18, 605–614.
Sikorska, M.; Dutkiewicz, M.; Zegrocka-Stendel, O.; Kowalewska, M.; Grabowska, I.; Koziak, K. Beneficial effects of beta-escin on muscle regeneration in rat model of skeletal muscle injury. Phytomedicine 2021, 93, 153791.

© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.

Upload a video for this entry

Information

Subjects: Oncology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Sunnatullo Fazliev

Khurshid Tursunov

Jamoliddin Razzokov

Avez Sharipov

View Times: 752

Update Date: 27 Feb 2023

Table of Contents

Video Upload Options

Confirm