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| REVIEW ARTICLE |
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| Year : 2018 | Volume
: 1
| Issue : 1 | Page : 9-15 |
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Ursolic acid and quercetin: Promising anticancer phytochemicals with antimetastatic and antiangiogenic potential
Dharambir Kashyap1, Hardeep Singh Tuli2, Vivek Kumar Garg3, Suhasini Bhatnagar4, Anil K Sharma2
1 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab, India
2 Department of Biotechnology, M.M. University, Mulana, Ambala, Haryana, India
3 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab, India
4 University Institute of Engineering and Technology, Panjab University, Chandigarh, India
| Date of Web Publication | 30-Jan-2018 |
Correspondence Address:
Dr. Hardeep Singh Tuli
Department of Biotechnology, M.M. University, Mulana, Ambala, Haryana
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/tme.tme_3_17
Despite available treatments, the incidence of the cancer is increasing and known to be a major cause of mortality worldwide. Plant-derived terpenoids and flavonoids are considered as promising therapeutic molecules, possessing a range of medicinal properties. These phytochemicals have been used as therapeutic agents for the treatment of the various chronic infections. Terpenoids and flavonoids, particularly ursolic acid (UA) and quercetin (Quer), respectively, are emerging as effective antitumor molecules with minimal cytotoxic effects on the normal body tissues. The regulatory role of these molecules in apoptosis, angiogenesis, invasion, or metastasis has been well documented in earlier studies. Angiogenesis and metastasis are the two important hallmarks for the survival of tumor and are responsible for 50% mortality in the cancer patients. Tumor angiogenesis and metastasis have been found to be significantly inhibited in the presence of UA and Quer. Evidence suggested that these phytochemicals inhibit the initiator and progressive cytokines, chemokines, and growth factors such as matrix metalloproteinases involved in extracellular matrix remodeling during tumor metastasis. In addition, the angiogenesis-associated factors such as hypoxia-inducible factor-α and vascular endothelial growth factor/vascular endothelial growth factor receptor have also been downregulated by UA and Quer. In the present review, molecular targets of UA and Quer, in tumor metastasis and angiogenesis, have been summarized.
Keywords: Antiangiogenesis, antimetastasis, cancer, flavonoids, quercetin, terpenoids, ursolic acid
How to cite this article:
Kashyap D, Tuli HS, Garg VK, Bhatnagar S, Sharma AK. Ursolic acid and quercetin: Promising anticancer phytochemicals with antimetastatic and antiangiogenic potential. Tumor Microenviron 2018;1:9-15 |
How to cite this URL:
Kashyap D, Tuli HS, Garg VK, Bhatnagar S, Sharma AK. Ursolic acid and quercetin: Promising anticancer phytochemicals with antimetastatic and antiangiogenic potential. Tumor Microenviron [serial online] 2018 [cited 2023 Dec 3];1:9-15. Available from: http://www.TMEResearch.org/text.asp?2018/1/1/9/207484 |
| Introduction | |  |
Metastasis and angiogenesis, the two important hallmarks of tumor that are responsible for more than 50% mortality.[1] In the tumor microenvironment (TME), signals are generated by the tumor cells, stromal cells, and immune cells so as to induce tumor invasion or metastasis and angiogenesis.[2] Metastasis is a crucial nature of vigorously growing cancer which spreads the cancer cells to the distant sites. Growing cancer requires continues food supply provided by new vessel formation, extension from the preexisting blood vessel into the tumor mass, and by the formation of tube-like structure by tumor cells itself to maintain aggressive proliferation.[3] Stromal cells are identified to play a vital role in tumor migration by secreting various growth signals (Epidermal growth factor (EGF), fibroblast growth factor [FGF], hepatocyte growth factor (HGF), transforming growth factor-β [TGF-β], and vascular endothelial growth factor [VEGF]) and cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2).[4] Immune cells such as mast cells and macrophages, present in the TME, secret various cell surface molecules that stimulate the tumor cells for the invasion or metastasis. In addition, macrophages and mast cells are also known to stimulate endothelial cells for blood vessel formation.[5]
The mechanistic insight of metastasis process has revealed that matrix metalloproteases (MMPs) are mainly responsible for the degradation of extracellular matrix (ECM) and basement membrane during cancer progression and facilitate in the migration of cancer cells.[6] Whereas hypoxia-inducible factor-α (HIF-α), a central molecule in the angiogenesis, expresses under low nutrient and oxygen conditions and initiates the angiogenesis through VEGFs binding with the VEGF receptors (VEGFRs).[7] Since these are central molecules in the cancer growth; therefore, they may be used as prognostic or predictive markers and could be targeted to develop as an effective anticancer therapy.[8] Although a range of targeted therapies have been developed against these molecular markers to halt the cancer growth, due to laps in detailed mechanistic insight of tumor development and progression, their full effectiveness remains a challenge.
A variety of phytochemicals with promising antitumor potential has been tested against the various human cancer as well as associated malignancies.[9],[10],[11],[12],[13],[14],[15] Among these, ursolic acid (UA) and Quercetin (Quer), possessing widespread pharmacological importance, especially studied more intensively for anticancer properties.[16],[17],[18] UA, also called 3β-hydroxy-urs-12-en-28-oic-acid, is a pentacyclic triterpenoid [Figure 1]a, which has been reported from numerous classes of medicinal plants, such as Ligustrum lucidum, Glechoma riobotrya japonica, Rosmarinus offıcinalis, Hedyotis diffusa, hederacea, Vaccinium macrocarpon, Rhododendron hymenanthes Makino, Arctostaphylos uva-ursi Calluna vulgaris, Ocimum sanctum, and Eugenia jambolana and also present in wax coating of many fruits including apples, prunes, and pears.[19] Whereas, Quer (3, 5, 7, 3',4'-Pentahydroxyflavone) is a flavonol belonging to the class of polyphenolic flavonoids which is characterized by the presence of five hydroxyl groups on C6-C3-C6 backbone structure, especially a 3-OH group on the pyrone ring [Figure 1]b.[20] These phytochemicals have multiple targets in the cancer cell for inhibition of the tumor growth. The present review highlights the recent trends and advancements in antimetastasis and antiangiogenic mechanisms of action of UA and Quer [Figure 1]. | Figure 1: Physical properties and chemical structures of ursolic acid (a) and quercetin (b)
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| Inhibition of Matrix Metalloproteinases | | |
Studies over more than 40 years yielded enough evidence that are supporting the involvement of TME in the cancer survival and progression.[21] Stromal cell present in TME secretes MMPs which belong to the diverse family of endopeptidases that are capable of degrading various components of ECM.[22] MMPs and urokinase regulate the four important hall markers of cancer invasion such migration, invasion, metastasis, and angiogenesis by dissociates cell–cell and cell–ECM interaction and facilitates the tumor cell migration.[23] These zinc-dependent endopeptidases have been considered as potential prognostic and diagnostic marker in many types of human cancers and are being utilized as therapeutic targets in cancer treatment for the past 20 years.[6],[24],[25],[26] MMPs modulate the availability and function of several growth factors and their receptors such as insulin-like growth factors (IGFs) and epidermal growth factor receptor (EGFR) ligands.[27],[28],[29],[30] They also act as an antiapoptotic agent by cleaving Fas ligand death receptor through activating serine/threonine kinase Akt/protein kinase B signaling cascades using EGFR and IGFR pathways.[31],[32] UA and Quer, both phytochemicals have shown the inhibitory actions of these tumor supporting enzymes. For example, the cytokines such as IL-1β and TNF-α dependent expression of MMPs have been reduced after UA treatment in C6 glioma cells through the inactivation of NF-kβ-dependent signaling pathway.[33] Similarly, in the presence of UA, human breast cancer cells resulted in inactivation of NF-kβ and shown the downregulation MMP-2, u-PA, and upregulation of plasminogen activator inhibitor-1 through dephosphorylation of JNK, Akt, and mTOR.[34] The MAPK/P38, a class of MAPKs which stimulates overexpression of MMPs in cancer, has been suppressed by UA treatment found in a study on SNU-484 (Seoul National University-484) human gastric cancer cells.[35]
Further, a similar pattern of MMP-2 and MMP-9 activity was observed in different cancer cell lines in the presence of Quer, such as, an alimental supplement Flavin 7® having Quer and other bioactive as ingredients has been determined as an inhibitor of MMP-9 enzyme and capillary tube formation in in vitro studies done on human leukemia Jurkat cells and HeLa cells.[36] In melanoma, Quer inhibited STAT3 signaling and subsequently downregulated their target genes like MMP-2, MMP-9, Mcl-1, and VEGF importantly responsible for cell proliferation, invasion, or metastasis.[37] Lai et al. in 2013, during the study on oral cancer cells using Quer as an anticancer agent noted downregulation of PKC and RhoA which was further confirmed by the inhibition of MAPK, PI3K/AKT, NF-kβ, and uPA signaling pathways.[38]
In a similar way, UA also regulates the others substance that are associated with the initiation and progression of cancer.[16] The activity of proteases such as urokinase and cathepsin B correlated with cancer invasion and metastasis have been significantly inhibited after UA treatment.[39] Shanmugam et al. presented a study on TRAMP mice revealed that UA inhibits the cancer growth by suppressing proinflammatory cytokines and CXCR4/CXCL12 axis-dependent signaling pathways.[40] Furthermore, the same anticancer effect of UA was reported in H3255, A549, and Calu-6 cell lines which occurred through the inhibition of TGF-β1, Na(+)–K(+)-ATPase, and ICAM-1 expression.[41] Similarly, the inactivation of proteins that are associated with the adhesion and migration of tumor cells was reported in UA treated SW620 (human colonic adenocarcinoma cell line), B16-F10 (mouse melanoma cell line), and HepG2 cancer cell lines. Furthermore, using metastatic melanoma lung cancer C57BL/6 mice model, UA was sought as a promising antimetastatic drug.[42] Clearly, UA has the potential to suppress cancer metastasis to distant sites by regulating several cancer-associated mechanisms which provoke utilization of this molecule to inhibit the growth and increase patient's survival.
| Inhibition of Vascular Endothelial Growth Factor/vascular Endothelial Growth Factor Receptor | | |
Blood vessel formation which requires VEGF and VEGFR is a crucial process for invasion and migration of solid malignancies.[43],[44],[45] VEGF receptor family has three tyrosine kinase members VEGFR-1, VEGFR-2, and VEGFR-3 also called Flt-1, KDR/Flk-1, and Flt-4, respectively, and these regulates the blood and lymphatic vessel formation.[46] VEGF/VEGFRs pathway is a key regulator of angiogenesis, usually expressed in endothelial cells during healthy physiology, which is also reported to be expressed during malignancy and associated with tumor growth, migration, and chemoresistance.[47],[48],[49],[50] VEGF-A which is secreted by both cancer and stromal cells preferentially binds to VEGFR-2 present on endothelial cells surface and then stimulates new vessel formation.[43] It is also found that VEGF can synergize with EGFR to promote autocrine signal-mediated tumor cell proliferation.[51] Therefore, VEGF/VEGFRs pathway may be considered as an important therapeutic marker to block the angiogenesis, and hence, the cancer proliferation.[52] UA and Quer in different experiments have been proven as the blocker of angiogenesis by targeting the VEGF and VEGFRs. The inhibitory effect of UA on H-ras, VEGF, and beta FGF (βFGF) was also described in a study using rat models.[53] Further, evidence also determined that Quer causes inhibition of HIF-1α, a protein known for production and secretion of VEGF which is essential for the angiogenesis.[54],[55],[56] Quer has also noticed as an antiangiogenic molecule in human umbilical vein and artery endothelial cells (HUVECs) and prostate cancer mouse model by inhibiting VEGF-R2-regulated AKT/mTOR/P70S6K signaling pathway.[57],[58] Studies on C57BL/6 and RF/6A mice models suggested that Quer attenuates VEGF-induced cancer proliferation and migration.[59],[60]
Similarly, the study on C57BL/6 mice model described that UA suppressed the expression of VEGF and inducible nitric oxide (iNO) that has associated with angiogenesis initiation.[61] Saraswati et al. analyzed that the UA acted as anticancer molecule by downregulating angiogenesis promoting factors such as VEGF, iNO synthase, TNF-α in Swiss Albino mice model with EAC tumor and significantly inhibited the cancer cell growth.[62] In addition, Lin et al. described that the antiangiogenic effect of UA in vivo as well as in vitro in HT-29 through downregulation of VEGF-A and βFGF which downstream control several cancer signaling pathways [Figure 2].[63] | Figure 2: High-metabolic rate during proliferation shifted aerobic metabolism toward anaerobic which lead to hypoxia in the tumor microenvironment. Hypoxia activates the hypoxia-inducible factor-α which subsequently activates the ligand of vascular endothelial growth factor receptor and stimulates the endothelia cells. Inducible nitric oxide synthase is another factor that could start angiogenesis pathway by activating the vascular endothelial growth factor. Similarly, activated matrix metalloproteases degrade the extracellular matrix for tumor cell migration. The presence of ursolic acid/quercetin modulates the multiple molecules in the cancer cell and hence stop the angiogenesis and metastasis (adopted from Kashyap et al. 2017)
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| Inhibition of Hypoxia-Inducible Factor-1α | | |
Hypoxia or limited oxygen is a common condition in all solid malignancies where proliferating cells face deprived of oxygen and nutrients due to less blood supply.[64],[65] Under such environment, HIF-1α described as a key regulator of hypoxia-induced angiogenesis. Overexpressed HIF-1α regulates many substances that has associated with various aspects of the tumor, including angiogenesis, invasion and metastasis, cell survival, oxygen transport, iron metabolism, glycolysis, and glucose transport.[66],[67],[68],[69] It has found that it targets several genes including VEGFA, PIGF, VEGFR1, Tie-2, angiopoietin 1 and 2, MMPs, prolyl-4-hydroxylase, uPAR, FGF2, MCP-1, PDGF, SDF-1, and CXCR4, which has a significant role in angiogenesis.[7],[70],[71],[72],[73],[74] UA and Quer both phytochemicals with medicinal importance are considered as anticancer bioactive molecules in multiple studies. For example, a study utilizing Hep3B, Huh7, and HA22T cell lines, scientists claimed that UA suppresses the HIF-1α which then abolishes the expression of angiogenic factors such as VEGF and βFGF. Further, downregulation of HIF-1α could also be associated with the antioxidant effect of UA caused by reactive oxygen species (ROS) and NO species.[75] This flavonol molecule was found to inhibit several signaling pathways in malignancy associated with angiogenesis such as proliferation, cancer cell migration, and tube formation of endothelial cells.[76] Furthermore, the antiangiogenic effects of Quer were also proposed by chicken chorioallantoic membrane (CAM) assay.[77] Moreover, antitumor effect of Quer has associated with the reduced expression of endothelial NO synthase and arrest of mitotic microtubule polymerization in endothelial cells.[78],[79] Similarly, the antiangiogenic effect of Quer was also described in in vivo and in vitro studies on zebrafish embryos and HUVECs, respectively.[59] In addition, Quer also inhibited the ERK-signaling pathway determined in in vivo and in vitro studies.[59],[80],[81] This plant-derived molecule significantly suppressed TPA-induced activation of PKCd/ERK/AP-1-signaling in human breast cancer.[82] In MDA-MB-231 cells, an elevation in connexin 43 levels was noted after Quer treatment which ameliorated gap junctional intercellular communication, and hence, block the cancer proliferation and metastasis.[83] Thrombospondin-1, an endogenous antiangiogenic factor, was found to be upregulated in the presence of Quer which resulted in the suppression of prostate cancer PC-3 cell.[84] Quer also acted against the HGF/c-Met signaling pathway that has been proved by its inhibitory action on melanoma.[85] Since Quer inhibits multiple targets in angiogenesis and/or metastasis, it may be used as a potential anticancer drug molecule.
In addition, in vivo CAM assay revealed the potential role of UA in the inhibition of the newly forming vascularization system in the tumor mass.[86] Authors reported that UA treatment resulted in inhibition of STAT3, Akt/p70S6K, and sonic hedgehog signaling pathways which are already correlated with tumor survival, proliferation, invasion, and angiogenesis.[63] Clearly, UA has the potential to suppress tumor angiogenesis through numerous mechanisms, thereby this molecule could be considered as a potential tumor inhibiting agent in the years to come.
| Antioxidative Potential of Ursolic Acid and Quercetin | | |
The microenvironment of the tumor is known to be affected by ROS generated during the high-rate metabolism. Further, these ROS have also been associated with the initiation and progression of other diseases such as neurodegeneration and cardiovascular.[87] Previous studies have shown that natural metabolites can be utilized as promising therapeutic agents to neutralize these ROS molecules. Proven in multiple studies, Nrf2 regulates the genes for antioxidant enzymes such as superoxide dismutase, catalase, glutathione, and glutathione peroxidase contains replication elements (AREs). Various in vivo and in vitro models have shown that UA may not only overturned the reduced expression of these enzymes but may also significantly enhanced the survival rate.[88] Similarly, the hepatoprotective role of UA was observed against ethanol-induced oxidative effect in rat through modulating the expression levels of stress-associated molecular markers including ascorbic acid and tocopherol.[89] Furthermore, Quer has also been found to directly affect the ARE binding activity as well as gene expression of NQO1 in HepG2 cells.[90] In addition, Quer also known to stabilize Nrf2 protein by averting its degradation as well as by decrementing the expression levels of Keap1 repressor protein.[90] Similar effects of Quer have also been documented in various other cell lines such as colorectal adenocarcinoma (Caco-2 cells) and duodenum adenocarcinoma (HuTu 80) cells.[91]
| Drug Dosage and Toxicological Aspects of Ursolic Acid and Quercetin | | |
Evidence has clearly suggested that UA and Quer might be utilized as valuable therapeutic agents for the treatment of the human cancers.[16],[18] However, drug dosage and toxicological studies of both molecules are further needed to be defined accurately. Besides, a number of positively published reports, few studies have reported the genotoxic effects of Quer.[92],[93] For example, at a concentration of 1133 mg/kg body weight/day in the male Wistar rats, Quer decreased the systolic blood pressure as well as cardiac hypertrophy along with increased in proteinuria.[94] In a 6-week study using Long-Evans Cinnamon rats, it was noted that 1% administration of Quer in the diet may lead to tubular necrosis.[95] On the other hand, toxicological study using UA has reported its LD50 concentration at 9.26 g/kg and nongenotoxic effects of UA extract.[96] Toxicological and pharmacokinetics studies of UAL (Ursolic acid liposomes) on 63 controls have revealed the manageable side effects with a tolerable dosage of 98 mg/m 2.[97]
| Conclusions and Future Perspectives | | |
Evidence has supported that naturopathy significantly helps cure the difficult to treat diseases.[11],[98],[99] Being natural dietary molecules, UA and Quer possess lesser side effects as compared to cytotoxic drugs. These moieties also exhibit important anti-inflammatory and antioxidant effects by regulating the expression of Nrf-2 and NF-kβ. Since chronic inflammation has been significantly associated with initiation and progression of various human cancer types such as breast cancer, lung cancer, and colon cancer, the anti-inflammatory of these molecules further contributes to their anticancer role.[16],[100] Synergistically, in combination with natural or synthetic drugs, these bioactive molecules have been successfully shown to have the enhanced efficacy.[101] Therefore, the available information on antiangiogenic and antimetastatic role of UA and Quer may help the scientific community to design the novel therapeutic strategy which may increase the disease-free survival.In vitro studies and limited preclinical in vivo studies have suggested potential role of both UA and Quer in chemoprevention or cancer therapy, but lacking human data restricts their clinical use. A human study conducted to assess the potential role of Quer in ovarian cancer prevention concluded that dietary availability Quer did not decreased the risk of ovarian cancer.[102] In addition, it was shown that Quer exacerbated estrogen-induced breast tumors in rats.[103] Consequently, to increase the clinical utility of these phytochemicals, more data on human health control has to be required.
Acknowledgement
The authors fully acknowledge Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh for providing the requisite facility for the study.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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