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Review

Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention

by
Pratibha Pandey
1,†,
Fahad Khan
1,*,†,
Huda A. Qari
2 and
Mohammad Oves
3,*
1
Department of Biotechnology, Noida Institute of Engineering and Technology, 19, Knowledge Park-II, Institutional Area, Greater Noida 201306, India
2
Department of Biological Science, Faculty of Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia
3
Center of Excellence in Environmental Studies, King Abdulaziz University, Jeddah 21589, Saudi Arabia
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally for this manuscript.
Pharmaceuticals 2021, 14(11), 1069; https://doi.org/10.3390/ph14111069
Submission received: 26 September 2021 / Revised: 16 October 2021 / Accepted: 18 October 2021 / Published: 22 October 2021
(This article belongs to the Topic Compounds with Medicinal Value)
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Abstract

:
Cancer is a complex ailment orchestrated by numerous intrinsic and extrinsic pathways. Recent research has displayed a deep interest in developing plant-based cancer therapeutics for better management of the disease and limited side effects. A wide range of plant-derived compounds have been reported for their anticancer potential in the quest of finding an effective therapeutic approach. Rutin (vitamin P) is a low-molecular weight flavonoid glycoside (polyphenolic compound), abundantly present in various vegetables, fruits (especially berries and citrus fruits), and medicinal herbs. Numerous studies have delineated several pharmacological properties of rutin such as its antiprotozoal, antibacterial, anti-inflammatory, antitumor, antiviral, antiallergic, vasoactive, cytoprotective, antispasmodic, hypolipidemic, antihypertensive, and antiplatelet properties. Specifically, rutin-mediated anticancerous activities have been reported in several cancerous cell lines, but the most common scientific evidence, encompassing several molecular processes and interactions, including apoptosis pathway regulation, aberrant cell signaling pathways, and oncogenic genes, has not been thoroughly studied. In this direction, we attempted to project rutin-mediated oncogenic pathway regulation in various carcinomas. Additionally, we also incorporated advanced research that has uncovered the notable potential of rutin in the modulation of several key cellular functions via interaction with mRNAs, with major emphasis on elucidating direct miRNA targets of rutin as well as the process needed to transform these approaches for developing novel therapeutic interventions for the treatment of several cancers.

1. Introduction

Cancer is a multifactorial ailment with an entangled cell landscape highlighted by a chain of complex molecular mechanisms and interactions. Advancements in proteomic- and genomic-based approaches have made it possible to unveil the tumor microenvironment in order to gain a better insight into key mechanisms such as overexpression, gene suppression, altered cellular signaling pathways, genomic instability, and mutations at the genetic/epigenetic level within the genetic framework involved in cancer progression [1,2].
Accumulating evidence has led to plant extract-based formulations and compounds gaining special attention in the management of several malignancies including cancer, neurodegenerative disorders, cardiovascular diseases, and diabetes [3,4]. Further, they have displayed significant potential in modulating the expression of chief signaling pathways associated with cancer progression [5,6,7,8]. Numerous plant-based chemotherapeutic drugs have displayed significant increases in the anticancer efficacies of numerous chemotherapeutic agents, including vinblastine, doxorubicin, camptothecin, and paclitaxel [9,10,11]. Plant metabolites have displayed pleiotropic efficacies, and they target numerous cancer hallmarks such as inflammation, angiogenesis, cancer cell growth and proliferation, invasion, migration, and metastasis [12,13,14].
The name rutin (green-yellow-colored, needle-shaped crystal) originates from Ruta graveolens L., a plant that is rich in rutin. Rutin has also been named rutoside, vitamin P, quercetin-3-O-rutinoside, and sophorin, with the chemical formula, C27H30O16 and a molecular weight of 610.53. The natural sources of rutin are fruits, medicinal herbs, and plants (Figure 1A,B).
Rutin can be considered a safe anticancerous agent with very few or limited side effects (such as MDR (multiple drug resistance)) and limitations (high cost) in comparison to other cancer therapies including surgery, stem cell therapy, radiotherapy, chemo/immunotherapies, and photodynamic therapy [15,16,17,18,19]. This has further motivated us to comprehensively cover the therapeutic potential of rutin in tumor proliferation and invasiveness leading to apoptotic induction in cancerous cells. Rutin is a naturally occurring bioflavonoid abundantly reported in medicinal herbs, fruits, vegetables, and plant-based beverages. Research has further presented the in vitro potential of rutin in the suppression of numerous human cancers such as lung cancer, prostate cancer, colorectal cancer, breast cancer, liver cancer, glioblastoma, melanoma, osteosarcoma, ovarian cancer, leukemia, cervical cancer, and pancreatic cancer via apoptosis induction, immunity enhancement, or cell migration knockdown, which leads to a significant reduction in the motility rate of cancerous cells [20,21,22,23,24].

2. Anticancerous Therapeutic Potential of Rutin

Rutin has been reported to counteract numerous cancers via several mechanisms such as cell cycle arrest, inflammation, malignant cell growth inhibition, oxidative stress, apoptosis induction, and angiogenesis modulation, and all of these are mediated through the regulation of cellular signaling pathways. Several in vitro studies have reported the significant anticancerous potential of rutin via its inhibition of the proliferation of several cancer types including glioma, breast, liver, pancreas, colon, lung, prostate, skin, ovarian, and cervical cancer (Table 1).
Apoptosis has been recognized as a crucial phenomenon for the maintenance of balanced cell growth [68]. However, altered cell signaling has been widely reported with a distressed apoptotic balance, leading to cancer proliferation and invasiveness. DDR (death receptor pathway) initiation has been linked with TRAIL (TNF-related apoptosis inducing ligand) and FasL (Fas ligand) binding with transmembrane receptors. This interaction ultimately results in caspase activation that subsequently promotes apoptosis pathway (intrinsic or extrinsic) activation. In addition, apoptosome formation (associated with caspase-9, cytochrome-C, and apoptotic protease-activating factor) triggers caspase-3 activation, leading to cell death. Several in vitro and in vivo studies have elaborated the chemopreventive potential of rutin against several cancer types (Table 2).

3. Interaction of Rutin with Numerous Molecular Signaling Pathways

Cancer cells rapidly develop drug resistance against various therapeutic approaches which presents a major hindrance in the cancer management research of several pharmacologists and molecular biologists. This has further motivated researchers to develop drugs with limited cytotoxicity and high specificity. The following subsection explains rutin’s interactions with various molecular pathways.

3.1. Rutin’s Involvement in Modulation of Akt/PI3K/mTOR Signaling Pathway

Gene expression, translation, and transcription, and cell growth and proliferation are some of the major roles controlled by the Akt/PI3K/mTOR signaling pathway. Several reports have established the association between abrogation in this signaling cascade and the progression of numerous carcinomas by triggering tumor growth, invasion, and metastasis [81,82]. In brief, PI3K is found downstream of tyrosine kinase growth receptors, due to which mutations in the Akt protein can inversely affect effector proteins and downstream signaling, thereby stimulating cancer cell growth and development [83]. Rutin has been found to employ its effect on the AkT/PI3K/mTOR pathway by modulating the expression of several key proteins, including AkT, PTEN, ERK, and others [84,85,86]. Later, it was further reported that rutin blocks the cross-talk between AkT and PI3K by blocking PI3K activity. Rutin treatment has also resulted in the attenuation of H2O2-induced oxidative damage and in apoptotic induction in Leydig cells via PI3K/Akt signaling pathways [87]. In addition, rutin prevents AkT phosphorylation by disturbing the PI3K-ATP binding domain and mTORC2 complex. Rutin mediated apoptotic induction via modulating Bcl-2, Bax, and caspase expression levels and also induced antioxidant activity by increasing antioxidants levels [88]. Rutin also deregulated the expression of numerous molecules, including GSK-3 (Glycogen synthase kinase-3). Further, rutin promoted TNF-α-induced apoptosis in A549 human lung cancer cells by modulating the expression level of the GSK-3β protein [89]. Rutin has also prevented GSK-3β phosphorylation by regulating PI3K expression and has displayed protection against γ-radiation or acrylamide-induced neurotoxicity through activation of the PI3K/AKT pathway by deregulating phosphorylation. Rutin prevents GSK-3β (AkT target) phosphorylation via PI3K inhibition [90]. Additionally, rutin has also been reported to increase the expression level of tumor suppressor proteins including FOXO3a, p21, KIP1, and CIP/WAF. The increased expression levels of these reported tumor suppressor proteins further promoted growth arrest in cancer cells. Rutin treatment prevented cisplatin (CP)-induced ovarian damage by regulating FOXO3a and PTEN phosphorylation and antioxidant activity in a mouse model [91]. Rutin has also been associated with the regulation of mTOR activity by modulating TSC2 expression [92]. Rutin-mediated protein kinase β activation promotes AMPK activation which results in TSC2 phosphorylation and inhibition of mTOR activity [93,94,95]. Altogether, these findings strongly suggest a reciprocal feedback mechanism which involves mTOR and AMPK in cancer cells and could be targeted for elucidating and developing potent therapeutics.

3.2. Rutin’s Involvement in Modulation of STAT Signaling

The STAT pathway is an evolutionarily conserved signaling pathway that is involved in the regulation of numerous cell processes including inflammation, immune cell development, migration, cell survival, apoptosis, cell homeostasis, and cell proliferation. Aberrant STAT signaling has been recognized as a hallmark of numerous cancers [96,97,98,99]. Rutin has been exploited for its potential role in inhibiting cancer cell growth and metastasis by inhibiting this signaling pathway. Rutin modulates this cellular pathway via the repression of SRC (kinases) phosphorylation, thereby inhibiting STAT 3 (signal transducers and activators of transcription 3) activation which further blocks the translocation of STAT to the nucleus [100,101]. STAT 3 has also been associated with the regulation of MMPs (membrane metalloproteases), VEGF, and TWIST1 which are crucial for cancer cell migration, proliferation, invasion, and angiogenesis. Rutin blocks the activation of TWIST1, MMPs, and VEGF via the inhibition of STAT3 phosphorylation [102,103]. Another study also reported that rutin treatment blocked UVB-induced STAT 3 activation via the inhibition of Tyr705 phosphorylation which explains the usefulness of rutin in preventing skin cancer [103]. Several studies have evidenced its potential anticancerous role in regulating the expression of key signaling components (STAT5, STAT3, and JAK2) in numerous carcinomas, thereby preventing cancer cell growth and differentiation (Figure 2).

3.3. Rutin’s Involvement in Modulation of Wnt/β Catenin Signaling

Wnt/β catenin signaling contributes a crucial role in differentiation, organogenesis, cell migration, tissue homeostasis, and neuronal patterning. Modulated Wnt/β catenin signaling has been associated with the invasiveness and progression of several carcinomas [104,105,106]. Rutin has also been reported to induce variation in the expression level of downstream effectors of Wnt/β catenin signaling, including AXIN2, c-MYC, and cyclin D1 [107]. Further research studies have also revealed that rutin prevents the stabilization and accumulation of β-catenin in the cytoplasm and also blocks its translocation in the nucleus via the repression of the PI3K/AkT/mTOR pathway [68]. From these research findings, it can be concluded that rutin can be considered a potent therapeutic option for the management of numerous carcinomas.

3.4. Rutin’s Involvement in Modulation of MAPK Signaling

The MAPK family consists of three major classes of activated kinases including ERK/MAPK, p38 kinase, and c-JUN/SAPK that play a crucial role in cell proliferation, invasion, homeostasis, and differentiation and cell death. Overexpression of numerous ERK protein family members has been exclusively reported in the modulation of the MAPK-ERK pathway [108]. In numerous carcinomas, ERK signaling is activated via mutation in either the tyrosine kinase receptor or the kinase genes RAS and RAF. Rutin has presented significant antiproliferative effects in numerous cancer cell lines by modulating the expression of DR4/DR5, AkT, ERK, and NF-kB. Rutin exposure has promoted TRAIL-mediated apoptosis in numerous carcinomas such as lung cancer [109,110,111,112]. Additionally, rutin has been utilized to suppress the growth, invasion, proliferation, and metastasis of several melanoma cells. Specifically, in A375 and C8161 melanoma cell lines, rutin administration promoted growth arrest via the downregulation of p-AkT, p-ERK1/2, and p-mTOR. Rutin treatment has significantly downregulated the expression level of p-ERK1/2 (phospho-extracellular signal-regulated kinase 1/2) in glioma cells [113]. Other studies have also reported that rutin treatment leads to a significant reduction in the expression level of p38 MAPK in lung cancer (A549) cells. Moreover, rutin has strong potential to activate p38 MAPK in colon cancer cells (HT-29), either alone or in combination with silibinin [112]. Conclusively, these experimental findings shed enormous light on the fact that rutin can induce apoptosis via the suppression of the aberrant MAPK/ERK signaling pathway.

3.5. Rutin’s Targeting of Apoptotic Pathways and Autophagy Signaling Molecules

Rutin has presented potent efficacy in apoptosis induction in cancer cells. Rutin elicited the intrinsic apoptosis pathway in neuroblastoma cells as shown by the reduced Bcl2 protein and Bcl2/Bax ratio [114]. Likewise, in HCT (colon cancer) cells, rutin treatment induced caspase-3 activation [43]. Furthermore, rutin has been shown to activate both the intrinsic and extrinsic apoptotic pathways in colon cancer cells (HT-29) by upregulating caspases and Bax, and downregulating Bcl-2 levels [110]. This evidence strongly supports the apoptosis-inducing potential of rutin in cancer cells via the induction of both the intrinsic (mitochondria-mediated) and extrinsic (death receptor-mediated) apoptotic pathways.
Rutin exposure to cancer cells can also induce apoptosis via p53 activation [33,54,110]. Rutin treatment can also lead to an increase in the PTEN (tumor suppressor) mRNA expression level, resulting in apoptosis-mediated growth arrest in breast cancer cells [33,115]. ER targeting has also emerged as one of the promising approaches for cancer prevention and treatment [116]. A study conducted by Nasri Nasrabadi [44] et al. identified altered molecular signaling pathways and differentially expressed genes in rutin-treated colorectal cancer cell lines. ROS (reactive oxygen species), generated during metabolism, are also associated with numerous physiological functions. The balance between ROS production and their elimination via the antioxidant defense system is properly regulated in normal cells, whereas ROS homeostasis is dysregulated in cancerous cells, leading to elevated ROS levels. ROS have also been explored as a potent therapeutic tool for cancer management because elevated ROS generation could trigger apoptosis in cancer cells [117]. Rutin treatment has induced significant apoptosis by activating ROS-dependent apoptosis pathways in numerous cancer cells including MCF-7, HepG2, LoVo, HeLa, and C33A cancer cells [35,40].
Deregulated autophagy (catabolic process) has also been crucially associated with several cancer types. Signaling molecules such as ATGs (autophagy-related genes), which are mainly involved in autophagy, include ATG6, ATG5, ATG12, and LC3 (microtubule associated protein 1 A/1B-light chain 3). Several studies have projected that autophagy greatly contributes to the inhibition of cancer cell growth. Further, rutin treatment has induced autophagy in several cancer cells such as A549, THP1, and CA9-22. Rutin treatment has also resulted in an enhanced expression level of Beclin1 and has triggered the formation of the ATG5/12 complex. LC3-II (hallmark of autophagy) activation was also observed in rutin-treated cancer cells, thereby leading to autophagy-mediated cancer cell death [57].

4. Rutin and miRNA (microRNAs) Interplay: Potent Approach in Cancer Management

MicroRNAs (small molecules with a size range of 10–25 bp) have received profound attention in cancer management therapies because of their potent involvement in gene transcription and translation [118]. Several studies have reported that dysregulated microRNAs (miRNA) make major contributions to cancer progression and thus they can be considered an effective target in cancer therapies. This section focuses on revealing the interplay between rutin and miRNAs, and how rutin treatment modulates the expression of various tumor suppressor and oncogenic miRNAs in cancer. Recently, it has come to light that rutin restrains the proliferation of mouse breast cancer cells via the regulation of the miR-129-1-3p/Ca2+ signaling pathway, thereby revealing its potential as a strong drug candidate for the inhibition of tumor growth. Rutin, in combination with various miRNA mimics and inhibitors, has aided in cell apoptosis or growth arrest in numerous cancer cells [119,120]. Rutin has also shown significant inhibition of myocardial oxidative insults by adjusting ROS (reactive oxygen species) levels. This further explains the protective effect of rutin on THP cardiotoxicity via the regulation of JunD gene expression by miR-125b-1-3p, which reveals the protective efficacy of rutin on THP-induced cardiotoxicity and provides a strong base for the utilization of rutin as a potent protective candidate against THP cardiotoxicity. Thus, it may be concluded that rutin could modulate several cancer-relevant miRNAs such as miR-155, let-7, miR-146a, and miR-21, thereby potentially inhibiting cancer development and progression [121,122,123,124]. However, more experimental research is still needed to study how rutin modulates this complex and broad range of both tumor suppressor and oncogenic miRNAs. Therefore, future studies should emphasize elucidating direct miRNA targets of rutin as well the process needed in transforming these approaches for developing novel therapeutic interventions for numerous cancers.

5. Conclusions

In several natural products, rutin contributes to potent biological activities including anticancerous effects. Rutin has been shown to utilize numerous mechanisms to obstruct cancer initiation and progression by modulating several deregulated signaling pathways involved in apoptosis, inflammation, angiogenesis, and autophagy. Specifically, the anticancer potential of rutin has been linked to the regulation of multiple signaling pathways, including NF-κB, PI3K/Akt/mTOR, Nrf2, ERK, JNK, and p38 MAPK. This bioactive plant-derived compound significantly interferes with numerous intracellular signaling molecules, such as TNF-α, Bax, ILs, Beclin, VEGF, Bcl-2, and caspases. Extensive in vitro and in vivo studies have clearly revealed therapeutic targets of rutin such as Bcl-2, p53, caspases, Bax, NF-κB, TNF-α, Akt, and GSH. Rutin has shown tremendous anticancer potential against a range of cancer cell lines including glioblastoma, breast cancer, lung adenocarcinoma, prostate cancer, cervical cancer, gastric cancer, leukemia, hepatocellular carcinoma, and colon cancer cell lines. Despite several preclinical mechanistic reports on the anticancer efficacies of rutin, the lack of well-framed clinical trials on the safety and therapeutic potential of rutin increases the need for more potent clinical studies. Further, more elaborative studies (concerning engineering methods) are also needed to achieve a better targeted drug delivery approach for cancer management. Altogether, researchers should focus their study towards elucidating the novel molecular targets of rutin and the associated mechanism by which rutin mediates cancer cell growth arrest via molecular cross-talks and signaling cascades. Overall, rutin has enormous medicinal potential and could be employed as a potent therapeutic agent through extensive investigation into its potential to modulate numerous cell signaling pathways and apoptosis pathways involved in cancer progression.

Author Contributions

Conceptualization, P.P. and F.K.; methodology, P.P. and F.K.; resources, P.P. and F.K.; writing—original draft preparation, P.P. and F.K.; writing—review and editing, P.P. and F.K.; visualization, P.P. and F.K.; supervision, P.P. and F.K.; project administration, P.P., F.K., H.A.Q. and M.O.; writing—review and editing, H.A.Q. and M.O.; funding acquisition, H.A.Q. and M.O. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Dean of Scientific Research (DSR), King Abdulaziz University, Jeddah (IFPRP:332-188-1442), with the name of the Institutional Funding Program.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data sharing not applicable.

Acknowledgments

We are highly grateful to the Dean of Scientific Research (DSR), King Abdulaziz University, Jeddah, for providing the grant (IFPRP:332-188-1442) with the name of the Institutional Funding Program.

Conflicts of Interest

The authors declare that they have no conflict of interest.

References

  1. The ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium. Pan-cancer analysis of whole genomes. Nature 2020, 578, 82–93. [Google Scholar] [CrossRef] [Green Version]
  2. Chen, Y.; Henson, E.S.; Xiao, W.; Huang, D.; McMillan-Ward, E.M.; Israels, S.J.; Gibson, S.B. Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia. Autophagy 2016, 12, 1029–1046. [Google Scholar] [CrossRef] [Green Version]
  3. Fakhri, S.; Abbaszadeh, F.; Jorjani, M.; Pourgholami, M.H. The effects of anticancer medicinal herbs on vascular endothelial growth factor based on pharmacological aspects: A review study. Nutr. Cancer 2019, 73, 1–15. [Google Scholar] [CrossRef]
  4. Ochwang’i, D.O.; Kimwele, C.N.; Oduma, J.A.; Gathumbi, P.K.; Mbaria, J.M.; Kiama, S.G. Medicinal plants used in treatment and management of cancer in Kakamega County, Kenya. J. Ethnopharmacol. 2014, 151, 1040–1055. [Google Scholar] [CrossRef]
  5. Slattery, M.L.; Herrick, J.S.; Mullany, L.E.; Samowitz, W.S.; Sevens, J.R.; Sakoda, L.; Wolff, R.K. The co-regulatory networks of tumor suppressor genes, oncogenes, and miRNAs in colorectal cancer. Genes Chromosom Cancer 2017, 56, 769–787. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  6. Croce, C.M.; Reed, J.C. Finally, an apoptosis-targeting therapeutic for cancer. Cancer Res. 2016, 76, 5914–5920. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  7. Monkkonen, T.; Debnath, J. Inflammatory signaling cascades and autophagy in cancer. Autophagy 2018, 14, 190–198. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  8. Telkoparan-Akillilar, P.; Panieri, E.; Cevik, D.; Suzen, S.; Saso, L. Therapeutic targeting of the NRF2 signaling pathway in cancer. Molecules 2021, 26, 1417. [Google Scholar] [CrossRef]
  9. Mahato, M.; Patra, S.; Gogoi, M. Herbal Nanocarriers for cancer therapy. In Nanopharmaceuticals: Principles and Applications; Springer: Cham, Switzerland, 2021; Volume 2, pp. 41–75. [Google Scholar]
  10. Najafi, M.; Mortezaee, K.; Rahimifard, M.; Farhood, B.; Haghi-Aminjan, H. The role of curcumin/curcuminoids during gastric cancer chemotherapy: A systematic review of non-clinical study. Life Sci. 2020, 257, 118051. [Google Scholar] [CrossRef]
  11. Bishayee, A.; Sethi, G. Bioactive natural products in cancer prevention and therapy: Progress and promise. Semin. Cancer Biol. 2016, 40–41, 1–3. [Google Scholar] [CrossRef]
  12. Bordoloi, D.; Roy, N.K.; Monisha, J.; Padmavathi, G.; Kunnumakkara, A. Multi-targeted agents in cancer cell chemosensitization: What we learnt from curcumin thus far. Recent Pat. Anticancer Drug Discov. 2016, 11, 67–97. [Google Scholar] [CrossRef]
  13. Fakhri, S.; Khodamorady, M.; Naseri, M.; Farzaei, M.H.; Khan, H. The ameliorating effects of anthocyanins on the cross-linked signaling pathways of cancer dysregulated metabolism. Pharmacol. Res. 2020, 159, 104895. [Google Scholar] [CrossRef] [PubMed]
  14. Braicu, C.; Zanoaga, O.; Zimta, A.-A.; Tigu, A.B.; Kilpatrick, K.L.; Bishayee, A.; Nabavi, S.M.; Berindan-Neagoe, I. Natural compounds modulate the crosstalk between apoptosis-and autophagy-regulated signaling pathways: Controlling the uncontrolled expansion of tumor cells. In Seminars in Cancer Biology; Academic Press: Cambridge, MA, USA, 2020. [Google Scholar] [CrossRef]
  15. Prasad, R.; Prasad, S.B. A review on the chemistry and biological properties of Rutin, a promising nutraceutical agent. Asian J. Pharm. Pharmacol. 2019, 5, 1–20. [Google Scholar] [CrossRef]
  16. Yang, C.-Y.; Hsiu, S.-L.; Wen, K.-C.; Lin, S.-P.; Tsai, S.-Y.; Hou, Y.-C.; Chao, P.-D. Bioavailability and metabolic pharmacokinetics of rutin and quercetin in rats. J. Food Drug Anal. 2005, 13, 5. [Google Scholar] [CrossRef]
  17. Gautam, R.; Singh, M.; Gautam, S.; Rawat, J.K.; Saraf, S.A.; Kaithwas, G. Rutin attenuates intestinal toxicity induced by Methotrexate linked with anti-oxidative and anti-inflammatory effects. BMC Complement. Altern. Med. 2016, 16, 99. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  18. Satari, A.; Ghasemi, S.; Habtemariam, S.; Asgharian, S.; Lorigooini, Z. Rutin: A Flavonoid as an Effective Sensitizer for Anticancer Therapy; Insights into Multifaceted Mechanisms and Applicability for Combination Therapy. Evid.-Based Complement. Altern. Med. 2021, 2021, 9913179. [Google Scholar] [CrossRef]
  19. Zheng, Y.; Zhao, Z.; Fan, L.; Meng, S.; Song, C.; Qiu, L.; Xu, P.; Chen, J. Dietary supplementation with rutin has pro-/anti-inflammatory effects in the liver of juvenile GIFT tilapia, Oreochromis niloticus. Fish Shellfish. Immunol. 2017, 64, 49–55. [Google Scholar] [CrossRef]
  20. Perk, A.A.; Shatynska-Mytsyk, I.; Gerçek, Y.C.; Boztaş, K.; Yazgan, M.; Fayyaz, S.; Farooqi, A.A. Rutin mediated targeting of signaling machinery in cancer cells. Cancer Cell Int. 2014, 14, 1–5. [Google Scholar] [CrossRef] [Green Version]
  21. Paudel, K.R.; Wadhwa, R.; Tew, X.N.; Lau, N.J.X.; Madheswaran, T.; Panneerselvam, J.; Zeeshan, F.; Kumar, P.; Gupta, G.; Anand, K.; et al. Rutin loaded liquid crystalline nanoparticles inhibit non-small cell lung cancer proliferation and migration in vitro. Life Sci. 2021, 276, 119436. [Google Scholar] [CrossRef] [PubMed]
  22. Chang, C.; Zhang, L.; Miao, Y.; Fang, B.; Yang, Z. Anticancer and apoptotic-inducing effects of rutin-chitosan nanoconjugates in triple negative breast cancer cells. J. Clust. Sci. 2021, 32, 331–340. [Google Scholar] [CrossRef]
  23. Hoai, T.T.; Yen, P.T.; Dao, T.T.B.; Long, L.H.; Anh, D.X.; Minh, L.H.; Anh, B.Q.; Thuong, N.T. Evaluation of the Cytotoxic Effect of Rutin Prenanoemulsion in Lung and Colon Cancer Cell Lines. J. Nanomater. 2020, 2020, 1–11. [Google Scholar] [CrossRef]
  24. Goitia, H.; Quispe, P.; Naso, L.G.; Martínez, V.R.; Rey, M.; Rizzi, A.C.; Ferrer, E.G.; Williams, P.A. Interactions of rutin with the oxidovanadium (iv) cation. Anticancer improvement effects of glycosylated flavonoids. New J. Chem. 2019, 43, 17636–17646. [Google Scholar] [CrossRef]
  25. Fu, Y.; Sui, B.; Xiang, L.; Yan, X.; Wu, D.; Shi, S.; Hu, X. Emerging understanding of apoptosis in mediating mesenchymal stem cell therapy. Cell Death Dis. 2021, 12, 1–12. [Google Scholar] [CrossRef]
  26. Li, X.H.; Liu, Z.Y.; Gu, Y.; Lv, Z.; Chen, Y.; Gao, H.C. Expression of NF-kappaB and p38 under intervention of rutin in lung cancer therapy. Biomed. Res. 2017, 28, 2344–2347. [Google Scholar]
  27. ben Sghaier, M.; Pagano, A.; Mousslim, M.; Ammari, Y.; Kovacic, H.; Luis, J. Rutin inhibits proliferation, attenuates superoxide production and decreases adhesion and migration of human cancerous cells. Biomed. Pharmacother. 2016, 84, 1972–1978. [Google Scholar] [CrossRef]
  28. Vasilijević, B.; Knežević-Vukčević, J.; Mitić-Ćulafić, D.; Orčić, D.; Francišković, M.; Srdic-Rajic, T.; Jovanović, M.; Nikolić, B. Chemical characterization, antioxidant, genotoxic and in vitro cytotoxic activity assessment of Juniperus communis var. saxatilis. Food Chem Toxicol. 2018, 112, 118–125. [Google Scholar] [CrossRef]
  29. Zhang, Z.; Shi, J.; Nice, E.C.; Huang, C.; Shi, Z. The Multifaceted Role of Flavonoids in Cancer Therapy: Leveraging Autophagy with a Double-Edged Sword. Antioxidants 2021, 10, 1138. [Google Scholar] [CrossRef]
  30. Choiprasert, W.; Dechsupa, N.; Kothan, S.; Garrigos, M.; Mankhetkorn, S. Quercetin, quercetrin except rutin potentially increased pirarubicin cytotoxicity by non-competitively inhibiting the P-glycoprotein-and MRP1 function in living K562/adr and GLC4/adr cells. Am. J. Pharm. Toxicol. 2010, 5, 24–33. [Google Scholar] [CrossRef]
  31. Ghasemzadeh, A.; Jaafar, H.Z.; Rahmat, A.; Devarajan, T. Evaluation of bioactive compounds, pharmaceutical quality, and anticancer activity of curry leaf (Murraya koenigii L.). Evid.-Based Complement. Altern. Med. 2014, 2014, 873803. [Google Scholar] [CrossRef] [Green Version]
  32. Makrane, H.; El Messaoudi, M.; Melhaoui, A.; El Mzibri, M.; Benbacer, L.; Aziz, M. Cytotoxicity of the Aqueous Extract and Organic Fractions from Origanum majorana on Human Breast Cell Line MDA-MB-231 and Human Colon Cell Line HT-29. Adv. Pharmacol. Sci. 2018, 2018, 3297193. [Google Scholar] [CrossRef] [Green Version]
  33. Hasani, N.A.H.; Amin, I.M.; Kamaludin, R.; Rosdyd, N.M.M.N.M.; Ibahim, M.J.; Kadir, S.H.S.A. P53 and cyclin B1 mediate apoptotic effects of apigenin and rutin in ERaþ-breast cancer MCF-7 cells. J. Teknol. 2018, 80, 133–140. [Google Scholar]
  34. Noman, O.M.; Nasr, F.A.; Alqahtani, A.S.; Al-zharani, M.; Cordero, M.A.W.; Alotaibi, A.A.; Asmatanzeem, B.; Saud, A.; Daoud, A. Comparative study of antioxidant and anticancer activities and HPTLC quantification of rutin in white radish (Raphanus sativus L.) leaves and root extracts grown in Saudi Arabia. Open Chem. 2021, 19, 408–416. [Google Scholar] [CrossRef]
  35. Yang, S.; Zhang, H.; Yang, X.; Zhao, H.; Zhu, Y. Evaluation of antiproliferative activities of rutin on human colon cancer LoVo cells and breast cancer MCF-7 cells. Anal. Quant. Cytopathol. Histopathol. 2017, 39, 99–107. [Google Scholar]
  36. Iriti, M.; Kubina, R.; Cochis, A.; Sorrentino, R.; Varoni, E.M.; Kabała-Dzik, A.; Azzimonti, B.; Dziedzic, A.; Rimondini, L.; Wojtyczka, R.D. Rutin, a Quercetin Glycoside, Restores Chemosensitivity in Human Breast Cancer Cells. Phytother. Res. 2017, 31, 1529–1538. [Google Scholar] [CrossRef]
  37. Alonso-Castro, A.J.; Domınguez, F.; Garcıa-Carranca, A. Rutin exerts antitumor effects on nude mice bearing SW480 tumor. Arch. Med. Res. 2013, 44, 346–351. [Google Scholar] [CrossRef]
  38. Deepika, M.S.; Thangam, R.; Sheena, T.S.; Sasirekha, R.; Sivasubramanian, S.; Babu, M.D.; Jeganathan, K.; Thirumurugan, R. A novel rutin-fucoidan complex based phytotherapy for cervical cancer through achieving enhanced bioavailability and cancer cell apoptosis. Biomed. Pharmacother. 2019, 109, 1181–1195. [Google Scholar] [CrossRef] [PubMed]
  39. Pandey, P.; Khan, F.; Maurya, P. Targeting Jab1 using hesperidin (dietary phytocompound) for inducing apoptosis in HeLa cervical cancer cells. J. Food Biochem. 2021, 45, e13800. [Google Scholar] [CrossRef] [PubMed]
  40. Khan, F.; Pandey, P.; Upadhyay, T.K.; Jafri, A.; Jha, N.K.; Mishra, R.; Singh, V. Anti-cancerous effect of rutin against HPVC33A cervical cancer cells via G0/G1 cell cycle arrest and apoptotic induction. Endocr. Metab. Immune Disord. Drug Targets 2020, 20, 409–418. [Google Scholar] [CrossRef] [PubMed]
  41. Guon, T.E.; Chung, H.S. Hyperoside and rutin of Nelumbo nucifera induce mitochondrial apoptosis through a caspase-dependent mechanism in HT-29 human colon cancer cells. Oncol. Lett. 2016, 11, 2463–2470. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Nafees, S.; Mehdi, S.H.; Zafaryab, M.; Zeya, B.; Sarwar, T.; Rizvi, M.A. Synergistic interaction of rutin and silibinin on human colon cancer cell line. Arch. Med. Res. 2018, 49, 226–234. [Google Scholar] [CrossRef]
  43. Jayameena, P.; Sivakumari, K.; Ashok, K.; Rajesh, S. Rutin: A potential anticancer drug against human colon cancer (HCT116) cells. Int. J. Biol. Pharm. Allied Sci. 2018, 7, 1731–1745. [Google Scholar]
  44. Nasri Nasrabadi, P.; Zareian, S.Z.; Nayeri, R.; Salmanipour, S.; Parsafar, E.; Gharib, E.H.A.; Zali, M.R. A detailed image of rutin underlying intracellular signaling pathways in human SW480 colorectal cancer cells based on miRNAs-lncRNAs-mRNAsTFs interactions. J. Cell. Physiol. 2019, 234, 15570–15580. [Google Scholar] [CrossRef]
  45. Romero, I.; Paez, A.; Ferruelo, A.; Lujan, M.; Berenguer, A. Polyphenols in red wine inhibit the proliferation and induce apoptosis of LNCaP cells. BJU Int. 2002, 89, 950–954. [Google Scholar] [CrossRef] [Green Version]
  46. Ding, Y.; Ren, K.; Dong, H.; Song, F.; Chen, J.; Guo, Y.; Liu, Y.; Tao, W.; Zhang, Y. Flavonoids from persimmon (Diospyros kaki L.) leaves inhibit proliferation and induce apoptosis in PC-3 cells by activation of oxidative stress and mitochondrial apoptosis. Chem. Biol. Interact. 2017, 275, 210–217. [Google Scholar] [CrossRef] [PubMed]
  47. Saleh, A.; El Fayoumi, H.M.; Youns, M.; Barakat, W. Rutin and orlistat produce antitumor effects via antioxidant and apoptotic actions. Naunyn Schmiedeb. Arch. Pharmacol. 2019, 392, 165–175. [Google Scholar] [CrossRef] [PubMed]
  48. Shen, Q.; Zhen, M.A.; Chen, G. Effect of rutin on proliferation of HepG2 cells. Acta Acad. Med. Mil. Tertiae 2006, 28, 1885–1887. [Google Scholar]
  49. Karakurt, S. Modulatory effects of rutin on the expression of cytochrome P450s and antioxidant enzymes in human hepatoma cells. Acta Pharm. 2016, 66, 491–502. [Google Scholar] [CrossRef] [Green Version]
  50. Li, Y.; Duan, S.; Jia, H.; Bai, C.; Zhang, L.; Wang, Z. Flavonoids from tartary buckwheat induce G2/M cell cycle arrest and apoptosis in human hepatoma HepG2 cells. Acta Biochim. Biophys. Sin. 2014, 46, 460–470. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  51. Alia, M.; Mateos, R.; Ramos, S.; Lecumberri, E.; Bravo, L.; Goya, L. Influence of quercetin and rutin on growth and antioxidant defense system of a human hepatoma cell line (HepG2). Eur. J. Nutr. 2006, 45, 19–28. [Google Scholar] [CrossRef] [PubMed]
  52. Marcarini, J.C.; Tsuboy, M.S.F.; Luiz, R.C.; Ribeiro, L.R.; Hoffmann-Campo, C.B.; Mantovani, M.S. Investigation of cytotoxic, apoptosis-inducing, genotoxic and protective effects of the flavonoid rutin in HTC hepatic cells. Exp. Toxicol. Pathol. 2011, 63, 459–465. [Google Scholar] [CrossRef]
  53. Chen, H.; Miao, Q.; Geng, M.; Liu, J.; Hu, Y.; Tian, L.; Pan, J.; Yang, Y. Anti-tumor effect of rutin on human neuroblastoma cell lines through inducing G2/M cell cycle arrest and promoting apoptosis. Sci. World J. 2013, 2013, 269165. [Google Scholar] [CrossRef] [Green Version]
  54. Yan, X.; Hao, Y.; Chen, S.; Jia, G.; Guo, Y.; Zhang, G.; Wang, C.; Cheng, R.; Hu, T.; Zhang, X.; et al. Rutin induces apoptosis via P53 up-regulation in human glioma CHME cells. Transl. Cancer Res. 2019, 8, 2005–2013. [Google Scholar] [CrossRef]
  55. Vad, N.; Naik, B.; Moridani, M. Abstract #678: Biochemical Mechanism of Rutin Toxicity in SK-MEL-28 Melanoma Cells: A Tyrosinase Bioactivation Prodrug Approach; American Association for Cancer Research (AACR): Denver, CO, USA; Philadelphia, PA, USA, 2009. [Google Scholar]
  56. Zhan, P.; Peng, X.S.; Xu, X.M.; Zhou, Y.F.; Zhang, X.P.; He, R.; Zhou, G.J. The anti-cancer study on combinating paeonol and rutin. Chin. Arch. Trad Chin. Med. 2010, 28, 1710–1712. [Google Scholar]
  57. Park, M.H.; Kim, S.; Song, Y.R.; Kim, S.; Kim, H.J.; Na, H.S.; Chung, J. Rutin induces autophagy in cancer cells. Int. J. Oral Biol. 2016, 41, 45–51. [Google Scholar] [CrossRef]
  58. Thani, W.; Vallisuta, O.; Siripong, P.; Ruangwises, N. Antiproliferative and antioxidative activities of Thai noni/Yor (Morinda citrifolia Linn.) leaf extract. Southeast Asian J. Trop. Med. Public Health 2010, 41, 482–489. [Google Scholar] [PubMed]
  59. Luo, H.; Jiang, B.H.; King, S.M.; Chen, Y.C. Inhibition of cell growth and VEGF expression in ovarian cancer cells by flavonoids. Nutr. Cancer 2008, 60, 800–809. [Google Scholar] [CrossRef]
  60. Caparica, R.; Julio, A.; Araujo, M.E.M.; Baby, A.R.; Fonte, P.; Costa, J.G.; Santos de Almeida, T. Anticancer activity of rutin and its combination with ionic liquids on renal cells. Biomolecules 2020, 10, 233. [Google Scholar] [CrossRef] [Green Version]
  61. Li, Q.; Ren, L.; Zhang, Y.; Gu, Z.; Tan, Q.; Zhang, T.; Qin, M.; Chen, S. P38 signal transduction pathway has more cofactors on apoptosis of SGC-7901 gastric cancer cells induced by combination of rutin and oxaliplatin. Biomed Res. Int. 2019, 2019, 6407210. [Google Scholar] [CrossRef] [PubMed]
  62. Santos, U.P.; Campos, J.F.; Torquato, H.F.V.; Paredes-Gamero, E.J.; Carollo, C.A.; Estevinho, L.M.; Souza, K.P.; Dos Santos, E.L. Antioxidant, antimicrobial and cytotoxic properties as well as the phenolic content of the extract from Hancornia speciosa Gomes. PLoS ONE 2016, 11, e0167531. [Google Scholar]
  63. Beckmann, L.; Rolling, C.C.; Voigtländer, M.; Mäder, J.; Klingler, F.; Schulenkorf, A.; Lehr, C.; Bokemeyer, C.; Ruf, W.; Langer, F. Bacitracin and Rutin Regulate Tissue Factor Production in Inflammatory Monocytes and Acute Myeloid Leukemia Blasts. Cancers 2021, 13, 3941. [Google Scholar] [CrossRef]
  64. Kikuchi, H.; Yuan, B.; Hu, X.; Okazaki, M. Chemopreventive and anticancer activity of flavonoids and its possibility for clinical use by combining with conventional chemotherapeutic agents. Am. J. Cancer Res. 2019, 9, 1517–1535. [Google Scholar]
  65. Wangchauy, C.; Chanprasert, S. Effects of Houttuynia cordata Thunb extract, isoquercetin and rutin on cell growth inhibition and apoptotic induction in K562 human leukemic cells. J. Chem. Pharm. Res. 2012, 4, 2590–2598. [Google Scholar]
  66. Canturk, Z.; Dikmen, M.; Artagan, O.; Ozarda, M.G.; Ozturk, N. Cytotoxic effects of resveratrol, rutin and rosmarinic acid on ARH-77 human (multiple myeloma) cell line. Nat. Prod. Commun. 2016, 11, 1441–1444. [Google Scholar] [CrossRef] [Green Version]
  67. Dubey, S.; Ganeshpurkar, A.; Bansal, D.; Dubey, N. Experimental studies on bioactive potential of rutin. Chron. Young Sci. 2013, 4, 153–157. [Google Scholar]
  68. Bourogaa, E.; Bertrand, J.; Despeaux, M.; Jarraya, R.; Fabre, N.; Payrastre, L.; Demur, C.; Fournie, J.-J.; Damak, M.; Feki, A.E. Hammada scoparia flavonoids and rutin kill adherent and chemoresistant leukemic cells. Leuk. Res. 2011, 35, 1093–1101. [Google Scholar] [CrossRef]
  69. Pinzaru, I.; Chioibas, R.; Marcovici, I.; Coricovac, D.; Susan, R.; Predut, D.; Georgescu, D.; Dehelean, C. Rutin Exerts Cytotoxic and Senescence-Inducing Properties in Human Melanoma Cells. Toxics 2021, 9, 226. [Google Scholar] [CrossRef]
  70. Moutinho, M.S.S.; Arag~ao, S.; Carmo, D.; Casaca, F.; Silva, S.; Ribeiro, J.; Sousa, H.; Pires, I.; Queiroga, F.; Colaço, B. Curcumin and rutin down-regulate cyclooxygenase-2 and reduce tumor-associated inflammation in HPV16-transgenic mice. Anticancer Res. 2018, 38, 1461–1466. [Google Scholar]
  71. Vadapalli, U.; Muvvala, S.; Alluri, R.; Lakshmi, B.V.S. Antiproliferative activity of rutin on HeLa cell line induced cervical cancer in rats. Int. J. Pharm. Sci. Res. 2017, 8, 4803–4811. [Google Scholar]
  72. Lin, J.-P.; Yang, J.-S.; Lin, J.-J.; Lai, K.-C.; Lu, H.-F.; Ma, C.-Y.; SaiChuen Wu, R.; Wu, K.-C.; Chueh, F.-S.; Gibson Wood, W.; et al. Rutin inhibits human leukemia tumor growth in a murine xenograft model in vivo. Environ. Toxicol. 2012, 27, 480–484. [Google Scholar] [CrossRef] [PubMed]
  73. Lin, J.-P.; Yang, J.-S.; Lu, C.-C.; Chiang, J.-H.; Wu, C.-L.; Lin, J.-J.; Lin, H.-L.; Yang, M.-D.; Liu, K.-C.; Chiu, T.-H.; et al. Rutin inhibits the proliferation of murine leukemia WEHI-3 cells in vivo and promotes immune response in vivo. Leuk. Res. 2009, 33, 823–828. [Google Scholar] [CrossRef] [PubMed]
  74. Calzada, F.; Solares-Pascasio, J.; Valdes, M.; Garcia-Hernandez, N.; Velazquez, C.; Ordonez-Razo, R.; Barbosa, E. Antilymphoma potential of the ethanol extract and rutin obtained of the leaves from Schinus molle Linn. Pharmacogn. Res. 2018, 10, 119. [Google Scholar] [CrossRef]
  75. Elsayed, H.E.; Ebrahim, H.Y.; Mohyeldin, M.M.; Siddique, A.B.; Kamal, A.M.; Haggag, E.G.; El Sayed, K.A. Rutin as A Novel c-Met Inhibitory Lead for The Control of Triple Negative Breast Malignancies. Nutr. Cancer 2017, 69, 1256–1271. [Google Scholar] [CrossRef] [PubMed]
  76. Yang, C.; Gundala, S.R.; Mukkavilli, R.; Vangala, S.; Reid, M.D.; Aneja, R. Synergistic interactions among flavonoids and acetogenins in Graviola (Annona muricata) leaves confer protection against prostate cancer. Carcinogenesis 2015, 36, 656–665. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Martínez Conesa, C.; Vicente Ortega, V.; Yáñez Gascón, M.J.; Alcaraz Baños, M.; Canteras Jordana, M.; Benavente-García, O.; Castillo, J. Treatment of metastatic melanoma B16F10 by the flavonoids tangeretin, rutin, and diosmin. J. Agric. Food Chem. 2005, 53, 6791–6797. [Google Scholar] [CrossRef] [PubMed]
  78. Zhang, P.; Sun, S.; Li, N.; Ho, A.S.W.; Kiang, K.M.Y.; Zhang, X.; Cheng, Y.S.; Poon, M.W.; Lee, D.; Pu, J.K.S.; et al. Rutin increases the cytotoxicity of temozolomide in glioblastoma via autophagy inhibition. J. Neurooncol. 2017, 132, 393–400. [Google Scholar] [CrossRef] [PubMed]
  79. Chandra, Y.P.; Viswanathswamy, A.H.M. Chemo preventive effect of rutin against N-nitrosodiethylamine-induced and phenobarbital-promoted hepatocellular carcinoma in Wistar rats. Indian J. Pharm. Educ. Res. 2018, 52, 78–86. [Google Scholar] [CrossRef] [Green Version]
  80. Webster, R.P.; Gawde, M.D.; Bhattacharya, R.K. Protective effect of rutin, a flavonol glycoside, on the carcinogen-induced DNA damage and repair enzymes in rats. Cancer Lett. 1996, 109, 185–191. [Google Scholar] [CrossRef]
  81. Park, S.; Chapuis, N.; Tamburini, J.; Bardet, V.; Cornillet-Lefebvre, P.; Willems, L.; Green, A.; Mayeux, P.; Lacombe, C.; Bouscary, D. Role of the PI3K/AKT and mTOR signaling pathways in acute myeloid leukemia. Haematologica 2010, 95, 819–828. [Google Scholar] [CrossRef] [Green Version]
  82. Sharma, V.R.; Gupta, G.K.; Sharma, A.K.; Batra, N.; Sharma, D.K.; Joshi, A.; Sharma, A.K. PI3K/Akt/mTOR Intracellular Pathway and Breast Cancer: Factors, Mechanism and Regulation. Curr. Pharm. Des. 2017, 23, 1633–1638. [Google Scholar] [CrossRef]
  83. Fattahi, S.; Amjadi-Moheb, F.; Tabaripour, R.; Ashrafi, G.H.; Akhavan-Niaki, H. PI3K/AKT/mTOR signaling in gastric cancer: Epigenetics and beyond. Life Sci. 2020, 262, 118513. [Google Scholar] [CrossRef]
  84. Hosseinzade, A.; Sadeghi, O.; Naghdipour Biregani, A.; Soukhtehzari, S.; Brandt, G.S.; Esmaillzadeh, A. Immunomodulatory effects of flavonoids: Possible induction of T CD4+ regulatory cells through suppression of mTOR pathway signaling activity. Front. Immunol. 2019, 10, 51. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Shakya, G.; Balasubramanian, S.; Hoda, M.; Rajagopalan, R. Inhibition of metastasis and angiogenesis in Hep-2 cells by wheatgrass extract–an in vitro and in silico approach. Toxicol. Mech. Methods 2018, 28, 205–218. [Google Scholar] [CrossRef] [PubMed]
  86. Zhao, B.; Xiong, Y.; Zhang, Y.; Jia, L.; Zhang, W.; Xu, X. Rutin promotes osteogenic differentiation of periodontal ligament stem cells through the GPR30-mediated PI3K/AKT/mTOR signaling pathway. Exp. Biol. Med. 2020, 245, 552–561. [Google Scholar] [CrossRef] [PubMed]
  87. Sun, J.; Wang, H.; Liu, B.; Shi, W.; Shi, J.; Zhang, Z.; Xing, J. Rutin attenuates H2O2-induced oxidation damage and apoptosis in Leydig cells by activating PI3K/Akt signal pathways. Biomed. Pharmacother. 2017, 88, 500–506. [Google Scholar] [CrossRef] [PubMed]
  88. Talebi, H.; Farahpour, M.R.; Hamishehkar, H. The effectiveness of Rutin for prevention of surgical induced endometriosis development in a rat model. Sci. Rep. 2021, 11, 1–7. [Google Scholar] [CrossRef]
  89. Wu, F.; Chen, J.; Fan, L.M.; Liu, K.; Zhang, N.; Li, S.W.; Zhu, H.; Gao, H.C. Analysis of the effect of rutin on GSK-3β and TNF-α expression in lung cancer. Exp. Med. 2017, 14, 127–130. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  90. Thabet, N.M.; Moustafa, E.M. Protective effect of rutin against brain injury induced by acrylamide or gamma radiation: Role of PI3K/AKT/GSK-3β/NRF-2 signalling pathway. Arch. Physiol. Biochem. 2018, 124, 185–193. [Google Scholar] [CrossRef] [PubMed]
  91. Lins, T.L.B.G.; Gouveia, B.B.; Barberino, R.S.; Silva, R.L.S.; Monte, A.P.O.; Pinto, J.G.C.; Campinho, D.S.P.; Palheta, R.C.; Matos, M.H.T. Rutin prevents cisplatin-induced ovarian damage via antioxidant activity and regulation of PTEN and FOXO3a phosphorylation in mouse model. Reprod. Toxicol. 2020, 98, 209–217. [Google Scholar] [CrossRef] [PubMed]
  92. Chattopadhyay, D.; Thirumurugan, K. Longevity-promoting efficacies of rutin in high fat diet fed Drosophila melanogaster. Biogerontology 2020, 21, 653–668. [Google Scholar] [CrossRef] [PubMed]
  93. Crino, P.B. mTOR: A pathogenic signaling pathway in developmental brain malformations. Trends Mol. Med. 2011, 17, 734–742. [Google Scholar] [CrossRef] [PubMed]
  94. Bruning, A. Inhibition of mTOR signaling by quercetin in cancer treatment and prevention. Anticancer Agents Med. Chem. 2013, 13, 1025–1031. [Google Scholar] [CrossRef] [PubMed]
  95. Bose, S.; Banerjee, S.; Mondal, A.; Chakraborty, U.; Pumarol, J.; Croley, C.R.; Bishayee, A. Targeting the JAK/STAT signaling pathway using phytocompounds for cancer prevention and therapy. Cells 2020, 9, 1451. [Google Scholar] [CrossRef]
  96. Gutiérrez-Hoya, A.; Soto-Cruz, I. Role of the JAK/STAT pathway in cervical cancer: Its relationship with HPV E6/E7 oncoproteins. Cells 2020, 9, 2297. [Google Scholar] [CrossRef] [PubMed]
  97. Qureshy, Z.; Johnson, D.E.; Grandis, J.R. Targeting the JAK/STAT pathway in solid tumors. J. Cancer Metastasis Treat. 2020, 6, 27. [Google Scholar] [PubMed]
  98. Oh, H.; Park, S.H.; Kang, M.K.; Kim, Y.H.; Lee, E.J.; Kim, D.Y.; Kang, Y.H. Asaronic acid attenuates macrophage activation toward M1 phenotype through inhibition of NF-κB pathway and JAK-STAT signaling in glucose-loaded murine macrophages. J. Agric. Food Chem. 2019, 67, 10069–10078. [Google Scholar] [CrossRef]
  99. Mohan, C.D.; Rangappa, S.; Preetham, H.D.; Chandra, N.S.; Gupta, V.K.; Basappa, S.; Sethi, G.; Rangappa, K.S. Targeting STAT3 signaling pathway in cancer by agents derived from Mother Nature. Semin. Cancer Biol. 2020, in press. [Google Scholar] [CrossRef]
  100. Selloum, L.; Bouriche, H.; Tigrine, C.; Boudoukha, C. Anti-inflammatory effect of rutin on rat paw oedema, and on neutrophils chemotaxis and degranulation. Exp. Toxicol. Pathol. 2003, 54, 313–318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  101. Fan, J.J.; Hsu, W.H.; Lee, K.H.; Chen, K.C.; Lin, C.W.; Lee, Y.L.; Ko, T.P.; Lee, L.T.; Lee, M.T.; Chang, M.S.; et al. Dietary flavonoids luteolin and quercetin inhibit migration and invasion of squamous carcinoma through reduction of Src/Stat3/S100A7 signaling. Antioxidants 2019, 8, 557. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  102. Nouri, Z.; Fakhri, S.; Nouri, K.; Wallace, C.E.; Farzaei, M.H.; Bishayee, A. Targeting multiple signaling pathways in cancer: The rutin therapeutic approach. Cancers 2020, 12, 2276. [Google Scholar] [CrossRef] [PubMed]
  103. Choi, K.S.; Kundu, J.K.; Chun, K.S.; Na, H.K.; Surh, Y.J. Rutin inhibits UVB radiation-induced expression of COX-2 and iNOS in hairless mouse skin: p38 MAP kinase and JNK as potential targets. Arch. Biochem. Biophys. 2014, 559, 38–45. [Google Scholar] [CrossRef]
  104. Arend, R.C.; Londoño-Joshi, A.I.; Straughn, J.M., Jr.; Buchsbaum, D.J. The Wnt/β-catenin pathway in ovarian cancer: A review. Gynecol. Oncol. 2013, 131, 772–779. [Google Scholar] [CrossRef] [PubMed]
  105. Khalaf, A.M.; Fuentes, D.; Morshid, A.I.; Burke, M.R.; Kaseb, A.O.; Hassan, M.; Hazle, J.D.; Elsayes, K.M. Role of Wnt/β-catenin signaling in hepatocellular carcinoma, pathogenesis, and clinical significance. J. Hepatocell Carcinoma 2018, 5, 61–73. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Hung, S.W.; Zhang, R.; Tan, Z.; Chung, J.P.W.; Zhang, T.; Wang, C.C. Pharmaceuticals targeting signaling pathways of endometriosis as potential new medical treatment: A review. Med. Res. Rev. 2021, 41, 2489–2564. [Google Scholar] [CrossRef] [PubMed]
  107. Kalita, B.; Ranjan, R.; Gupta, M.L. Combination treatment of podophyllotoxin and rutin promotes mouse Lgr5+ ve intestinal stem cells survival against lethal radiation injury through Wnt signaling. Apoptosis 2019, 24, 326–340. [Google Scholar] [CrossRef] [PubMed]
  108. Santarpia, L.; Lippman, S.M.; El-Naggar, A.K. Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy. Expert Opin. Targets 2012, 16, 103–119. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  109. Schulz, G.B.; Elezkurtaj, S.; Börding, T.; Schmidt, E.M.; Elmasry, M.; Stief, C.G.; Kirchner, T.; Karl, A.; Horst, D. Therapeutic and prognostic implications of NOTCH and MAPK signaling in bladder cancer. Cancer Sci. 2021, 112, 1987–1996. [Google Scholar] [CrossRef] [PubMed]
  110. Semwal, R.; Joshi, S.K.; Semwal, R.B.; Semwal, D.K. Health benefits and limitations of rutin-A natural flavonoid with high nutraceutical value. Phytochem. Lett. 2021, 46, 119–128. [Google Scholar] [CrossRef]
  111. Choi, S.; Lim, T.G.; Hwang, M.K.; Kim, Y.A.; Kim, J.; Kang, N.J.; Jang, T.S.; Park, J.S.; Yeom, M.H.; Lee, K.W. Rutin inhibits B[a]PDE-induced cyclooxygenase-2 expression by targeting EGFR kinase activity. Biochem. Pharmacol. 2013, 86, 1468–1475. [Google Scholar] [CrossRef] [PubMed]
  112. Nafees, S.; Rashid, S.; Ali, N.; Hasan, S.K.; Sultana, S. Rutin ameliorates cyclophosphamide induced oxidative stress and inflammation in Wistar rats: Role of NFjB/MAPK pathway. Chem. Biol. Interact. 2015, 231, 98–107. [Google Scholar] [CrossRef] [PubMed]
  113. Santos, B.L.; Silva, A.R.; Pitanga, B.P.S.; Sousa, C.S.; Grangeiro, M.S.; Fragomeni, B.O.; Coelho, P.L.C.; Oliveira, M.N.; Menezes Filho, N.J.; Costa, M.F.; et al. Antiproliferative, proapoptotic and morphogenic effects of the flavonoid rutin on human glioblastoma cells. Food Chem. 2011, 127, 404–411. [Google Scholar] [CrossRef] [PubMed]
  114. Tatipamula, V.B.; Kukavica, B. Phenolic compounds as antidiabetic, anti-inflammatory, and anticancer agents and improvement of their bioavailability by liposomes. Cell Biochem. Funct. 2021. [published online ahead of print, 9 September 2021]. [Google Scholar] [CrossRef] [PubMed]
  115. Kim, D.H.; Suh, J.; Surh, Y.J.; Na, H.K. Regulation of the tumor suppressor PTEN by natural anticancer compounds. Ann. N. Y. Acad. Sci. 2017, 1401, 136–149. [Google Scholar] [CrossRef] [PubMed]
  116. Misra, U.K.; Pizzo, S.V. Modulation of the unfolded protein response in prostate cancer cells by antibody-directed against the carboxyl-terminal domain of GRP78. Apoptosis 2010, 15, 173–182. [Google Scholar] [CrossRef] [PubMed]
  117. Trachootham, D.; Alexandre, J.; Huang, P. Targeting cancer cells by ROS-mediated mechanisms: A radical therapeutic approach? Nat. Rev. Drug Discov. 2009, 8, 579–591. [Google Scholar] [CrossRef] [PubMed]
  118. Javed, Z.; Ullah, M.; Ashfaq, H.A.; Shah, A.H.; Shahzad, M.; Bilal, M.; Sumrin, A.; Bashir, H.; Siddiqi, M.H.; Sadia, H. Role of MicroRNA in endometrial carci noma. Adv. Life Sci. 2016, 4, 08–13. [Google Scholar]
  119. Ozbey, U.; Attar, R.; Romero, M.A.; Alhewairini, S.S.; Afshar, B.; Sabitaliyevich, U.Y.; Hanna-Wakim, L.; Ozcelik, B.; Farooqi, A.A. Apigenin as an efective anti cancer natural product: Spotlight on TRAIL, WNT/β-catenin, JAK-STAT pathways, and microRNAs. J. Cell Biochem. 2019, 120, 1060–1067. [Google Scholar] [CrossRef] [PubMed]
  120. Chakrabarti, M.; Banik, N.L.; Ray, S.K. miR-138 overexpression is more powerful than hTERT knockdown to potentiate apigenin for apoptosis in neuroblastoma in vitro and in vivo. Exp. Cell Res. 2013, 319, 1575–1585. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  121. Cannataro, R.; Fazio, A.; La Torre, C.; Caroleo, M.C.; Cione, E. Polyphenols in the Mediterranean Diet: From Dietary Sources to microRNA Modulation. Antioxidants 2021, 10, 328. [Google Scholar] [CrossRef] [PubMed]
  122. Zhou, M.; Zhang, G.; Hu, J.; Zhu, Y.; Lan, H.; Shen, X.; Lv, Y.; Huang, L. Rutin attenuates Sorafenib-induced Chemoresistance and Autophagy in Hepatocellular Carcinoma by regulating BANCR/miRNA-590-5P/OLR1 Axis. Int. J. Biol. Sci. 2021, 17, 3595–3607. [Google Scholar] [CrossRef] [PubMed]
  123. Li, Q.; Xu, D.; Gu, Z.; Li, T.; Huang, P.; Ren, L. Rutin restrains the growth and metastasis of mouse breast cancer cells by regulating the microRNA-129-1-3p-mediated calcium signaling pathway. J. Biochem. Mol. Toxicol. 2021, 35, e22794. [Google Scholar] [CrossRef] [PubMed]
  124. Qin, M.; Li, Q.; Wang, Y.; Li, T.; Gu, Z.; Huang, P.; Ren, L. Rutin treats myocardial damage caused by pirarubicin via regulating miR-22-5p-regulated RAP1/ERK signaling pathway. J. Biochem. Mol. Toxicol. 2021, 35, e22615. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. Structure and dietary sources of rutin (bioflavonoid): (A) structure and (B) dietary sources.
Figure 1. Structure and dietary sources of rutin (bioflavonoid): (A) structure and (B) dietary sources.
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Figure 2. Mechanism associated with the anticancer potential of rutin via the targeting of numerous molecular signaling pathways.
Figure 2. Mechanism associated with the anticancer potential of rutin via the targeting of numerous molecular signaling pathways.
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Table
Table 1. In vitro antitumor efficacy of rutin and its mechanisms of action.
Table 1. In vitro antitumor efficacy of rutin and its mechanisms of action.
CancerCell LinesDosesAnticancer MechanismMolecular TargetsReferences
Lung cancerA549 20–560 µMCell growth, invasion, and adhesion inhibition; apoptosis and autophagy inductionp38, NF-κB, TNF-α, GSK-3b, Beclin-1[25,26,27,28,29]
GLC4 cells4 µMCell growth inhibition [30]
Breast CancerMDA-MB-231 cells80.0–640 µg/mLCell growth, invasion, metastasis, and adhesion inhibition; apoptosis and inductionc-Met kinase[31,32]
MCF-7 cells19.4–46.1 µMCell growth inhibition via apoptotic inductionp53, PTEN, p21; Cyclin B, caspase 3/7, ROS[33,34,35,36]
Cervical cancerHeLa cells30–265 µg/mLCell growth inhibition via apoptotic inductionROS, caspase-3, E6, E7[37,38,39]
C33A cells120 µMCell growth inhibition via apoptotic inductionROS mediated[40]
Colorectal cancerHT-29 cells100–300 µMCell growth inhibition via apoptotic inductionBax, Bcl2, p53
caspases-3, -8, and-9, PARP, NF-κB, IKK-a and IKK-b, p38, and MK-2		[27,41,42]
Caco-2 cells711 µMCell growth inhibitionSuperoxide[27]
LoVo cells29 µMCell growth inhibition via apoptotic induction and cell cycle arrestROS[35]
HCT 116 cells Cell growth inhibition via apoptotic inductionCaspase-3[43]
SW480 cells600 mMCell growth inhibitionCancer cell metabolism[37,44]
Prostate cancerLNCaP cells75.0 mMCell growth inhibition via apoptotic induction-[45]
PC-3 cells91 µg/mLCell growth inhibition-[46]
Pancreatic cancerPANC-1 cells26 µg/mLCell growth inhibition via apoptotic inductionCaspase-3/7[47]
Liver cancerHep G2 cells10–200 µMCell growth inhibition via apoptotic induction-[36,47,48,49,50,51]
Murine HTC cells810 µMCell growth inhibition-[52]
NeuroblastomaLAN-5 cells 25–100 µg/mLCell growth, invasion, and adhesion inhibitionMYCN, Bax, Bcl2, TNFa[53]
Neuro-2a cells 24 µMCell growth inhibition-[54]
SK-N-SH cells 36 µMCell growth inhibition-[54]
MelanomaSK-MEL-2840 µMCell growth inhibition via apoptotic inductionGSH, ROS, MMP[55]
Nasopharyngeal carcinomaCNE-2 cells5–80 mg/LCell growth inhibition-[56]
Oral cancerCA9-22 cells20–40 µMAutophagy inductionNF-κB, ATG5/12 conjugation, LC3-II, Beclin-1, TNF-alpha[57]
KB cells 167 µg/mLCell growth inhibition-[58]
Ovarian cancerOVCAR-3 -Cell growth and VEGF inhibition-[59]
Renal cancer786-O45.2 µMCell growth inhibition-[60]
Gastric cancerSGC-7901300 µMCell growth inhibition via apoptotic inductionp38 MAPK pathway[61]
GliomaGL-15 cells50–100 µMCell growth inhibition via apoptotic inductionp-ERK1/2[62]
CHME cells 15 µMCell growth inhibition via apoptotic inductionp53, Bax, Bcl2, caspase-3/-9[54]
LN-229 cells22 µMCell growth inhibition-[54]
LeukemiaU-937 cells9.6 µg/mLCell growth inhibition-[63]
K562 cells98.56 µg/mLCell growth inhibition via apoptotic induction-[64,65]
ARH-77 cells 50–200 µMCell growth inhibition via mitochondrial and lysosomal activities-[66]
Leukocytes 1.50 µg/mLCell growth inhibition-[67]
U937 cells80 µg/mLCell growth inhibition via apoptotic inductionGSK-3β[68]
THP-1 cell-derived
macrophages		20–40 µMAutophagy inductionNF-κB, ATG5/12 conjugation, LC3-II, Beclin-1[69]
Leukemia stem
cells (CD123+/
CD34+/CD38+)		160 µg/mLCell growth inhibition via apoptotic inductionGSK-3β[68]
Abbreviations: Atg5/12, autophagy related 5/12; Bax, Bcl-2 associated X protein; Bcl-2, B cell lymphoma 2; GSK-3β, glycogen synthase kinase 3 beta; LC3-II, light chain 3; PARP, poly (ADP ribose) polymerase; IKK, IκB kinase; MAPK, mitogen-activated protein kinase; MMP, mitochondrial membrane potential; N-myc proto-oncogene protein; NF-κB, nuclear factor kappa; B ROS, reactive oxygen species; TNF-α, tumor necrosis factor alpha.
Table
Table 2. In vivo antitumor efficacy of rutin and its mechanisms of action.
Table 2. In vivo antitumor efficacy of rutin and its mechanisms of action.
Cancer ModelCell LinesDoses/TreatmentAnticancer MechanismMolecular TargetsReferences
Cervical cancerHuman papillomavirus type 16 (HPV16)-transgenic mice24 weeksTumor growth inhibitionCOX-2[70]
HeLa cells induced cervical cancer
(i.p.) in female Wistar albino rats		50 mg/kg and 70 mg/kg rutin
for 45 days		Tumor growth inhibitionModulation of
hematological parameters and lipid
peroxidation		[71]
LeukemiaHuman leukemia HL-60 cells (s.c.) inboth flanks of female BALB/
cnu/nu mice		120 mg/kg rutin once every
four days		Tumor growth inhibition-[72]
Murine leukemia WEHI-3 cells (i.p.)
in male BALB/c mice		6 mg/kg and 12 mg/kg rutin for up to 3 weeks orallyTumor growth inhibitionModulation of whole blood cell surface markers [73]
Human leukemic U-937 cells in
male CD1 nu/nu nude mice and
CD-1 mice		5, 10, and 15 mg/kg for 9 days orallyTumor growth inhibition-[74]
Breast cancerMDA-MB-231/GFP cells induced breast cancer in female
athymic Foxn1nu/Foxn1þ mice		30.0 mg/kg rutin three times a weekReduction in tumor growthROS, caspase-3, E6, E7[75]
Prostate cancerPC-3-luc cells induced prostate cancer in male nude BALB/c mice100 mg/kg rutin
daily for 4 weeks orally		Tumor growth inhibition-[76]
Lung cancerB16F10 melanoma cells induced lung cancer in female Swiss albino mice0.2% w/v rutin for 21 days orallyLung metastasis inhibitionDecrease in lung tumor nodules and invasion index[77]
Colon cancerSW480 colon cancer cells induced colon cancer in nu/nu mice1, 10, and 20 mg/kg rutin daily for 32 days i.p.Tumor growth and angiogenesis inhibition VEGF [37]
GlioblastomaU87 glioblastoma cells induced cancer in BALB/c athymic mice20 mg/kg rutin thrice a week for two weeksTumor growth inhibition via apoptotic inductionDecrease in autophagy and JNK expression[78]
Liver cancerDEN induced hepatocellular carcinoma in Wistar rats50 mg/kg rutin for 16 weeks orallyInhibition of cell proliferationDecrease in hepatocellular marker enzymes and tumor invasion[79]
Aflatoxin B1 and N-nitrosodimethylamine induced hepatocellular carcinoma in Wistar rats1 and 10 mg/100 g rutin for 2 weeks orallyProtection from carcinogenesis by enzyme modulationDecrease in PARP, DNA ligase, and polymerase beta[80]
Abbreviations: HPV, human papilloma virus; COX-2, cyclooxygenase-2; I.P., intraperitoneal; JNK, c-Jun N-terminal kinase; PARP, poly-ADP ribose polymerase; VEGF, vascular endothelial growth factor; ROS, reactive oxygen species.
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Pandey, P.; Khan, F.; Qari, H.A.; Oves, M. Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention. Pharmaceuticals 2021, 14, 1069. https://doi.org/10.3390/ph14111069

AMA Style

Pandey P, Khan F, Qari HA, Oves M. Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention. Pharmaceuticals. 2021; 14(11):1069. https://doi.org/10.3390/ph14111069

Chicago/Turabian Style

Pandey, Pratibha, Fahad Khan, Huda A. Qari, and Mohammad Oves. 2021. "Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention" Pharmaceuticals 14, no. 11: 1069. https://doi.org/10.3390/ph14111069

APA Style

Pandey, P., Khan, F., Qari, H. A., & Oves, M. (2021). Rutin (Bioflavonoid) as Cell Signaling Pathway Modulator: Prospects in Treatment and Chemoprevention. Pharmaceuticals, 14(11), 1069. https://doi.org/10.3390/ph14111069

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