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Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential

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Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential biomolecules Review Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential Dharambir Kashyap 1, Vivek Kumar Garg 2, Hardeep Singh Tuli 3,*, Mukerrem Betul Yerer 4 , Katrin Sak 5 , Anil Kumar Sharma 3, Manoj Kumar 6, Vaishali Aggarwal 1 and Sardul Singh Sandhu 7 1 Department of Histopathology, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh 160012, Punjab, India; [email protected] (D.K.); [email protected] (V.A.) 2 Department of Biochemistry, Government Medical College and Hospital (GMCH), Chandigarh 160031, Punjab, India; [email protected] 3 Department of Biotechnology, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala 133 207, Haryana, India; [email protected] 4 Department of Pharmacology, Faculty of Pharmacy, Erciyes University, Kayseri 38039, Turkey; [email protected] 5 NGO Praeventio, Tartu 50407, Estonia; [email protected] 6 Department of Chemistry, Maharishi Markandeshwar University, Sadopur 134007, Haryana, India; [email protected] 7 Department of Biological Sciences, RD University, Jabalpur 482001, India; [email protected] * Correspondence: [email protected]; Tel.: +91-9896619923 Received: 2 April 2019; Accepted: 30 April 2019; Published: 6 May 2019 Abstract: Despite advancements in healthcare facilities for diagnosis and treatment, cancer remains the leading cause of death worldwide. As prevention is always better than cure, efficient strategies are needed in order to deal with the menace of cancer. The use of phytochemicals as adjuvant chemotherapeutic agents in heterogeneous human carcinomas like breast, colon, lung, ovary, and prostate cancers has shown an upward trend during the last decade or so. Flavonoids are well-known products of plant derivatives that are reportedly documented to be therapeutically active phytochemicals against many diseases encompassing malignancies, inflammatory disorders (cardiovascular disease, neurodegenerative disorder), and oxidative stress. The current review focuses on two key flavonols, fisetin and quercetin, known for their potential pharmacological relevance. Also, efforts have been made to bring together most of the concrete studies pertaining to the bioactive potential of fisetin and quercetin, especially in the modulation of a range of cancer signaling pathways. Further emphasis has also been made to highlight the molecular action of quercetin and fisetin so that one could explore cancer initiation pathways and progression, which could be helpful in designing effective treatment strategies. Keywords: apoptosis; cell cycle arrest; extracellular matrix remodeling; epithelial to mesenchymal transition; signaling cascades; flavonoids; fisetin; quercetin 1. Introduction The incidence of malignant diseases and the prevalence of cancer mortality is proliferating at an amplified rate across the developed and developing countries [1]. New Globocan 2018 cancer data from 185 countries documented 18.1 million new cancer cases and 9.6 million cancer-related deaths (GALOBOCAN 2018). Although the improvement of diagnostic tools, advanced treatment approaches, and cancer awareness programs have resulted in a remarkable drop in cancer mortality in the United States, cancer prevalence is still growing continuously [1]. This is attributed to smoking Biomolecules 2019, 9, 174; doi:10.3390/biom9050174 www.mdpi.com/journal/biomolecules Biomolecules 2019, 9, x FOR PEER REVIEW 2 of 22 Biomolecules 2019, 9, 174 2 of 22 in the United States, cancer prevalence is still growing continuously [1]. This is attributed to smoking habits,habits, alcohol alcohol consumption, consumption, unhealthy unhealthy food, food, stress, stress, and and no no or insuor insufficientfficient exercise exercise amongst amongst people people in thein developedthe developed and developingand developing world [world2]. There [2]. are There different are different therapeutic therapeutic modalities modalities for cancer treatmentfor cancer available,treatment including available, surgery, including radiation surgery, therapy, radiat chemotherapy,ion therapy, immunotherapy,chemotherapy, immunotherapy, and targeted therapy. and Tamoxifentargeted therapy. in estrogen Tamoxifen receptor-positive in estrogen breast receptor-pos tumor, Herceptinitive breast in tumor, Her 2 +Herceptinbreast cancer, in Her epithelial 2+ breast growthcancer, factor epithelial receptor growth (EGRF) factor inhibitors receptor (erlotinib, (EGRF) afatinib, inhibitors osimertinib, (erlotinib, and afatinib, fefitinib) inosimertinib, non-small celland lungfefitinib) carcinoma in non-small (NSCLC), cellK-ras lunginhibitors carcinoma (cetuximab) (NSCLC), inK-ras colon inhibitors cancer, B-Raf(cetuximab)inhibitors in colon (vemurafenib, cancer, B- dabrafenib,Raf inhibitors and (vemurafenib, encorafenib) inda melanoma,brafenib, and and encorafenib) gleevec for inABL-BCL melanoma,(translocation and gleevec of forc-ABL ABL-BCLgene sequences(translocation from of chromosome c-ABL gene 9sequences into the BCR fromgene chromosome on chromosome 9 into the 22) BCR positive gene leukemia on chromosome have been 22) usedpositive widely leukemia in clinical have settings been used [3]. However,widely in cancerclinical cells settings can evade[3]. However, death by cancer gaining cells resistance can evade to variousdeath by treatment gaining modalities,resistance to which various has treatment diluted the modalities, expected which outcome has ofdiluted these the therapies expected [4– 6outcome]. This hasof these necessitated therapies the [4–6]. discovery This has of alternativenecessitated treatment the discovery strategies of alternative to cure cancer treatment patients. strategies Numerous to cure incancer vitro studiespatients. in Numerous conjunction in with vitro ex studies vivo studies in conj haveunction exemplified with ex vivo the anti-cancerstudies have eff exemplifiedects of natural the productsanti-cancer such effects as flavonoids of natural [7 products–10]. Specifically, such as flavonoids fisetin and [7–10]. quercetin, Specifically, two well-studied fisetin and flavonoids, quercetin, havetwo shownwell-studied remarkable flavonoids, anti-cancer have eshownffects inremarkable multiple in anti-cancer vitro and ineffects vivo insystems. multiple Di ffinerent vitro events and in invivo cancer systems. initiation Different and progressionevents in cancer such initiation as apoptosis, and extracellularprogression such matrix as remodeling,apoptosis, extracellular epithelial tomatrix mesenchymal remodeling, transition, epithelial cancer-associated to mesenchymal inflammation, transition, andcancer-associated oxidative stress inflammation, can be controlled and byoxidative fisetin andstress quercetin can be controlled [11,12]. In by vitro fisetinstudies and quer showedcetin [11,12]. that fisetin In vitro and studies quercetin showed could that also fisetin act againstand quercetin chemotherapeutic could also resistance act against in several chemothera cancerspeutic [13,14 ].resistance Numerous in cancer-related several cancers molecules [13,14]. suchNumerous as anti-apoptotic cancer-related and pro-apoptotic molecules such proteins, as anti-apoptotic cyclin-dependent and kinasespro-apoptotic (CDKs), proteins, cyclins, matrixcyclin- metalloproteinasesdependent kinases (MMPs),(CDKs), cyclins, and growth matrix factors metallopr haveoteinases been shown (MMPs), to be and modulated growth factors by fisetin have andbeen quercetinshown to (Figures be modulated1 and2). by Quercetin fisetin and can quercetin also bind (F toigures a G protein 1 and coupled2). Quercetin receptors can toalso activate bind to a Ga G proteinprotein and coupled calcium-dependent receptors to activate pathway a G which protei leadsn and to calcium-dependent tumor cell death [13 pathway–15]. In addition, which leads these to phytochemicalstumor cell death also [13–15]. exhibit In addition, synergistic these effects phytoche wheremicals they enhance also exhibit the synergistic anti-tumor effects activity where of many they anti-cancerenhance the drug anti-tumor molecules activity (Table 1of). Themany present anti-can reviewcer drug highlights molecules the important (Table 1). anti-cancerThe present roles review of quercetinhighlights and the fisetin important in various anti-cancer in-vitro roles/ex-vivo of querceti studies.n and fisetin in various in-vitro/ex-vivo studies. FigureFigure 1. 1.Showing showing regulation regulation of of di differentfferent cancer cancer related related processes processes under under the the e ffeffectect of of flavonoids. flavonoids. All All thesethese processes processes are are crucial crucial in in carcinogenesis carcinogenesis and and play play key key roles roles for for cancer cancer initiation initiation and and progression. progression. FlavonoidsFlavonoids e ffeffectivelyectively act act at at these these processes processes to to inhibit inhibit cancer cancer growth. growth. Biomolecules 2019, 9, x FOR PEER REVIEW 3 of 22 Biomolecules 2019, 9, 174 3 of 22 Figure 2. Figure showing regulationregulation ofof didifferentfferent cancer cancer associated associated signaling signaling pathways. pathways. Deregulation Deregulation of ofthese these pathways pathways has has been been determined determined in humanin human malignancies. malignancies. Flavonoids Flavonoids control control the the deregulation deregulation of ofthese these pathways pathways and and cancer cancer proliferation. proliferation. Table 1. Synergistic effects. Table 1. Synergistic effects. PhytochemicalPhytochemical
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