Skip to main content
SpringerLink
Log in

Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention

  • Review
  • Published:
Biologia Futura Aims and scope Submit manuscript

Abstract

Discouraging statistics of cancer disease has projected an increase in the global cancer burden from 19.3 to 28.4 million incidences annually within the next two decades. Currently, there has been a revival of interest in nutraceuticals with evidence of pharmacological properties against human diseases including cancer. Diet is an integral part of lifestyle, and it has been proposed that an estimated one-third of human cancers can be prevented through appropriate lifestyle modification including dietary habits; hence, it is considered significant to explore the pharmacological benefits of these agents, which are easily accessible and have higher safety index. Accordingly, an impressive embodiment of evidence supports the concept that the dietary factors are critical modulators to prevent, retard, block, or reverse carcinogenesis. Such an action reflects the ability of these molecules to interfere with multitude of pathways to subdue and neutralize several oncogenic factors and thereby keep a restraint on neoplastic transformations. This review provides a series of experimental evidence based on the current literature to highlight the translational potential of nutraceuticals for the prevention of the disease through consumption of enriched diets and its efficacious management by means of novel interventions. Specifically, this review provides the current understanding of the chemopreventive pharmacology of nutraceuticals such as cucurbitacins, morin, fisetin, curcumin, luteolin and garcinol toward their potential as anticancer agents.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Data availability

Data associated with this manuscript can be obtained on request.

References

  • Abou-Salim MA, Shaaban MA, Abd El Hameid MK, Elshaier YAMM, Halaweish F (2019) Design, synthesis and biological study of hybrid drug candidates of nitric oxide releasing cucurbitacin-inspired estrone analogs for treatment of hepatocellular carcinoma. Bioorg Chem 85:515–533

    Article  CAS  PubMed  Google Scholar 

  • Abuajah CI, Ogbonna AC, Osuji CM (2015) Functional components and medicinal properties of food a review. J Food Sci Technol 52:2522–2529

    Article  CAS  PubMed  Google Scholar 

  • Adan A, Baran Y (2015) Fisetin and hespereitin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumor Biol 37:5781–5795

    Article  Google Scholar 

  • Adiwidjaja J, McLachlan AJ, Boddy AV (2017) Curcumin as a clinically-promising anti-cancer agent: pharmacokinetics and drug interactions. Expert Opin Drug Metab Toxicol 13:953–972

    Article  CAS  PubMed  Google Scholar 

  • Aggarwal S, Das SN (2016) Garcinol inhibits tumour cell proliferation, angiogenesis, cell cycle progression and induces apoptosis via NF-κB inhibition in oral cancer. Tumour Biol 37(6):7175–7184

  • Aggarwal BB, Sung B (2011) NF-κB in cancer: a matter of life and death. Cancer Discov 1:469–471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmad A, Sarkar SH, Aboukameel A et al (2012b) Anticancer action of garcinol in vitro and in vivo is in part mediated through inhibition of STAT-3 signaling. Carcinogenesis 33:2450–2456

    Article  CAS  PubMed  Google Scholar 

  • Ahmad A, Padhye S, Sarkar FH (2012) Role of novel nutraceuticals garcinol, plumbagin and mangiferin in the prevention and therapy of human malignancies: mechanisms of anticancer activity. In: Sarkar FH (ed) Nutraceuticals and Cancer. Springer, New York, pp 79–199

  • Anand P, Kunnumakara AB, Sundaram C et al (2008a) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25:2097–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anand P, Kunnumakkar AB, Sundaram C et al (2008b) Cancer is a preventable disease that requires major lifestyle changes. Pharm Res 25:2097–2116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Anand P, Sundaram C, Jhurani S et al (2008c) Curcumin and cancer: an ‘‘old-age” disease with an ‘‘age-old” solution. Cancer Lett 267:133–164

    Article  CAS  PubMed  Google Scholar 

  • Aqil F, Munagala R, Jeyabalan J, Vadhanam MV (2013) Bioavailability of phytochemicals and its enhancement by drug delivery systems. Cancer Lett 334:133–141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Arai Y, Watanabe S, Kimira M et al (2000) Dietary intakes of flavonols, flavones and isoflavones by Japanese women and the inverse correlation between quercetin intake and plasma LDL cholesterol concentration. J Nutr 130:2243–2250

    Article  CAS  PubMed  Google Scholar 

  • Arif M, Pradhan SK,Thanuja GR et al (2009) Mechanism of p300 specific histone acetyltransferase inhibition by small molecules. J Med Chem 52:267–277

  • Aziz N, Kim MY, Cho JY (2018) Anti-inflammatory effects of luteolin: a review of in vitro, in vivo, and in silico studies. J Ethnopharmacol 225:342–358

    Article  CAS  PubMed  Google Scholar 

  • Bendris N, Lemmers B, Blanchard JM (2015) Cell cycle, cytoskeleton dynamics and beyond: the many functions of cyclins and CDK inhibitors. Cell Cycle 14:1786–1798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bieg D, Sypniewski D, Nowak E et al (2018) Morin decreases galectin-3 expression and sensitizes ovarian cancer cells to cisplatin. Arch Gynecol Obstet 298:1181–1194

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bishayee A, Sethi G (2016) Bioactive natural products in cancer prevention and therapy: progress and promise. Semin Cancer Biol 40:1–3

    Article  PubMed  Google Scholar 

  • Boykin C, Zhang G, Chen YH, et al (2011) CucurbitacinIIa: a novel class of anti-cancer drug inducing non-reversible actin aggregation and inhibiting survivin independent of JAK2/STAT3 phosphorylation. British J Cancer 104:781–789

    Article  CAS  Google Scholar 

  • Brown J, O’Prey J, Harrison PR (2003) Enhanced sensitivity of human oral tumours to the flavonol, morin, during cancer progression: involvement of the Akt and stress kinase pathways. Carcinogenesis 24:171–177

    Article  CAS  PubMed  Google Scholar 

  • Cai Y, Fang X, He C et al (2015) Cucurbitacins: a systematic review of the phytochemistry and anticancer activity. Am J Chin Med 43:1331–1350

    Article  CAS  PubMed  Google Scholar 

  • Cháirez-Ramírez MH, de la Cruz-López KG, García-Carrancá A (2021). Polyphenols as antitumor agents targeting key players in cancer-driving signaling pathways. Front Pharmacol 12:710304.

  • Chang R, Sun L, Webste TJ (2014) Short communication: selective cytotoxicity of curcumin on osteosarcoma cells compared to healthy osteoblasts. Int J Nanomed 9:461–465

    Google Scholar 

  • Chauhan DP (2002) Chemotherapeutic potential of curcumin for colorectal cancer. Curr Pharm Des 8:1695–1706

    Article  CAS  PubMed  Google Scholar 

  • Chen JC, Chiu MH, Nie RL (2005a) Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Rep 22:386–399

    Article  CAS  PubMed  Google Scholar 

  • Chen JC, Chiu MH, Nie RL et al (2005b) Cucurbitacins and cucurbitane glycosides: structures and biological activities. Nat Prod Reports 22:386–399

    Article  CAS  Google Scholar 

  • Chen KC, Hsu WH, Ho JY et al (2008) Flavonoids Luteolin and Quercetin Inhibit RPS19 and contributes to metastasis of cancer cells through c-Myc reduction. J Food Drug Analysis 26:1180–1191

    Article  Google Scholar 

  • Chen J, Li Y, Yu TS et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488:522–526

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chuang SE, Cheng AL, Lin JK et al (2000) Inhibition by curcumin of diethylnitrosamine-induced hepatic hyperplasia, inflammation, cellular gene products and cell-cycle-related proteins in rats. Food ChemToxicol 38:991–995

    Article  CAS  Google Scholar 

  • Cragg GM, Newman DJ (2004) Plants as a source of anti-cancer agents. In: Elisabetsky E, Etkin NL (eds) Ethnopharmacology. In Encyclopedia of Life Support Systems (EOLSS). Developed under the Auspices of the UNESCO. Eolss Publishers, Oxford

  • Dhillon N, Aggarwal BB, Newman RA et al (2008) Phase II trial of curcumin in patients with advanced pancreatic cancer. Clin Cancer Res 14:4491–4499

    Article  CAS  PubMed  Google Scholar 

  • Di Martino RMC, Bisi A, Rampa A (2017) Recent progress on curcumin-based therapeutics: a patent review (2012–2016). Part II: curcumin derivatives in cancer and neurodegeneration. Exp Opin Therap Patents 27:953–961

    Article  Google Scholar 

  • Ding XL, Chi JD, Yang X et al (2017) Cucurbitacin B synergistically enhances the apoptosis-inducing effect of arsenic trioxide by inhibiting STAT3 phosphorylation in lymphoma Ramos cells. Leuk Lymphoma 58(10):2439–2451

    Article  CAS  PubMed  Google Scholar 

  • Fang J, Zhou Q, Shi XL, Jiang BH (2007) Luteolin inhibits insulin-like growth factor 1 receptor signaling in prostate cancer cells. Carcinogenesis 28:713–723

    Article  CAS  PubMed  Google Scholar 

  • Feng T, Wei Y, Lee RJ et al (2017) Liposomal curcumin and its application in cancer. Int J Nanomed 12:6027–6044

    Article  CAS  Google Scholar 

  • Gaonkar RH, Ganguly S, Dewanjee S et al (2017) Garcinol loaded vitamin E TPGS emulsified PLGA nanoparticles: preparation, physicochemical characterization, in vitro and in vivo studies. Sci Rep 7:30

    Article  Google Scholar 

  • Golombick T, Diamond TH, Manoharan A et al (2012) Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4 g study and an open-label 8 g extension study. Am J Hematol 87:455–460

    Article  CAS  PubMed  Google Scholar 

  • Gritsko T (2006) Persistent activation of Stat3 signaling induces survivin gene expression and confers resistance to apoptosis in human breast cancer cells. Clin Cancer Res 12:11–19

  • Haddad AQ, Fleshner N, Nelson C et al (2010) Antiproliferative mechanisms of the flavonoids 2, 2′-dihydroxychalcone and fisetin in human prostate cancer cells. Nutr Cancer 62:668–681

    Article  CAS  PubMed  Google Scholar 

  • Han S, Chung ST, Robertson DA et al (1999) Curcumin causes the growth arrest and apoptosis of B cell lymphoma by downregulation of egr-1, c-myc, bcl-XL, NF-kappa B, and p53. ClinImmunol 93:152–161

    CAS  Google Scholar 

  • Han K, Meng W, Zhang J et al (2016) Luteolin inhibited proliferation and induced apoptosis of prostate cancer cells through miR-301. Oncotargets Ther 9:3085–3094

    Article  CAS  Google Scholar 

  • Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100:57–70

    Article  CAS  PubMed  Google Scholar 

  • Heath DD, Khwaja FF, Rock CL (2004) Curcumin content of turmeric and curry powders. J FASEB 18:A125

    Google Scholar 

  • Hokaiwado N, Asamoto M, Tsujimura K et al (2004) Rapid analysis of gene expression changes caused by liver carcinogens and chemopreventive agents using a newly developed three-dimensional microarray system. Cancer Sci 95:123–130

    Article  CAS  PubMed  Google Scholar 

  • Hong JH, Ahn KS, Bae E et al (2006) The effects of curcumin on the invasiveness of prostate cancer in vitro and in vivo. Prostate Cancer Prostatic Dis 9:147–152

    Article  CAS  PubMed  Google Scholar 

  • Hong SJ, Kwon S, Sang et al (2007) Effects of garcinol and its derivatives on intestinal cell growth: inhibitory effects and autoxidation-dependent growth-stimulatory effects. Free Rad Biol Med 42:1211–1221

    Article  CAS  PubMed  Google Scholar 

  • Huanga WC, Kuo KT, Adebayo BO et al (2018) Garcinol inhibits cancer stem cell-like phenotype via suppression of the Wnt/β-catenin/STAT3 axis signalling pathway in human non-small cell lung carcinomas. J Nutr Biochem 54:140–150

    Article  Google Scholar 

  • Hunecke D, Spanel R, Langer F (2012) MYC-regulated genes involved in liver cell dysplasia identified in a transgenic model of liver cancer. J Pathol 228:520–533

    Article  CAS  PubMed  Google Scholar 

  • Hyun HB, Lee WS, Go SI et al (2015) The flavonoid morin from Moraceae induces apoptosis by modulation of Bcl-2 family members and Fas receptor in HCT 116 cells. Int J Oncol 46:2670–2678

    Article  CAS  PubMed  Google Scholar 

  • International Agency for Research on Cancer (2003) IARC handbooks of cancer prevention. Volume 8; fruits and vegetables. IARC Press, Lyon

  • Ito C, Itoigawa M, Miyamoto Y et al (2003) Polyprenylated benzophenones from Garcinia assigu and their potential cancer chemopreventive activities. J Nat Prod 66:206–209

    Article  CAS  PubMed  Google Scholar 

  • Jia W, Deng F, Fu W et al (2019) Curcumin suppresses wilms’ tumor metastasis by inhibiting RECK methylation. Biomed Pharmacother 111:1204–1212

    Article  CAS  PubMed  Google Scholar 

  • Jin H, Lee WS, Eun SY et al (2014) Morin, a flavonoid from Moraceae, suppresses growth and invasion of the highly metastatic breast cancer cell line MDA-MB231 partly through suppression of the Akt pathway. Int J Oncol 45:1629–1637

    Article  CAS  PubMed  Google Scholar 

  • Jing S, Zou H, Wu Z, Ren L, Zhang T, Zhang J, Wei Z (2020) Cucurbitacins: Bioactivities and synergistic effect with small-molecule drugs. J Functional Foods 72:104042

  • Kammerud SC, Metge BJ, Elhamamsy AR, Weeks SE, Alsheikh HA, Mattheyses AL, Shevde LA, Samant RS (2021) Novel role of the dietary flavonoid fisetin in suppressing rRNA biogenesis. Lab Invest (in press)

  • Kang KA, Piao MJ, Hyun JW (2015) Fisetin induces apoptosis in human nonsmall lung cancer cells via a mitochondria-mediated pathway. In Vitro Cell Dev Biol Anim 51:300–309

    Article  CAS  PubMed  Google Scholar 

  • Kashyap D, Sharma A, Sak K et al (2018) Fisetin: a bioactive phytochemical with potential for cancer prevention and pharmacotherapy. Life Sci 194:75–87

    Article  CAS  PubMed  Google Scholar 

  • Khan N, Afaq F, Mukhtar H (2010) Lifestyle as risk factor for cancer: evidence from human studies. Cancer Lett 293:133–143

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Khan F, Niaz K, Maqbool F et al (2016) Molecular targets underlying the anticancer effects of quercetin: an update. Nutrients 29:e529

  • Kim N, Kang MJ, Lee SH, Son JH, Lee JE, Paik WH, Ryu JK, Kim YT (2018) Fisetin enhances the cytotoxicity of gemcitabine by down-regulating ERK-MYC in MiaPaca-2 human pancreatic cancer cells. Anticancer Res 38(6):3527

    Article  CAS  PubMed  Google Scholar 

  • Koeberle A, Northoff H, Werz O (2009) Identification of 5-lipoxygenase and microsomal prostaglandin E2 synthase-1 as functional targets of the anti-inflammatory and anti-carcinogenic garcinol. Biochem Pharmacol 77:1513–1521

    Article  CAS  PubMed  Google Scholar 

  • Koehn FE, Carter GT (2005) The evolving role of natural products in drug discovery. Nat Rev Drug Discov 4:206–220

    Article  CAS  PubMed  Google Scholar 

  • Ku JM, Hong SH, Kim HI et al (2017) Cucurbitacin D exhibits its anti-cancer effect in human breast cancer cells by inhibiting Stat3 and Akt signaling. Euro J Inflammation 16:1–9

    Google Scholar 

  • Kumar VK, Vennila S, Nalini N (2009) Modifying effects of morin on the development of aberrant crypt foci and bacterial enzymes in experimental colon cancer. Food Chem Toxicol 47:309–315

    Article  Google Scholar 

  • Kumar VK, Vennila S, Nalini N (2010) Inhibitory effect of morin on DMH-induced biochemical changes and aberrant crypt foci formation in experimental colon carcinogenesis. Environ Toxicol Pharmacol 29:50–57

    Article  Google Scholar 

  • Kunnumakkara AB, Anand P, Aggarwal BB (2008) Curcumin inhibits proliferation, invasion, angiogenesis, and metastasis of different cancers through interaction with multiple cell signaling proteins. Cancer Lett 269:199–225

    Article  CAS  PubMed  Google Scholar 

  • Lee DH, Iwanski GB, Thoennissen NH (2010) Cucurbitacin: ancient compound shedding new light on cancer treatment. Scientific World J 10:413–418

    Article  CAS  Google Scholar 

  • Lee J, Jin H, Lee WS et al (2016) Morin, a flavonoid from Moraceae, inhibits cancer cell adhesion to endothelial cells and EMT by downregulating VCAM1 and Ncadherin. Asian Pac J Cancer Prev 17:3071–3075

    PubMed  Google Scholar 

  • Lev-Ari S, Strier L, Kazanov D et al (2005) Celecoxib and curcumin synergistically inhibit the growth of colorectal cancer cells. Clin Cancer Res 11:6738–6744

    Article  CAS  PubMed  Google Scholar 

  • Li J, Cheng Y, Qu W et al (2011) Fisetin, a dietary flavonoid, induces cell cycle arrest and apoptosis through activation of p53 and inhibition of NF-Kappa B pathways in bladder cancer cells. Basic Clin Pharmacol Toxicol 108:84–93

    Article  CAS  PubMed  Google Scholar 

  • Li F, Shanmugam MK, Siveen KS et al (2015) Garcinol sensitizes human head and neck carcinoma to cisplatin in a xenograft mouse model despite downregulation of proliferative biomarkers. Oncotarget 6:5147–5163

    Article  PubMed  PubMed Central  Google Scholar 

  • Li J, Gong X, Jiang R, Lin D, Zhou T, Zhang A, Li H, Zhang X, Wan J, Kuang G, Li H (2018) Fisetin inhibited growth and metastasis of triple-negative breast cancer by reversing epithelial-to-mesenchymal transition via PTEN/Akt/GSK3β signal pathway. Front Pharmacol 9:772

    Article  PubMed  PubMed Central  Google Scholar 

  • Lim DY, Park JH (2009) Induction of p53 contributes to apoptosis of HCT-116 human colon cancer cells induced by the dietary compound fisetin. Am J Physiol Gastrointest Liver Physiol 296:G1060–G1068

    Article  CAS  PubMed  Google Scholar 

  • Lin YS, Tsai PH, Kandaswami CC et al (2011) Effects of dietary flavonoids, luteolin, and quercetin on the reversal of epithelial-mesenchymal transition in A431 epidermal cancer cells Cancer Sci 102:1829–1839

  • Lindsey AT, Rebecca LS, Elizabeth MW et al (2016) Global cancer incidence and mortality rates and trends—an update. Cancer Epidemiol Biomarkers Prev 25:16–27

    Article  Google Scholar 

  • Liu T, Zhang M, Zhang H et al (2008) Inhibitory effects of cucurbitacin B on laryngeal squamous cell carcinoma. Eur Arch Otorhinolaryngol 265:1225–1232

    Article  PubMed  Google Scholar 

  • Liu F, Gao S, Yang Y et al (2018) Antitumor activity of curcumin by modulation of apoptosis and autophagy in human lung cancer A549 cells through inhibiting PI3K/Akt/mTOR pathway. Oncol Rep 39(3):1523–1531

    CAS  PubMed  Google Scholar 

  • Liu P, Ying Q, Liu H, Yu SQ, Bu LP, Shao L, Li XY (2020) Curcumin enhances anti-cancer efficacy of either gemcitabine or docetaxel on pancreatic cancer cells. Oncol Rep 44:1393–1402

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lu X, Cho HJ, Lee HS (2005) Fisetin inhibits the activities of cyclin-dependent kinases leading to cell cycle arrest in HT-29 human colon cancer cells. J Nutr 135:2884–2890

    Article  CAS  PubMed  Google Scholar 

  • Mahammedi H, Planchat E, Pouget M et al (2016) The new combination docetaxel, prednisone and curcumin in patients with castration-resistant prostate cancer: A pilot phase II study. Oncology 90:69–78

    Article  CAS  PubMed  Google Scholar 

  • Mahnashi M, Elgazwi SM, Ahmed MS, Halaweish FT (2019) Cucurbitacins inspired organic synthesis: potential dual inhibitors targeting EGFR - MAPK pathway. Eur J Med Chem 173:294–304

    Article  CAS  PubMed  Google Scholar 

  • Majeed M, Bani S, Bhat B, Pandey A, Mundkur L, Neupane P (2018) Safety profile of 40% Garcinol from Garcinia indica in experimental rodents. Toxicol Rep 5:750–758

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Manach C, Scalbert A, Morand C et al (2004) Polyphenols: food sources and bioavailability. Am J Clin Nutr 79:727–747

    Article  CAS  PubMed  Google Scholar 

  • Manju V, Nalini N (2007) Protective role of luteolin in 1,2-dimethylhydrazine induced experimental colon carcinogenesis. Cell Biochem Funct 25:189–194

    Article  CAS  PubMed  Google Scholar 

  • Marino M, Del Bo’ C, Martini D, Porrini M, Riso P (2020) A review of registered clinical trials on dietary (Poly)Phenols: past efforts and possible future directions. Foods 9(11):1606

    Article  CAS  PubMed Central  Google Scholar 

  • Marostica LL, de Barros ALB, Oliveira J et al (2017) Antitumor effectiveness of a combined therapy with a new cucurbitacin B derivative and paclitaxel on a human lung cancer xenograft model. Toxicol Applied Pharmacol 329:272–281

    Article  CAS  Google Scholar 

  • Menon LG, Kuttan R, Kuttan G (1995) Inhibition of lung metastasis in mice induced by B16F10 melanoma cells by polyphenolic compounds. Cancer Lett 16:221–225

    Article  Google Scholar 

  • Mottaghi, S, Abbaszadeh H (2021) The anticarcinogenic and anticancer effects of the dietary flavonoid, morin: Current status, challenges, and future perspectives. Phytotherapy Res (Online First)

  • Mukhtar H (2012) Chemoprevention: making it a success story for controlling human cancer. Cancer Lett 326:123–127

    Article  CAS  PubMed  Google Scholar 

  • Nandhakumar R, Salini K, Devaraj SN (2012) Morin augments anticarcinogenic and antiproliferative efficacy against 7,12-dimethylbenz (a)-anthracene induced experimental mammary carcinogenesis. Mol Cell Biochem 364:9–92

    Article  Google Scholar 

  • Nandhakumar R, Kasinathan NK, Sivasithamparam ND (2013) Protective role of morin on the attenuation of chemotherapeutic agent, 5-fluorouracil, induced biochemical alterations in erythrocyte membrane—an in vivo animal study. Biomed Prev Nutr 3:19–25

    Article  Google Scholar 

  • Naso LG, Badiola I, Clavijo JM et al (2016) Inhibition of the metastatic progression of breast and colorectal cancer in vitro and in vivo in murine model by the oxidovanadium (IV) complex with luteolin. Bioorg Med Chem 24:6004–6011

    Article  CAS  PubMed  Google Scholar 

  • Newman DJ, Cragg GM (2016) Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79:629–661

    Article  CAS  PubMed  Google Scholar 

  • Nowak E, Sypniewski D, Bednarek I (2020) Morin exerts anti-metastatic, anti-proliferative and anti-adhesive effect in ovarian cancer cells: an in vitro studies. Mol Biol Rep 47:1965–1978

    Article  CAS  PubMed  Google Scholar 

  • Padhye S, Ahmad A, Oswal N et al (2009) Emerging role of Garcinol, the antioxidant chalcone from Garcinia indicaChoisy and its synthetic analogs. J Hematol Oncol 2:38

    Article  PubMed  PubMed Central  Google Scholar 

  • Pal HC, Sharma S, Elmets CA et al (2013) Fisetin inhibits growth, induces G2/M arrest and apoptosis of human epidermoid carcinoma A431 cells: role of mitochondrial membrane potential disruption and consequent caspases activation. Exp Dermatol 22:470–475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pal HC, Baxter RD, Hunt KM et al (2015) Fisetin, a phytochemical, potentiates sorafenib-induced apoptosis and abrogates tumor growth in athymic nude mice implanted with BRAF-mutated melanoma cells. Oncotarget 6:28296–28311

    Article  PubMed  PubMed Central  Google Scholar 

  • Pandeya MK, Gupta SC, Nabavizadeh A et al (2017) Regulation of cell signaling pathways by dietary agents for cancer prevention and treatment. Sem Cancer Biol 46:158–181

    Article  Google Scholar 

  • Parasramka MA, Ho E, Williams DE et al (2012) MicroRNAs, diet, and cancer: new mechanistic insights on the epigenetic actions of phytochemicals. Mol Carcinog 51:213–230

    Article  CAS  PubMed  Google Scholar 

  • Parasramka MA, Ali S, Banerjee S et al (2013) Garcinol sensitizes human pancreatic adenocarcinoma cells to gemcitabine in association with microRNA signatures. Mol Nutr Food Res 57:235–248

    Article  CAS  PubMed  Google Scholar 

  • Park C, Lee WS, Go SI (2015) Morin, a flavonoid from moraceae, induces apoptosis by induction of BAD protein in human leukemic cells. Int J Mol Sci 16:645–659

    Article  Google Scholar 

  • Park BS, Choi NE, Lee JH et al (2019) Crosstalk between fisetin-induced apoptosis and autophagy in human oral squamous cell carcinoma. J Cancer 10(1):138–146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Potočnjak I, Šimić L, Gobin I, Vukelić I, Domitrović R (2020) Antitumor activity of luteolin in human colon cancer SW620 cells is mediated by the ERK/FOXO3a signaling pathway. Toxicol In Vitro 66:104852.

  • Ríos JL, Andújar I, Escandell JM et al (2012) Cucurbitacins as inducers of cell death and a rich source of potential anticancer compounds. Curr Pharm Des 18:1663–1676

    Article  PubMed  Google Scholar 

  • Ruiz PV, Bystrup S, Martınez-Cardus A et al (2016) Curcumin mediates oxaliplatin acquired resistance reversion in colorectal cancer cell lines through modulation of CXC-Chemokine/NF-kB signalling pathway. Sci Rep 6:24675

    Article  Google Scholar 

  • Sadzuka Y, Fujiki S, Itai S (2012) Enhancement of doxorubicin-induced antitumor activity and reduction of adverse reactions by cucurbitacin I. Food Res Internat 47:64–69

    Article  CAS  Google Scholar 

  • Saghatelyan T, Tananyan A, Janoyan N et al (2020) Efficacy and safety of curcumin in combination with paclitaxel in patients with advanced, metastatic breast cancer: a comparative, randomized, double-blind, placebo-controlled clinical trial. Phytomedicine 70:153218

  • Seelinger G, Merfort I, Wölfle U (2008) Anti-carcinogenic effects of the flavonoid luteolin. Molecules 13:2628–2651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Seydi E, Salimi A, Rasekh HR (2018) Selective cytotoxicity of Luteolin and Kaempferol on cancerous hepatocytes obtained from rat model of hepatocellular carcinoma: involvement of ROS-mediated mitochondrial targeting. Nutr Cancer 70:594–604

    Article  CAS  PubMed  Google Scholar 

  • Sharmaa SH, ThulasingamaS CDR et al (2017) Morin and Esculetin supplementation modulates c-myc induced energy metabolism and attenuates neoplastic changes in rats challenged with the procarcinogen 1,2-dimethylhydrazine. Euro J Pharmacol 796:20–31

    Article  Google Scholar 

  • Sharmaa SH, Kumara JS, Chellappanb DR et al (2018) Molecular chemoprevention by morin—a plant flavonoid that targets nuclear factor kappa B in experimental colon cancer. Biomed Pharmacotherapy 100:367–373

    Article  Google Scholar 

  • Shin SS, Won SY, Noh DH et al (2017) Morin inhibits proliferation, migration, and invasion of bladder cancer EJ cells via modulation of signaling pathways, cell cycle regulators, and transcription factor-mediated MMP-9 expression. Drug Dev Res 78:81–90

    Article  CAS  PubMed  Google Scholar 

  • Siddiqui IA, Adhami VM, Ahmad N et al (2010) Nanochemoprevention: sustained release of bioactive food components for cancer prevention. Nutr Cancer 62:883–890

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sikander M, Hafeez BB, Malik S et al (2016) Cucurbitacin D exhibits potent anticancer activity in cervical cancer. Sci Rep 6:36594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Silva IT, Geller FC, Persich L et al (2016) Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549. Invest New Drugs 34:139–148

    Article  CAS  PubMed  Google Scholar 

  • Sivaramakrishnan V, Devaraj SN (2010) Morin fosters apoptosis in experimental hepatocellular carcinogenesis model. Chem Biol Interact 183:284–292

    Article  CAS  PubMed  Google Scholar 

  • Smith ML, Murphy K, Doucette CD et al (2016a) The dietary flavonoid fisetin causes cell cycle arrest, caspase-dependent apoptosis, and enhanced cytotoxicity of chemotherapeutic drugs in triple-negative breast cancer cells. J Cell Biochem 9999:1–13

    Google Scholar 

  • Smith ML, Murphy K, Doucette CD et al (2016b) The dietary flavonoid fisetin causes cell cycle arrest caspase-dependent apoptosis, and enhanced cytotoxicity of chemotherapeutic drugs in triple-negative breast cancer cells. J Cell Biochem 117:1912–1925

    Article  Google Scholar 

  • Song S, Su Z, Xu H et al (2017) Luteolin selectively kills STAT3 highly activated gastric cancer cells through enhancing the binding of STAT3 to SHP-1. Cell Death Dis 8:e2612

  • Suh Y, Afaq F, Johnson JJ (2009) A plant flavonoid fisetin induces apoptosis in colon cancer cells by inhibition of COX2 and Wnt/EGFR/NF-kappa B-signaling pathways. Carcinogenesis 30:300–307

    Article  CAS  PubMed  Google Scholar 

  • Sun J, Blaskovich MA, Jove R et al (2005) Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity. Oncogene 24:3236–3245

    Article  CAS  PubMed  Google Scholar 

  • Sun Y, Zhan J, Zhou J et al (2015) Synergistic effect of cucurbitacin B in combination with curcumin via enhancing apoptosis induction and reversing multidrug resistance in human hepatoma cells. European J Pharmacol 768:28–40

    Article  CAS  Google Scholar 

  • Sung B, Pandey MK, Aggarwal BB (2007) Fisetin, an inhibitor of cyclin-dependent kinase 6, down-regulates nuclear factor-kappa B-regulated cell proliferation, antiapoptotic and metastatic gene products through the suppression of TAK-1 and receptor-interacting protein-regulated I kappa B alpha kinase activation. Mol Pharmacol 71:1703–1714

    Article  CAS  PubMed  Google Scholar 

  • Sung H, Ferlay J, Siegel RL et al (2021) Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 71:209–249

    Article  PubMed  Google Scholar 

  • Syed DN, Chamcheu JC, Khan MI et al (2014) Fisetin inhibits human melanoma cell growth through direct binding to p70S6K and mTOR: findings from 3-D melanoma skin equivalents and computational modeling. Biochem Pharmacol 89:349–360

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szebeni GJ, BalázsA MI et al (2017) Achiral Mannich-base curcumin analogs induce unfolded protein response and mitochondrial membrane depolarization in PANC-1 Cells. Int J Mol Sci 18:2105

    Article  PubMed Central  Google Scholar 

  • Tsai PH, Cheng CH, Lin CY et al (2016) Dietary Flavonoids Luteolin and Quercetin suppressed cancer stem cell properties and metastatic potential of isolated prostate cancer cells. Anticancer Res 36:6367–6380

    Article  CAS  PubMed  Google Scholar 

  • Tsvetkov P, Asher G, Reiss V et al (2005) Inhibition of NAD(P)H:quinone oxidoreductase 1 activity and induction of p53 degradation by the natural phenolic compound curcumin. Proc Natl Acad Sci USA 102:5535–5540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Uddin MN, Park SY (2019) Luteolin sensitizes human liver cancer cells to TRAIL-induced apoptosis via autophagy and JNK-mediated death receptor 5 upregulation. Int J Oncol 54(2):665–672

  • Ullah MF (2015) Sulforaphane (SFN): an isothiocyanate in a cancer chemoprevention paradigm. Medicines 2:141–156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ullah MF, Khan MW (2008) Food as medicine: potential therapeutic tendencies of plant derived polyphenolic compounds. Asian Pacific J Cancer Prev 9:187–196

    Google Scholar 

  • Ullah MF, Bhat SH, Husain E et al (2014) Cancer chemopreventive pharmacology of phytochemicals derived from plants of dietary and non-dietary origin: implication for alternative and complementary approaches. Phytochem Rev 13:811–833

    Article  CAS  Google Scholar 

  • Ullah MF, Bhat SH, Husain E et al (2016) Pharmacological intervention through dietary nutraceuticals in gastrointestinal neoplasia. Crit Rev Food Sci Nutr 56:1501–1518

    Article  CAS  PubMed  Google Scholar 

  • Ullah MF, Usmani S, Shah A et al (2020) Dietary molecules and experimental evidence of epigenetic influence in cancer chemoprevention: an insight. Semin Cancer Biol (in Press)

  • Vainio H, Weiderpress E (2006) Fruit and vegetables in cancer prevention. Nutr Cancer 54:111–142

    Article  CAS  PubMed  Google Scholar 

  • Vanithaa P, Senthilkumar S, Dornadula S et al (2017) Morin activates the Nrf2-ARE pathway and reduces oxidative stress-induced DNA damage in pancreatic beta cells. Euro J Pharmacol 801:9–18

    Article  Google Scholar 

  • Vyas A, Danadawate P, Padhye S et al (2013) Perspective on new synthetic curcumin analogs and their potential anticancer properties. Curr Pharm Des 19:2047–2069

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wang Y, Tsai ML, Chiou LY, Ho CT, Pan MH et al (2015a) Antitumor activity of garcinol in human prostate cancer cells and xenograft mice. J Agric Food Chem 63:9047–9052

    Article  CAS  PubMed  Google Scholar 

  • Wang ZY, Liu WQ, Wei ZT (2015b) Fisetin induces G2/M phase cell cycle arrest by inactivating cdc25C-cdc2 via ATM-Chk1/2 activation in human endometrial cancer cells. Bangladesh J Pharmacol 10:279–287

    Article  Google Scholar 

  • Wang J, Wang L, Ho CT et al (2017a) Garcinol from Garcinia indica downregulates cancer stem-like cell biomarker ALDH1A1 in nonsmall cell lung cancer A549 cells through DDIT3 activation. J Agric Food Chem 65:3675–3683

    Article  CAS  PubMed  Google Scholar 

  • Wang X, Tanaka M, Peixoto HS et al (2017) Cucurbitacins: elucidation of their interactions with the cytoskeleton. Peer J 5:e3357

  • WHO (2013) WHO traditional medicine strategy, 2014–2023. WHO Press, Geneva

    Google Scholar 

  • Wisniewska AK, Wi´sniewska MH,Grzanka A, et al (2018) Evaluation of anti-metastatic potential of the combination of fisetin with paclitaxel on A549 non-small cell lung cancer cells. Int J Mol Sci 19:e661

  • Won DH, Chung SH, Shin JA, Hong KO, Yang IH, Yun JW, Cho SD (2019) Induction of sestrin 2 is associated with fisetin-mediated apoptosis in human head and neck cancer cell lines. J Clin Biochem Nutr 64(2):97–105

    Article  CAS  PubMed  Google Scholar 

  • Wu HT, Lin J, Liu YE et al (2021) Luteolin suppresses androgen receptor-positive triple-negative breast cancer cell proliferation and metastasis by epigenetic regulation of MMP9 expression via the AKT/mTOR signaling pathway. Phytomedicine 81:153437.

  • Xiao X, Zou J, Fang Y et al (2018) Fisetin and polymeric micelles encapsulating fisetin exhibit potent cytotoxic effects towards ovarian cancer cells. BMC Complement Altern Med 18:91

    Article  PubMed  PubMed Central  Google Scholar 

  • Yang X, Li Z, Wang N et al (2015) Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo. Sci Rep 5:10322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, Wang C, Zhang Z et al (2017) Curcumin inhibits the survival and metastasis of prostate cancer cells via the Notch-1 signaling pathway. APMIS 125:134–140

    Article  CAS  PubMed  Google Scholar 

  • Zhang C, He LJ, Ye HZ et al (2018a) Nrf2 is a key factor in the reversal effect of curcumin on multidrug resistance in the HCT-8/5-Fu human colorectal cancer cell line. Mol Med Rep 18(6):5409–5416

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang M, Lu Q, Hou H et al (2021) Garcinol inhibits the proliferation of endometrial cancer cells by inducing cell cycle arrest. Oncol Rep 45:630–640

    Article  CAS  PubMed  Google Scholar 

  • Zhang Q, Zhang F, Thakur K et al (2018) Molecular mechanism of anti-cancerous potential of Morin extracted from mulberry in Hela cells. Food Chem Toxicol 112:466e475

  • Zhao J, Yang T, Ji J, Li C, Li Z, Li L (2018) Garcinol exerts anti-cancer effect in human cervical cancer cells through upregulation of T-cadherin. Biomed Pharmacother 107:957–966

    Article  CAS  PubMed  Google Scholar 

  • Zheng M, Ekmekcioglu S, Walch ET et al (2004) Inhibition of nuclear factor-kappaB and nitric oxide by curcumin induces G2/M cell cycle arrest and apoptosis in human melanoma cells. Melanoma Res 14:165–171

    Article  CAS  PubMed  Google Scholar 

  • Zheng Y, Guo C, Zhang X, Wang X, Ma A (2020) Garcinol acts as an antineoplastic agent in human gastric cancer by inhibiting the PI3K/AKT signaling pathway. Oncol Lett 20:667–676

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Wang Y, Ju X et al (2015) Clinicopathological significance of ALDH1A1 in lung, colorectal, and breast cancers: a meta-analysis. Biomark Med 9:777–790

    Article  CAS  PubMed  Google Scholar 

  • Zhou Y, Dingc BZ, Lind YP et al (2018) MiR-34a, as a suppressor, enhance the susceptibility of gastric cancer cell to luteolin by directly targeting HK1.Gene 644:56–65

  • Zhu J, Yang X, Chen Y et al (2017) Curcumin suppresses lung cancer stem cells via inhibiting Wnt/b-catenin and sonic hedgehog pathways. Phytother Res 31:680–688

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

All the studies in the literature from which this manuscript has been derived and referred as an evidence of the subject have been duly cited.

Funding

There is no funding to be disclosed for this review article.

Author information

Authors and Affiliations

  1. Prince Fahd Research Chair, Department of Medical Laboratory Technology, Faculty of Applied Medical Science, University of Tabuk, Tabuk, Saudi Arabia

    Mohammad Fahad Ullah, Showket H. Bhat & Faisel M. Abuduhier

  2. University of Alabama at Birmingham, Birmingham, AL, USA

    Aamir Ahmad

  3. Interim Translational Research Institute, Hamad Medical Corporation, Doha, Qatar

    Aamir Ahmad

  4. Department of Medical Laboratory Technology and Molecular Diagnostics, Center for Vocational Studies, Islamic University of Science and Technology, Awantipora, Jammu & Kashmir, India

    Showket H. Bhat

  5. Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, Saudi Arabia

    Syed Khalid Mustafa

  6. Faculty of Pharmacy, Integral University, Lucknow, India

    Shazia Usmani

Authors
  1. Mohammad Fahad Ullah
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aamir Ahmad
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Showket H. Bhat
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Faisel M. Abuduhier
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Syed Khalid Mustafa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shazia Usmani
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MFU contributed to concept, design, analysis and manuscript preparation; AA designed the study and prepared the manuscript; SHB and FMA conducted comparative analysis; SKM and SU performed literature review and editing.

Corresponding author

Correspondence to Mohammad Fahad Ullah.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

The current manuscript is a review article which does not involve experimental protocols involving human subjects or laboratory animals.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ullah, M.F., Ahmad, A., Bhat, S.H. et al. Diet-derived small molecules (nutraceuticals) inhibit cellular proliferation by interfering with key oncogenic pathways: an overview of experimental evidence in cancer chemoprevention. BIOLOGIA FUTURA 73, 55–69 (2022). https://doi.org/10.1007/s42977-022-00110-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s42977-022-00110-x

Keywords

Search

Navigation