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Molecular Mechanistic Approach of Important Antileukemic Compounds Present in Honey

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Therapeutic Applications of Honey and its Phytochemicals

Abstract

Homeostasis is a collective name for the self-regulating cellular processes that maintain cell stability and survival. Any variation from normal functioning in any biological process can lead to different diseases or syndromes such as cancer, diabetes, and metabolic syndromes. Cancer results by the uncontrolled division of cells in any organ or tissue and can metastasize to other organs as well. Derailment in the process of cell division is the main cause for caner development. Leukemia—a type of cancer in which the function and production of blood cells gets affected, is one of the leading cancers-related mortalities throughout the world. Scientific research has witnessed a great interest in the pharmacodynamics of naturally occurring food products or other plants or plant products of medicinal value in order to make them novel drug agents to target various diseases including cancer. This chapter vividly describes phenolic compounds that can be used as signature drugs to target leukemias. Gene expression and microarray studies have depicted the various signaling pathways regulated by these compounds and, hence, serve in inducing decreased cell growth and malignancy in leukemias. Honey is well-known for its nutritional and medicinal properties since ages and is continuously being explored for its wide pharmacological properties. Studies have attributed significant anti-cancerous action to honey, but very less literature is available on its antileukemic action. In this present chapter, we have summarized the anti-leukemic activities associated with bioactive components present in honey. Honey is a storehouse of biologically essential phenolic compounds such as phenolic acids, tannins, flavonoids, terpenoids, and coumarins. These compounds show tumor reduction or inhibitory action by arresting the cell cycle, up- or downregulating mRNA expression of proteins involved in apoptotic cascades like Bax, caspase-3, Bcl-2, NOXA, MCL-1, rTRAIL, FAS, SCF/c-Kit complex, p-ATM, p-ATR, 14-3-3 proteins sigma, MGMT, and HDACs; deactivating drug efflux ABC transporters; various cyclins and CDKs; and decreasing mitochondrial membrane potential. Till date no study elucidating the effect of raw honey-derived phenolic compounds has been undertaken and, therefore, a wide scope exists for studying the effective chemotherapeutic mechanisms of these compounds.

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References

  • Abubakar MB, Abdullah WZ, Sulaiman SA, Suen AB (2012) A review of molecular mechanisms of the anti-leukemic effects of phenolic compounds in honey. Int J Mol Sci 13(11):15054–15073

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Adan A, Baran Y (2016) Fisetin and hesperetin induced apoptosis and cell cycle arrest in chronic myeloid leukemia cells accompanied by modulation of cellular signaling. Tumor Biol 37(5):5781–5795

    Article  CAS  Google Scholar 

  • Alvarez MC, Maso V, Torello CO, Ferro KP, Saad STO (2018) The polyphenol quercetin induces cell death in leukemia by targeting epigenetic regulators of pro-apoptotic genes. Clin Epigenetics 10(1):139

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bae CS, Lee CM, Ahn T (2020) Encapsulation of apoptotic proteins in lipid nanoparticles to induce death of cancer cells. Biotechnol Bioproc Eng 25:264–271

    Article  CAS  Google Scholar 

  • Baig S, Attique H (2014) Cytotoxic activity of honey in hepatoma cells: in vitro evaluation. Pak J Med Dent 3(1):12–16

    Google Scholar 

  • Bestwick CS, Milne L (2006) Influence of galangin on HL-60 cell proliferation and survival. Cancer Lett 243(1):80–89

    Article  CAS  PubMed  Google Scholar 

  • Bestwick CS, Milne L, Duthie SJ (2007) Kaempferol induced inhibition of HL-60 cell growth results from a heterogeneous response, dominated by cell cycle alterations. Chemico-Biol Interact 170(2):76–85

    Article  CAS  Google Scholar 

  • Billard C (2014) Apoptosis inducers in chronic lymphocytic leukemia. Oncotarget 5(2):309

    Article  PubMed  Google Scholar 

  • Biswal BN, Das SN, Das BK, Rath R (2017) Alteration of cellular metabolism in cancer cells and its therapeutic prospects. J Oral Maxillofac Pathol 21:244–251

    Article  PubMed  PubMed Central  Google Scholar 

  • Budhraja A, Gao N, Zhang Z, Son YO, Cheng S, Wang X, Shi X (2012) Apigenin induces apoptosis in human leukemia cells and exhibits anti-leukemic activity in vivo. Mol Canc Therapeut 11(1):132–142

    Article  CAS  Google Scholar 

  • Calgarotto AK, Maso V, Junior GCF, Nowill AE, Latuf Filho P, Vassallo J, Saad STO (2018) Antitumor activities of Quercetin and Green Tea in xenografts of human leukemia HL60 cells. Sci Rep 8(1):1–7

    Article  CAS  Google Scholar 

  • Cavaliere V, Papademetrio DL, Lombardo T, Costantino SN, Blanco GA, Álvarez EM (2014) Caffeic acid phenylethyl ester and MG132, two novel nonconventional chemotherapeutic agents, induce apoptosis of human leukemic cells by disrupting mitochondrial function. Target Oncol 9(1):25–42

    Article  PubMed  Google Scholar 

  • Chang JL, Chow JM, Chang JH, Wen YC, Lin YW, Yang SF, Chien MH (2017) Quercetin simultaneously induces G0/G1-phase arrest and caspase-mediated crosstalk between apoptosis and autophagy in human leukemia HL-60 cells. Environ Toxicol 32(7):1857–1868

    Article  CAS  PubMed  Google Scholar 

  • Chang L, Hou Y, Zhu L, Wang Z, Chen G, Shu C, Liu Y (2020) Veliparib overcomes multidrug resistance in liver cancer cells. Biochem Biophys Res Commun 521(3):596–602

    Article  CAS  PubMed  Google Scholar 

  • Chen D, Daniel KG, Chen MS, Kuhn DJ, Landis-Piwowar KR, Dou QP (2005) Dietary flavonoids as proteasome inhibitors and apoptosis inducers in human leukemia cells. Biochem Pharmacol 69(10):1421–1432

    Article  CAS  PubMed  Google Scholar 

  • Chen YJ, Shiao MS, Hsu ML, Tsai TH, Wang SY (2001) Effect of caffeic acid phenethyl ester, an antioxidant from propolis, on inducing apoptosis in human leukemic HL-60 cells. J Agri Food Chem 49(11):5615–5619

    Article  CAS  Google Scholar 

  • Chien ST, Shi MD, Lee YC, Te CC, Shih YW (2015) Galangin, a novel dietary flavonoid, attenuates metastatic feature via PKC/ERK signaling pathway in TPA-treated liver cancer HepG2 cells. Cancer Cell Int 15(1):15

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Čipák L, Rauko P, Miadoková E, Čipáková I, Novotny L (2003) Effects of flavonoids on cisplatin-induced apoptosis of HL-60 and L1210 leukemia cells. Leukemia Res 27(1):65–72

    Article  Google Scholar 

  • Cooper GM (2000) The cell: a molecular approach, 2nd edn. Sinauer Associates, Sunderland, MA. The Development and Causes of Cancer. https://www.ncbi.nlm.nih.gov/books/NBK9963/.Accessed 5 May 2020

    Google Scholar 

  • Csokay B, Prajda N, Weber G, Olah E (1997) Molecular mechanisms in the antiproliferative action of quercetin. Life Sci 60(24):2157–2163

    Article  CAS  PubMed  Google Scholar 

  • Deng X, Zhang X, Li W, Feng RX, Li L, Yi GR, Lu B (2018) Chronic liver injury induces conversion of biliary epithelial cells into hepatocytes. Cell Stem Cell 23(1):114–122

    Article  CAS  PubMed  Google Scholar 

  • Fauzi AN, Norazmi MN, Yaacob NS (2011) Tualang honey induces apoptosis and disrupts the mitochondrial membrane potential of human breast and cervical cancer cell lines. Food Chem Toxicol 49(4):871–878

    Article  CAS  PubMed  Google Scholar 

  • Fennell DA, Chacko A, Mutti L (2008) BCL-2 family regulation by the 20S proteasome inhibitor bortezomib. Oncogene 27(9):1189–1197

    Article  CAS  PubMed  Google Scholar 

  • Genovese G, Kähler AK, Handsaker RE, Lindberg J, Rose SA, Bakhoum SF, Purcell SM (2014) Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence. N Engl J Med 371(26):2477–2487

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Ghorbani A, Nazari M, Jeddi-Tehrani M, Zand H (2012) The citrus flavonoid hesperidin induces p53 and inhibits NF-κB activation in order to trigger apoptosis in NALM-6 cells: involvement of PPARγ-dependent mechanism. Eur J Nutr 51(1):39–46

    Article  CAS  PubMed  Google Scholar 

  • Goto H, Yanagimachi M, Goto S, Takeuchi M, Kato H, Yokosuka T, Yokota S (2012) Methylated chrysin reduced cell proliferation, but antagonized cytotoxicity of other anticancer drugs in acute lymphoblastic leukemia. Anti-Cancer Drugs 23(4):417–425

    Article  CAS  PubMed  Google Scholar 

  • Han Y, Yu H, Wang J, Ren Y, Su X, Shi Y (2015) Quercetin alleviates myocyte toxic and sensitizes anti-leukemic effect of adriamycin. Hematology 20(5):276–283

    Article  CAS  PubMed  Google Scholar 

  • Hassanzadeh A, Hosseinzadeh E, Rezapour S, Vahedi G, Haghnavaz N, Marofi F (2019) Quercetin promotes cell cycle arrest and apoptosis and attenuates the proliferation of human chronic myeloid leukemia cell line-K562 through interaction with HSPs (70 and 90), MAT2A and FOXM1. Anticancer Agents Med Chem 19(12):1523–1534

    Article  CAS  PubMed  Google Scholar 

  • He D, Guo X, Zhang E, Zi F, Chen J, Chen Q, Yang Y (2016) Quercetin induces cell apoptosis of myeloma and displays a synergistic effect with dexamethasone in vitro and in vivo xenograft models. Oncotarget 7(29):45489

    Article  PubMed  PubMed Central  Google Scholar 

  • Jaganathan SK, Mondhe D, Wani ZA, Supriyanto E (2014) Evaluation of selected honey and one of its phenolic constituent eugenol against L1210 lymphoid leukemia. Sci World J 2014:912051

    Article  CAS  Google Scholar 

  • Jin UH, Song KH, Motomura M, Suzuki I, Gu YH, Kang YJ, Kim CH (2008) Caffeic acid phenethyl ester induces mitochondria-mediated apoptosis in human myeloid leukemia U937 cells. Mol Cell Biochem 310(1-2):43–48

    Article  CAS  PubMed  Google Scholar 

  • Kang TB, Liang NC (1997) Studies on the inhibitory effects of quercetin on the growth of HL-60 leukemia cells. Biochem Pharmacol 54(9):1013–1018

    Google Scholar 

  • Kim KY, Jang WY, Lee JY, Jun DY, Ko JY, Yun YH, Kim YH (2016) Kaempferol activates G2-checkpoint of the cell cycle resulting in G2-arrest and mitochondria-dependent apoptosis in human acute leukemia Jurkat T cells. J Microbiol Biotechnol 26(2):287–294

    Article  CAS  PubMed  Google Scholar 

  • Kumazawa S, Ahn MR, Fujimoto T, Kato M (2010) Radical-scavenging activity and phenolic constituents of propolis from different regions of Argentina. Nat Prod Res 24(9):804–812

    Article  CAS  PubMed  Google Scholar 

  • Kuo HC, Kuo WH, Lee YJ, Wang CJ, Tseng TH (2006) Enhancement of caffeic acid phenethyl ester on all-trans retinoic acid-induced differentiation in human leukemia HL-60 cells. Toxicol App Pharmacol 216(1):80–88

    Article  CAS  Google Scholar 

  • Lee SJ, Yoon JH, Song KS (2007) Chrysin inhibited stem cell factor (SCF)/c-Kit complex-induced cell proliferation in human myeloid leukemia cells. Biochem Pharmacol 74(2):215–225

    Article  CAS  PubMed  Google Scholar 

  • Lee TJ, Kim OH, Kim YH, Lim JH, Kim S, Park JW, Kwon TK (2006) Quercetin arrests G2/M phase and induces caspase-dependent cell death in U937 cells. Cancer Lett 240(2):234–242

    Article  CAS  PubMed  Google Scholar 

  • Li B, Zhou P, Xu K, Chen T, Jiao J, Wei H, Xiao J (2020) Metformin induces cell cycle arrest, apoptosis and autophagy through ROS/JNK signaling pathway in human osteosarcoma. Int J Biol Sci 16(1):74

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lin CC, Yu CS, Yang JS, Lu CC, Chiang JH, Lin JP, Chung JG (2012) Chrysin, a natural and biologically active flavonoid, influences a murine leukemia model in vivo through enhancing populations of T-and B-cells, and promoting macrophage phagocytosis and NK cell cytotoxicity. In Vivo 26(4):665–670

    CAS  PubMed  Google Scholar 

  • Man N, Khuzaimi NM, Hassan R, Ang CY, Abdullah AD, Radzi M, Sulaiman SA (2015) Antileukemic effect of tualang honey on acute and chronic leukemia cell lines. Bio Med Res Int 2015:307094

    Google Scholar 

  • Monasterio A, Urdaci MC, Pinchuk IV, Lopez-Moratalla N, Martinez-Irujo JJ (2004) Flavonoids induce apoptosis in human leukemia U937 cells through caspase-and caspase-calpain-dependent pathways. Nutr Cancer 50(1):90–100

    Article  CAS  PubMed  Google Scholar 

  • Moradzadeh M, Tabarraei A, Sadeghnia HR, Ghorbani A, Mohamadkhani A, Erfanian S, Sahebkar A (2018) Kaempferol increases apoptosis in human acute promyelocytic leukemia cells and inhibits multidrug resistance genes. J Cell Biochem 119(2):2288–2297

    Article  CAS  PubMed  Google Scholar 

  • Murtaza G, Karim S, Akram MR, Khan SA, Azhar S, Mumtaz A, Hassan MH (2014) Caffeic acid phenethyl ester and therapeutic potentials. Bio Med Res Int 2014:145342

    Google Scholar 

  • Nikoletopoulou V, Markaki M, Palikaras K, Tavernarakis N (2013) Crosstalk between apoptosis, necrosis and autophagy. Biochim Biophys Acta 1833(12):3448–3459

    Article  CAS  PubMed  Google Scholar 

  • Pirtoli L, Belmonte G, Toscano M, Tini P, Miracco C (2020) Comment on “Everolimus induces G1 cell cycle arrest through autophagy-mediated protein degradation of cyclin D1 in breast cancer cells”. Am J Physiol Cell Physiol 18(2):448–449

    Article  CAS  Google Scholar 

  • Polier G, Ding J, Konkimalla BV, Eick D, Ribeiro N, Kohler R, Li-Weber M (2011) Wogonin and related natural flavones are inhibitors of CDK9 that induce apoptosis in cancer cells by transcriptional suppression of Mcl-1. Cell Death Dis 2(7):182–182

    Article  CAS  Google Scholar 

  • Ramos AM, Aller P (2008) Quercetin decreases intracellular GSH content and potentiates the apoptotic action of the antileukemic drug arsenic trioxide in human leukemia cell lines. Biochem Pharmacol 75(10):912–1923

    Article  CAS  Google Scholar 

  • Ren HJ, Hao HJ, Shi YJ, Meng XM, Han YQ (2010) Apoptosis-inducing effect of quercetin and kaempferol on human HL-60 cells and its mechanism. Zhongguo Shi Yan Xue Ye Xue Za Zhi 18(3):629–633

    CAS  PubMed  Google Scholar 

  • Rocha LD, Monteiro MC, Teodoro AJ (2012) Anticancer properties of hydroxycinnamic acids—a review. Cancer Clin Oncol 1(2):109–121

    Google Scholar 

  • Salimi A, Roudkenar MH, Seydi E, Sadeghi L, Mohseni A, Pirahmadi N, Pourahmad J (2017) Chrysin as an anti-cancer agent exerts selective toxicity by directly inhibiting mitochondrial complex II and V in CLL B-lymphocytes. Cancer Investig 35(3):174–186

    Article  CAS  Google Scholar 

  • Shehata M, Schnabl S, Demirtas D, Hilgarth M, Hubmann R, Ponath E, Gaiger A (2010) Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia. Blood 116(14):2513–2521

    Article  CAS  PubMed  Google Scholar 

  • Spagnuolo C, Russo M, Bilotto S, Tedesco I, Laratta B, Russo GL (2012) Dietary polyphenols in cancer prevention: the example of the flavonoid quercetin in leukemia. Ann N Y Acad Sci 1259(1):95–103

    Article  CAS  PubMed  Google Scholar 

  • Spilioti E, Jaakkola M, Tolonen T, Lipponen M, Virtanen V, Chinou I, Kassi E, Karabournioti S, Moutsatsou P (2014) Phenolic acid composition, antiatherogenic and anticancer potential of honeys derived from various regions in Greece. PLoS One 9(4):e94860

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Stephens JM, Schlothauer RC, Morris BD, Yang D, Fearnley L, Greenwood DR, Loomes KM (2010) Phenolic compounds and methylglyoxal in some New Zealand manuka and kanuka honeys. Food Chem 120(1):78–86

    Article  CAS  Google Scholar 

  • Sulaiman GM (2016) Molecular structure and anti-proliferative effect of galangin in HCT-116 cells: in vitro study. Food Sci Biotechnol 25(1):247–252

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Swellam T, Miyanaga N, Onozawa M, Hattori K, Kawai K, Shimazui T, Akaza H (2003) Antineoplastic activity of honey in an experimental bladder cancer implantation model: in vivo and in vitro studies. Int J Urol 10(4):213–219

    Article  CAS  PubMed  Google Scholar 

  • Tanaka T, Tanaka T, Tanaka M (2011) Potential cancer chemopreventive activity of protocatechuic acid. J Exp Clin Med 3(1):27–33

    Article  CAS  Google Scholar 

  • Tolomeo M, Grimaudo S, Di Cristina A, Pipitone RM, Dusonchet L, Meli M, Simoni D (2008) Galangin increases the cytotoxic activity of imatinib mesylate in imatinib-sensitive and imatinib-resistant Bcr-Abl expressing leukemia cells. Cancer Lett 265(2):289–297

    Article  CAS  PubMed  Google Scholar 

  • Towers CG, Wodetzki D, Thorburn A (2020) Autophagy and cancer: modulation of cell death pathways and cancer cell adaptations. J Cell Biol 219(1):e201909033

    PubMed  Google Scholar 

  • Vargo MA, Voss OH, Poustka F, Cardounel AJ, Grotewold E, Doseff AI (2006) Apigenin-induced-apoptosis is mediated by the activation of PKCδ and caspases in leukemia cells. Biochem Pharmacol 72(6):681–692

    Article  CAS  PubMed  Google Scholar 

  • Wang J, Li QX (2011) Chemical composition, characterization, and differentiation of honey botanical and geographical origins. Adv Food Nutr Res 62:89–137

    Article  CAS  PubMed  Google Scholar 

  • Woo KJ, Jeong YJ, Park JW, Kwon TK (2004) Chrysin-induced apoptosis is mediated through caspase activation and Akt inactivation in U937 leukemia cells. Biochem Biophys Res Commun 325(4):1215–1222

    Article  CAS  PubMed  Google Scholar 

  • Wu LY, Lu HF, Chou YC, Shih YL, Bau DT, Chen JC, Chung JG (2015) Kaempferol induces DNA damage and inhibits DNA repair associated protein expressions in human promyelocytic leukemia HL-60 cells. Am J Chin Med 43(02):365–382

    Article  CAS  PubMed  Google Scholar 

  • Xiang W, Yang CY, Bai L (2018) MCL-1 inhibition in cancer treatment. Onco Targets Ther 11:7301–7314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yan YY, Shi KY, Teng F, Chen J, Che JX, Dong XW, Zhang B (2020) A novel derivative of valepotriate inhibits the PI3K/AKT pathway and causes Noxa-dependent apoptosis in human pancreatic cancer cells. Acta Pharmacol Sin 41:835–842

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin J, Hou Y, Song X, Wang P, Li Y (2019) Cholate-modified polymer-lipid hybrid nanoparticles for oral delivery of quercetin to potentiate the antileukemic effect. Int J Nanomedicine 14:4045

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zaric M, Mitrovic M, Nikolic I, Baskic D, Popovic S, Djurdjevic P, Zelen I (2015) Chrysin induces apoptosis in peripheral blood lymphocytes isolated from human chronic lymphocytic leukemia. Anticancer Agents Med Chem 15(2):189–195

    Article  CAS  PubMed  Google Scholar 

  • Zhu B, Xi X, Liu Q, Cheng Y, Yang H (2019) MiR-9 functions as a tumor suppressor in acute myeloid leukemia by targeting CX chemokine receptor 4. Am J Transl Res 11(6):3384

    CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Tahir Maqbool Mir .

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Amin, I. et al. (2020). Molecular Mechanistic Approach of Important Antileukemic Compounds Present in Honey. In: Rehman, M.U., Majid, S. (eds) Therapeutic Applications of Honey and its Phytochemicals . Springer, Singapore. https://doi.org/10.1007/978-981-15-7305-7_1

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