Curcumin: Epigenetic Modulation and Tumor Immunity in Antitumor Therapy

Abstract

Curcumin (turmeric) is the main ingredient of the Chinese herbal turmeric rhizome, used to treat tumors, diabetes, inflammation, neurodegenerative diseases, cardiovascular diseases, metabolic syndrome, and liver diseases. The antitumor effects of curcumin have received even more attention. One of the main mechanisms of the antitumor effects includes inhibition of tumor invasion and migration, induction of tumor cell apoptosis, and inhibition of various cell signaling pathways. It has been found that the antitumor biological activity of curcumin in the body is associated with epigenetic mechanisms. That also implies that curcumin may act as a potential epigenetic modulator to influence the development of tumor diseases. The immune system plays an essential role in the development of tumorigenesis. Tumor immunotherapy is currently one of the most promising research directions in the field of tumor therapy. Curcumin has been found to have significant regulatory effects on tumor immunity and is expected to be a novel adjuvant for tumor immunity. This paper summarizes the antitumor effects of curcumin from four aspects: molecular and epigenetic mechanisms of curcumin against a tumor, mechanisms of curcumin modulation of tumor immunotherapy, reversal of chemotherapy resistance, and a novel drug delivery system of curcumin, which provide new directions for the development of new antitumor drugs.

Keywords

Curcuma longa. - Zingiberaceae - turmeric - curcumin - antitumor molecular mechanism - epigenetics - tumor immunity - drug delivery system

Publication History

Received: 01 August 2024

Accepted after revision: 11 November 2024

Accepted Manuscript online:
17 December 2024

Article published online:
18 March 2025

• References

• 1 Global Burden of Disease Cancer Collaboration. Fitzmaurice C, Abate D, Abbasi N, Abbastabar H, Abd-Allah F, Abdel-Rahman O, Abdelalim A, Abdoli A, Abdollahpour I, Abdulle ASM, Abebe ND, Abraha HN, Abu-Raddad LJ, Abualhasan A, Adedeji IA, Advani SM, Afarideh M, Afshari M, Aghaali M, … Murray CJL. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 cancer groups, 1990 to 2017: A systematic analysis for the global burden of disease study. JAMA Oncol 2019; 5: 1749-1768
• 2 Global Burden of Disease 2019 Cancer Collaboration. Kocarnik JM, Compton K, Dean FE, Fu W, Gaw BL, Harvey JD, Henrikson HJ, Lu D, Pennini A, Xu R, Ababneh E, Abbasi-Kangevari M, Abbastabar H, Abd-Elsalam SM, Abdoli A, Abedi A, Abidi H, Abolhassani H, Adedeji IA, … Force LM. Cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life years for 29 cancer groups from 2010 to 2019: A systematic analysis for the global burden of disease study 2019. JAMA Oncol 2022; 8: 420-444
• 3 Sioka C. Radiotherapy, chemotherapy, and heart disease. Breast Cancer Res Treat 2022; 193: 239-240
• 4 Giordano A, Tommonaro G. Curcumin and Cancer. Nutrients 2019; 11: 2376
• 5 Hassan FU, Rehman MS, Khan MS, Ali MA, Javed A, Nawaz A, Yang C. Curcumin as an alternative epigenetic modulator: Mechanism of action and potential effects. Front Genet 2019; 10: 514
• 6 Kumar G, Mittal S, Sak K, Tuli HS. Molecular mechanisms underlying chemopreventive potential of curcumin: Current challenges and future perspectives. Life Sci 2016; 148: 313-328
• 7 Choi H, Chun YS, Shin YJ, Ye SK, Kim MS, Park JW. Curcumin attenuates cytochrome P450 induction in response to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin by ROS-dependently degrading AhR and ARNT. Cancer Sci 2008; 99: 2518-2524
• 8 Garg R, Gupta S, Maru GB. Dietary curcumin modulates transcriptional regulators of phase I and phase II enzymes in benzo[a]pyrene-treated mice: mechanism of its anti-initiating action. Carcinogenesis 2008; 29: 1022-1032
• 9 DʼArcy MS. Cell death: A review of the major forms of apoptosis, necrosis and autophagy. Cell Biol Int 2019; 43: 582-592
• 10 Fu H, Wang C, Yang D, Wei Z, Xu J, Hu Z, Zhang Y, Wang W, Yan R, Cai Q. Curcumin regulates proliferation, autophagy, and apoptosis in gastric cancer cells by affecting PI3K and P53 signaling. J Cell Physiol 2018; 233: 4634-4642
• 11 Li W, Zhou Y, Yang J, Li H, Zhang H, Zheng P. Curcumin induces apoptotic cell death and protective autophagy in human gastric cancer cells. Oncol Rep 2017; 37: 3459-3466
• 12 Fratantonio D, Molonia MS, Bashllari R, Muscarà C, Ferlazzo G, Costa G, Saija A, Cimino F, Speciale A. Curcumin potentiates the antitumor activity of Paclitaxel in rat glioma C6 cells. Phytomedicine 2019; 55: 23-30
• 13 Sha J, Li J, Wang W, Pan L, Cheng J, Li L, Zhao H, Lin W. Curcumin induces G0/G1 arrest and apoptosis in hormone independent prostate cancer DU-145 cells by down regulating Notch signaling. Biomed Pharmacother 2016; 84: 177-184
• 14 Zheng R, Deng Q, Liu Y, Zhao P. Curcumin inhibits gastric carcinoma cell growth and induces apoptosis by suppressing the Wnt/β-catenin signaling pathway. Med Sci Monit 2017; 23: 163-171
• 15 Zhang L, Man S, Qiu H, Liu Z, Zhang M, Ma L, Gao W. Curcumin-cyclodextrin complexes enhanced the anti-cancer effects of curcumin. Environ Toxicol Pharmacol 2016; 48: 31-38
• 16 Yu X, Zhong J, Yan L, Li J, Wang H, Wen Y, Zhao Y. Curcumin exerts antitumor effects in retinoblastoma cells by regulating the JNK and p 38 MAPK pathways. Int J Mol Med 2016; 38: 861-868
• 17 Xu X, Zhu Y. Curcumin inhibits human non-small cell lung cancer xenografts by targeting STAT3 pathway. Am J Transl Res 2017; 9: 3633-3641
• 18 Liu WH, Yuan JB, Zhang F, Chang JX. [Curcumin inhibits proliferation, migration and invasion of gastric cancer cells via Wnt3a/β-catenin/EMT signaling pathway]. Zhongguo Zhong Yao Za Zhi 2019; 44: 3107-3115
• 19 Xu F, Ji Z, He L, Chen M, Chen H, Feng Q, Dong B, Yang X, Jiang L, Jin R. Downregulation of LINC01021 by curcumin analog Da0324 inhibits gastric cancer progression through activation of P53. Am J Transl Res 2020; 12: 3429-3444
• 20 Zhou X, Wang W, Li P, Zheng Z, Tu Y, Zhang Y, You T. Curcumin enhances the effects of 5-fluorouracil and oxaliplatin in inducing gastric cancer cell apoptosis both in vitro and in vivo. Oncol Res 2016; 23: 29-34
• 21 Chen Q, Gao Q, Chen K, Wang Y, Chen L, Li XU. Curcumin suppresses migration and invasion of human endometrial carcinoma cells. Oncol Lett 2015; 10: 1297-1302
• 22 Liu X, Sun K, Song A, Zhang X, Zhang X, He X. Curcumin inhibits proliferation of gastric cancer cells by impairing ATP-sensitive potassium channel opening. World J Surg Oncol 2014; 12: 389
• 23 Cao A, Li Q, Yin P, Dong Y, Shi H, Wang L, Ji G, Xie J, Wu D. Curcumin induces apoptosis in human gastric carcinoma AGS cells and colon carcinoma HT-29 cells through mitochondrial dysfunction and endoplasmic reticulum stress. Apoptosis 2013; 18: 1391-1402
• 24 Moragoda L, Jaszewski R, Majumdar AP. Curcumin induced modulation of cell cycle and apoptosis in gastric and colon cancer cells. Anticancer Res 2001; 21: 873-878
• 25 Xu Y, Yu H, Qin H, Kang J, Yu C, Zhong J, Su J, Li H, Sun L. Inhibition of autophagy enhances cisplatin cytotoxicity through endoplasmic reticulum stress in human cervical cancer cells. Cancer Lett 2012; 314: 232-243
• 26 Jin S, White E. Role of autophagy in cancer: Management of metabolic stress. Autophagy 2007; 3: 28-31
• 27 Laplante M, Sabatini DM. mTOR signaling in growth control and disease. Cell 2012; 149: 274-293
• 28 Galluzzi L, Bravo-San Pedro JM, Levine B, Green DR, Kroemer G. Pharmacological modulation of autophagy: Therapeutic potential and persisting obstacles. Nat Rev Drug Discov 2017; 16: 487-511
• 29 You L, Jin S, Zhu L, Qian W. Autophagy, autophagy-associated adaptive immune responses and its role in hematologic malignancies. Oncotarget 2017; 8: 12374-12388
• 30 Liu F, Gao S, Yang Y, Zhao X, Fan Y, Ma W, Yang D, Yang A, Yu Y. Curcumin induced autophagy anticancer effects on human lung adenocarcinoma cell line A549. Oncol Lett 2017; 14: 2775-2782
• 31 Jia YL, Li J, Qin ZH, Liang ZQ. Autophagic and apoptotic mechanisms of curcumin-induced death in K562 cells. J Asian Nat Prod Res 2009; 11: 918-928
• 32 Moustapha A, Pérétout PA, Rainey NE, Sureau F, Geze M, Petit JM, Dewailly E, Slomianny C, Petit PX. Curcumin induces crosstalk between autophagy and apoptosis mediated by calcium release from the endoplasmic reticulum, lysosomal destabilization and mitochondrial events. Cell Death Discov 2015; 1: 15017
• 33 Kim JY, Cho TJ, Woo BH, Choi KU, Lee CH, Ryu MH, Park HR. Curcumin-induced autophagy contributes to the decreased survival of oral cancer cells. Arch Oral Biol 2012; 57: 1018-1025
• 34 Pramanik KC, Makena MR, Bhowmick K, Pandey MK. Advancement of NF-κB signaling pathway: A novel target in pancreatic cancer. Int J Mol Sci 2018; 19: 3890
• 35 Vallée A, Lecarpentier Y, Vallée JN. Curcumin: A therapeutic strategy in cancers by inhibiting the canonical WNT/β-catenin pathway. J Exp Clin Cancer Res 2019; 38: 323
• 36 Ghasemi F, Shafiee M, Banikazemi Z, Pourhanifeh MH, Khanbabaei H, Shamshirian A, Amiri Moghadam S, ArefNezhad R, Sahebkar A, Avan A, Mirzaei H. Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells. Pathol Res Pract 2019; 215: 152556
• 37 Coker-Gurkan A, Celik M, Ugur M, Arisan ED, Obakan-Yerlikaya P, Durdu ZB, Palavan-Unsal N. Curcumin inhibits autocrine growth hormone-mediated invasion and metastasis by targeting NF-κB signaling and polyamine metabolism in breast cancer cells. Amino Acids 2018; 50: 1045-1069
• 38 Wang M, Jiang S, Zhou L, Yu F, Ding H, Li P, Zhou M, Wang K. Potential mechanisms of action of curcumin for cancer prevention: Focus on cellular signaling pathways and miRNAs. Int J Biol Sci 2019; 15: 1200-1214
• 39 Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: Beyond discovery and development. Cell 2019; 176: 1248-1264
• 40 Fan S, Xu Y, Li X, Tie L, Pan Y, Li X. Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: in silico, in vitro and in vivo studies. Biochim Biophys Acta 2014; 1842: 1742-1754
• 41 Nagaraju GP, Zhu S, Ko JE, Ashritha N, Kandimalla R, Snyder JP, Shoji M, El-Rayes BF. Antiangiogenic effects of a novel synthetic curcumin analogue in pancreatic cancer. Cancer Lett 2015; 357: 557-565
• 42 Fan S, Xu Y, Li X, Tie L, Pan Y, Li X. Opposite angiogenic outcome of curcumin against ischemia and Lewis lung cancer models: in silico, in vitro and in vivo studies. Biochim Biophys Acta 2014; 1842: 1742-1754
• 43 Wang S, Zhang Y. HMGB1 in inflammation and cancer. J Hematol Oncol 2020; 13: 116
• 44 Chhipa AS, Borse SP, Baksi R, Lalotra S, Nivsarkar M. Targeting receptors of advanced glycation end products (RAGE): Preventing diabetes induced cancer and diabetic complications. Pathol Res Pract 2019; 215: 152643
• 45 Da W, Zhang J, Zhang R, Zhu J. Curcumin inhibits the lymphangiogenesis of gastric cancer cells by inhibition of HMGB1/VEGF-D signaling. Int J Immunopathol Pharmacol 2019; 33: 2058738419861600
• 46 Da W, Zhu J, Wang L, Sun Q. Curcumin suppresses lymphatic vessel density in an in vivo human gastric cancer model. Tumour Biol 2015; 36: 5215-5223
• 47 Afrin R, Arumugam S, Rahman A, Wahed MI, Karuppagounder V, Harima M, Suzuki H, Miyashita S, Suzuki K, Yoneyama H, Ueno K, Watanabe K. Curcumin ameliorates liver damage and progression of NASH in NASH-HCC mouse model possibly by modulating HMGB1-NF-κB translocation. Int Immunopharmacol 2017; 44: 174-182
• 48 Kanakkanthara A, Miller JH. βIII-tubulin overexpression in cancer: Causes, consequences, and potential therapies. Biochim Biophys Acta Rev Cancer 2021; 1876: 188607
• 49 Lopes D, Maiato H. The tubulin code in mitosis and cancer. Cells 2020; 9: 2356
• 50 Chakraborti S, Das L, Kapoor N, Das A, Dwivedi V, Poddar A, Chakraborti G, Janik M, Basu G, Panda D, Chakrabarti P, Surolia A, Bhattacharyya B. Curcumin recognizes a unique binding site of tubulin. J Med Chem 2011; 54: 6183-6196
• 51 Ando Y, Mariano C, Shen K. Engineered in vitro tumor models for cell-based immunotherapy. Acta Biomater 2021; 132: 345-359
• 52 Sloas C, Gill S, Klichinsky M. Engineered CAR-macrophages as adoptive immunotherapies for solid tumors. Front Immunol 2021; 12: 783305
• 53 Mukherjee S, Fried A, Hussaini R, White R, Baidoo J, Yalamanchi S, Banerjee P. Phytosomal curcumin causes natural killer cell-dependent repolarization of glioblastoma (GBM) tumor-associated microglia/macrophages and elimination of GBM and GBM stem cells. J Exp Clin Cancer Res 2018; 37: 168
• 54 Zhang HG, Kim H, Liu C, Yu S, Wang J, Grizzle WE, Kimberly RP, Barnes S. Curcumin reverses breast tumor exosomes mediated immune suppression of NK cell tumor cytotoxicity. Biochim Biophys Acta 2007; 1773: 1116-1123
• 55 Mukherjee S, Hussaini R, White R, Atwi D, Fried A, Sampat S, Piao L, Pan Q, Banerjee P. TriCurin, a synergistic formulation of curcumin, resveratrol, and epicatechin gallate, repolarizes tumor-associated macrophages and triggers an immune response to cause suppression of HPV+ tumors. Cancer Immunol Immunother 2018; 67: 761-774
• 56 Zheng P, Ding B, Jiang Z, Xu W, Li G, Ding J, Chen X. Ultrasound-augmented mitochondrial calcium ion overload by calcium nanomodulator to induce immunogenic cell death. Nano Lett 2021; 21: 2088-2093
• 57 Tanaka A, Sakaguchi S. Regulatory T cells in cancer immunotherapy. Cell Res 2017; 27: 109-118
• 58 Varalakshmi CH, Ali AM, Pardhasaradhi BV, Srivastava RM, Singh S, Khar A. Immunomodulatory effects of curcumin: In-vivo. Int Immunopharmacol 2008; 8: 688-700
• 59 Bhattacharyya S, Md Sakib Hossain D, Mohanty S, Sankar Sen G, Chattopadhyay S, Banerjee S, Chakraborty J, Das K, Sarkar D, Das T, Sa G. Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts. Cell Mol Immunol 2010; 7: 306-315
• 60 Zhao GJ, Lu ZQ, Tang LM, Wu ZS, Wang DW, Zheng JY, Qiu QM. Curcumin inhibits suppressive capacity of naturally occurring CD4+CD25+ regulatory T cells in mice in vitro. Int Immunopharmacol 2012; 14: 99-106
• 61 Bhattacharyya S, Mandal D, Saha B, Sen GS, Das T, Sa G. Curcumin prevents tumor-induced T cell apoptosis through Stat-5a-mediated Bcl-2 induction. J Biol Chem 2007; 282: 15954-15964
• 62 Lv J, Shao Q, Wang H, Shi H, Wang T, Gao W, Song B, Zheng G, Kong B, Qu X. Effects and mechanisms of curcumin and basil polysaccharide on the invasion of SKOV3 cells and dendritic cells. Mol Med Rep 2013; 8: 1580-1586
• 63 Jeong YI, Kim SW, Jung ID, Lee JS, Chang JH, Lee CM, Chun SH, Yoon MS, Kim GT, Ryu SW, Kim JS, Shin YK, Lee WS, Shin HK, Lee JD, Park YM. Curcumin suppresses the induction of indoleamine 2, 3-dioxygenase by blocking the Janus-activated kinase-protein kinase Cdelta-STAT1 signaling pathway in interferon-gamma-stimulated murine dendritic cells. J Biol Chem 2009; 284: 3700-3708
• 64 Lim SO, Li CW, Xia W, Cha JH, Chan LC, Wu Y, Chang SS, Lin WC, Hsu JM, Hsu YH, Kim T, Chang WC, Hsu JL, Yamaguchi H, Ding Q, Wang Y, Yang Y, Chen CH, Sahin AA, Yu D, Hortobagyi GN, Hung MC. Deubiquitination and Stabilization of PD-L1 by CSN5. Cancer Cell 2016; 30: 925-939
• 65 Guo L, Li H, Fan T, Ma Y, Wang L. Synergistic efficacy of curcumin and anti-programmed cell death-1 in hepatocellular carcinoma. Life Sci 2021; 279: 119359
• 66 Dent P, Booth L, Roberts JL, Poklepovic A, Hancock JF. (Curcumin+sildenafil) enhances the efficacy of 5FU and anti-PD1 therapies in vivo. J Cell Physiol 2020; 235: 6862-6874
• 67 Dai L, Li X, Yao M, Niu P, Yuan X, Li K, Chen M, Fu Z, Duan X, Liu H, Cai K, Yang H. Programmable prodrug micelle with size-shrinkage and charge-reversal for chemotherapy-improved IDO immunotherapy. Biomaterials 2020; 241: 119901
• 68 Chang YF, Chuang HY, Hsu CH, Liu RS, Gambhir SS, Hwang JJ. Immunomodulation of curcumin on adoptive therapy with T cell functional imaging in mice. Cancer Prev Res (Phila) 2012; 5: 444-452
• 69 Lu Y, Miao L, Wang Y, Xu Z, Zhao Y, Shen Y, Xiang G, Huang L. Curcumin micelles remodel tumor microenvironment and enhance vaccine activity in an advanced melanoma model. Mol Ther 2016; 24: 364-374
• 70 Jiang GM, Xie WY, Wang HS, Du J, Wu BP, Xu W, Liu HF, Xiao P, Liu ZG, Li HY, Liu SQ, Yin WJ, Zhang QG, Liang JP, Huang HJ. Curcumin combined with FAPαc vaccine elicits effective antitumor response by targeting indolamine-2, 3-dioxygenase and inhibiting EMT induced by TNF-α in melanoma. Oncotarget 2015; 6: 25932-25942
• 71 Liu X, Feng Z, Wang C, Su Q, Song H, Zhang C, Huang P, Liang XJ, Dong A, Kong D, Wang W. Co-localized delivery of nanomedicine and nanovaccine augments the postoperative cancer immunotherapy by amplifying T-cell responses. Biomaterials 2020; 230: 119649
• 72 Jensen NF, Stenvang J, Beck MK, Hanáková B, Belling KC, Do KN, Viuff B, Nygård SB, Gupta R, Rasmussen MH, Tarpgaard LS, Hansen TP, Budinská E, Pfeiffer P, Bosman F, Tejpar S, Roth A, Delorenzi M, Andersen CL, Rømer MU, Brünner N, Moreira JM. Establishment and characterization of models of chemotherapy resistance in colorectal cancer: Towards a predictive signature of chemoresistance. Mol Oncol 2015; 9: 1169-1185
• 73 Toden S, Okugawa Y, Jascur T, Wodarz D, Komarova NL, Buhrmann C, Shakibaei M, Boland CR, Goel A. Curcumin mediates chemosensitization to 5-fluorouracil through miRNA-induced suppression of epithelial-to-mesenchymal transition in chemoresistant colorectal cancer. Carcinogenesis 2015; 36: 355-367
• 74 Zhang C, Xu Y, Wang H, Li G, Yan H, Fei Z, Xu Y, Li W. Curcumin reverses irinotecan resistance in colon cancer cell by regulation of epithelial-mesenchymal transition. Anticancer Drugs 2018; 29: 334-340
• 75 Su P, Yang Y, Wang G, Chen X, Ju Y. Curcumin attenuates resistance to irinotecan via induction of apoptosis of cancer stem cells in chemoresistant colon cancer cells. Int J Oncol 2018; 53: 1343-1353
• 76 Firouzi Amoodizaj F, Baghaeifar S, Taheri E, Farhoudi Sefidan Jadid M, Safi M, Seyyed Sani N, Hajazimian S, Isazadeh A, Shanehbandi D. Enhanced anticancer potency of doxorubicin in combination with curcumin in gastric adenocarcinoma. J Biochem Mol Toxicol 2020; 34: e22486
• 77 Yu LL, Wu JG, Dai N, Yu HG, Si JM. Curcumin reverses chemoresistance of human gastric cancer cells by downregulating the NF-κB transcription factor. Oncol Rep 2011; 26: 1197-1203
• 78 Li F, Chen X, Xu B, Zhou H. Curcumin induces p 53-independent necrosis in H1299 cells via a mitochondria-associated pathway. Mol Med Rep 2015; 12: 7806-7814
• 79 Zafon C, Gil J, Pérez-González B, Jordà M. DNA methylation in thyroid cancer. Endocr Relat Cancer 2019; 26: R415-R439
• 80 Nishiyama A, Nakanishi M. Navigating the DNA methylation landscape of cancer. Trends Genet 2021; 37: 1012-1027
• 81 Choi SJ, Jung SW, Huh S, Chung YS, Cho H, Kang H. Alteration of DNA methylation in gastric cancer with chemotherapy. J Microbiol Biotechnol 2017; 27: 1367-1378
• 82 Schübeler D. Function and information content of DNA methylation. Nature 2015; 517: 321-326
• 83 Tong R, Wu X, Liu Y, Liu Y, Zhou J, Jiang X, Zhang L, He X, Ma L. Curcumin-induced DNA Demethylation in human gastric cancer cells is mediated by the DNA-damage response pathway. Oxid Med Cell Longev 2020; 2020: 2543504
• 84 Chatterjee B, Ghosh K, Kanade SR. Curcumin-mediated demethylation of the proximal promoter CpG island enhances the KLF4 recruitment that leads to increased expression of p 21Cip1 in vitro. J Cell Biochem 2019; 120: 809-820
• 85 Yen HY, Tsao CW, Lin YW, Kuo CC, Tsao CH, Liu CY. Regulation of carcinogenesis and modulation through Wnt/β-catenin signaling by curcumin in an ovarian cancer cell line. Sci Rep 2019; 9: 17267
• 86 Cao D, Jia Z, Wu Y, Su T, Zhao D, Wu M, Tsukamoto T, Oshima M, Jiang J, Cao X. Demethylation of the RB1 promoter concomitant with reactivation of TET2 and TET3 impairs gastric carcinogenesis in K19-Wnt1/C2 mE transgenic mice. Life Sci 2020; 263: 118580
• 87 Sharma V, Kumar L, Mohanty SK, Maikhuri JP, Rajender S, Gupta G. Sensitization of androgen refractory prostate cancer cells to anti-androgens through re-expression of epigenetically repressed androgen receptor – Synergistic action of quercetin and curcumin. Mol Cell Endocrinol 2016; 431: 12-23
• 88 Khor TO, Huang Y, Wu TY, Shu L, Lee J, Kong AN. Pharmacodynamics of curcumin as DNA hypomethylation agent in restoring the expression of Nrf2 via promoter CpGs demethylation. Biochem Pharmacol 2011; 82: 1073-1078
• 89 Shu L, Khor TO, Lee JH, Boyanapalli SS, Huang Y, Wu TY, Saw CL, Cheung KL, Kong AN. Epigenetic CpG demethylation of the promoter and reactivation of the expression of Neurog1 by curcumin in prostate LNCaP cells. AAPS J 2011; 13: 606-614
• 90 Chen T, Yang C, Xi Z, Chen F, Li H. Reduced caudal type homeobox 2 (CDX2) promoter methylation is associated with curcuminʼs suppressive effects on epithelial-mesenchymal transition in colorectal cancer cells. Med Sci Monit 2020; 26: e926443
• 91 Guo Y, Shu L, Zhang C, Su ZY, Kong AN. Curcumin inhibits anchorage-independent growth of HT29 human colon cancer cells by targeting epigenetic restoration of the tumor suppressor gene DLEC1. Biochem Pharmacol 2015; 94: 69-78
• 92 Guo Y, Wu R, Gaspar JM, Sargsyan D, Su ZY, Zhang C, Gao L, Cheng D, Li W, Wang C, Yin R, Fang M, Verzi MP, Hart RP, Kong AN. DNA methylome and transcriptome alterations and cancer prevention by curcumin in colitis-accelerated colon cancer in mice. Carcinogenesis 2018; 39: 669-680
• 93 Al-Yousef N, Shinwari Z, Al-Shahrani B, Al-Showimi M, Al-Moghrabi N. Curcumin induces re-expression of BRCA1 and suppression of γ synuclein by modulating DNA promoter methylation in breast cancer cell lines. Oncol Rep 2020; 43: 827-838
• 94 Liu Y, Zhou J, Hu Y, Wang J, Yuan C. Curcumin inhibits growth of human breast cancer cells through demethylation of DLC1 promoter. Mol Cell Biochem 2017; 425: 47-58
• 95 Kumar U, Sharma U, Rathi G. Reversal of hypermethylation and reactivation of glutathione S-transferase pi 1 gene by curcumin in breast cancer cell line. Tumour Biol 2017; 39: 1010428317692258
• 96 Du L, Xie Z, Wu LC, Chiu M, Lin J, Chan KK, Liu S, Liu Z. Reactivation of RASSF1A in breast cancer cells by curcumin. Nutr Cancer 2012; 64: 1228-1235
• 97 Jiang A, Wang X, Shan X, Li Y, Wang P, Jiang P, Feng Q. Curcumin reactivates silenced tumor suppressor gene RARβ by reducing DNA methylation. Phytother Res 2015; 29: 1237-1245
• 98 Liu YL, Yang HP, Gong L, Tang CL, Wang HJ. Hypomethylation effects of curcumin, demethoxycurcumin and bisdemethoxycurcumin on WIF-1 promoter in non-small cell lung cancer cell lines. Mol Med Rep 2011; 4: 675-679
• 99 Jha AK, Nikbakht M, Parashar G, Shrivastava A, Capalash N, Kaur J. Reversal of hypermethylation and reactivation of the RARβ2 gene by natural compounds in cervical cancer cell lines. Folia Biol (Praha) 2010; 56: 195-200
• 100 Jia W, Deng F, Fu W, Hu J, Chen G, Gao X, Tan X, Li G, Liu G, Zhu S. Curcumin suppresses Wilmsʼ tumor metastasis by inhibiting RECK methylation. Biomed Pharmacother 2019; 111: 1204-1212
• 101 Wei X, Yi X, Zhu XH, Jiang DS. Posttranslational modifications in ferroptosis. Oxid Med Cell Longev 2020; 2020: 8832043
• 102 Audia JE, Campbell RM. Histone modifications and cancer. Cold Spring Harb Perspect Biol 2016; 8: a019521
• 103 Soflaei SS, Momtazi-Borojeni AA, Majeed M, Derosa G, Maffioli P, Sahebkar A. Curcumin: A natural pan-HDAC inhibitor in cancer. Curr Pharm Des 2018; 24: 123-129
• 104 Cianfruglia L, Minnelli C, Laudadio E, Scirè A, Armeni T. Side effects of curcumin: Epigenetic and antiproliferative implications for normal dermal fibroblast and breast cancer cells. Antioxidants (Basel) 2019; 8: 382
• 105 Guccione E, Richard S. The regulation, functions and clinical relevance of arginine methylation. Nat Rev Mol Cell Biol 2019; 20: 642-657
• 106 Tan YT, Lin JF, Li T, Li JJ, Xu RH, Ju HQ. LncRNA-mediated posttranslational modifications and reprogramming of energy metabolism in cancer,. Cancer Commun (Lond) 2021; 41: 109-120
• 107 Zhou X, Jiao D, Dou M, Zhang W, Lv L, Chen J, Li L, Wang L, Han X. Curcumin inhibits the growth of triple-negative breast cancer cells by silencing EZH2 and restoring DLC1 expression. J Cell Mol Med 2020; 24: 10648-10662
• 108 Chatterjee B, Ghosh K, Suresh L, Kanade SR. Curcumin ameliorates PRMT5-MEP50 arginine methyltransferase expression by decreasing the Sp1 and NF-YA transcription factors in the A549 and MCF-7 cells. Mol Cell Biochem 2019; 455: 73-90
• 109 Lu TX, Rothenberg ME. MicroRNA. J Allergy Clin Immunol 2018; 141: 1202-1207
• 110 Eniafe J, Jiang S. MicroRNA-99 family in cancer and immunity. Wiley Interdiscip Rev RNA 2021; 12: e1635
• 111 Hill M, Tran N. miRNA interplay: Mechanisms and consequences in cancer. Dis Model Mech 2021; 14: dmm047662
• 112 Tutar Y. miRNA and cancer; computational and experimental approaches. Curr Pharm Biotechnol 2014; 15: 429
• 113 Norouzi S, Majeed M, Pirro M, Generali D, Sahebkar A. Curcumin as an adjunct therapy and microRNA modulator in breast cancer. Curr Pharm Des 2018; 24: 171-177
• 114 Mudduluru G, George-William JN, Muppala S, Asangani IA, Kumarswamy R, Nelson LD, Allgayer H. Curcumin regulates miR-21 expression and inhibits invasion and metastasis in colorectal cancer. Biosci Rep 2011; 31: 185-197
• 115 Taverna S, Giallombardo M, Pucci M, Flugy A, Manno M, Raccosta S, Rolfo C, De Leo G, Alessandro R. Curcumin inhibits in vitro and in vivo chronic myelogenous leukemia cells growth: A possible role for exosomal disposal of miR-21. Oncotarget 2015; 6: 21918-21933
• 116 Taverna S, Fontana S, Monteleone F, Pucci M, Saieva L, De Caro V, Cardinale VG, Giallombardo M, Vicario E, Rolfo C, Leo GD, Alessandro R. Curcumin modulates chronic myelogenous leukemia exosomes composition and affects angiogenic phenotype via exosomal miR-21. Oncotarget 2016; 7: 30420-30439
• 117 Saini S, Arora S, Majid S, Shahryari V, Chen Y, Deng G, Yamamura S, Ueno K, Dahiya R. Curcumin modulates microRNA-203-mediated regulation of the Src-Akt axis in bladder cancer. Cancer Prev Res (Phila) 2011; 4: 1698-1709
• 118 Vrba L, Muñoz-Rodríguez JL, Stampfer MR, Futscher BW. miRNA gene promoters are frequent targets of aberrant DNA methylation in human breast cancer. PLoS One 2013; 8: e54398
• 119 Peng H, Dong JY, Zhao YN, Wu WB, Yang XL, Chen D, Hu KF, Chen LH, Liu J. [The effect of methylation level of microRNA promoter on the expression of microRNAs and on the proliferation, migration and invasion of lung cancer cells]. Sichuan Da Xue Xue Bao Yi Xue Ban 2019; 50: 182-187
• 120 Zhang J, Zhang T, Ti X, Shi J, Wu C, Ren X, Yin H. Curcumin promotes apoptosis in A549/DDP multidrug-resistant human lung adenocarcinoma cells through an miRNA signaling pathway. Biochem Biophys Res Commun 2010; 399: 1-6
• 121 Zhang J, Du Y, Wu C, Ren X, Ti X, Shi J, Zhao F, Yin H. Curcumin promotes apoptosis in human lung adenocarcinoma cells through miR-186* signaling pathway. Oncol Rep 2010; 24: 1217-1223
• 122 Lu Y, Wang J, Liu L, Yu L, Zhao N, Zhou X, Lu X. Curcumin increases the sensitivity of Paclitaxel-resistant NSCLC cells to Paclitaxel through microRNA-30c-mediated MTA1 reduction. Tumour Biol 2017; 39: 1010428317698353
• 123 Wu H, Liu Q, Cai T, Chen YD, Wang ZF. Induction of microRNA-146a is involved in curcumin-mediated enhancement of temozolomide cytotoxicity against human glioblastoma. Mol Med Rep 2015; 12: 5461-5466
• 124 Liu J, Li M, Wang Y, Luo J. Curcumin sensitizes prostate cancer cells to radiation partly via epigenetic activation of miR-143 and miR-143 mediated autophagy inhibition. J Drug Target 2017; 25: 645-652
• 125 Xu R, Li H, Wu S, Qu J, Yuan H, Zhou Y, Lu Q. MicroRNA-1246 regulates the radio-sensitizing effect of curcumin in bladder cancer cells via activating P53. Int Urol Nephrol 2019; 51: 1771-1779
• 126 Zhang J, Liu J, Xu X, Li L. Curcumin suppresses cisplatin resistance development partly via modulating extracellular vesicle-mediated transfer of MEG3 and miR-214 in ovarian cancer. Cancer Chemother Pharmacol 2017; 79: 479-487
• 127 Gao W, Chan JYW, Wong TS. Curcumin exerts inhibitory effects on undifferentiated nasopharyngeal carcinoma by inhibiting the expression of miR-125a-5 p. Clin Sci (Lond) 2014; 127: 571-579
• 128 Feng S, Wang Y, Zhang R, Yang G, Liang Z, Wang Z, Zhang G. Curcumin exerts its antitumor activity through regulation of miR-7/Skp2/p 21 in nasopharyngeal carcinoma cells. Onco Targets Ther 2017; 10: 2377-2388
• 129 Wu C, Ruan T, Liu W, Zhu X, Pan J, Lu W, Yan C, Tao K, Zhang W, Zhang C. Effect and mechanism of curcumin on EZH2 – miR-101 regulatory feedback loop in multiple myeloma. Curr Pharm Des 2018; 24: 564-575
• 130 Wang N, Feng T, Liu X, Liu Q. Curcumin inhibits migration and invasion of non-small cell lung cancer cells through up-regulation of miR-206 and suppression of PI3K/AKT/mTOR signaling pathway. Acta Pharm 2020; 70: 399-409
• 131 Pan Y, Sun Y, Liu Z, Zhang C. miR-192-5 p upregulation mediates the suppression of curcumin in human NSCLC cell proliferation, migration and invasion by targeting c-Myc and inactivating the Wnt/β-catenin signaling pathway. Mol Med Rep 2020; 22: 1594-1604
• 132 Mo F, Xiao Y, Zeng H, Fan D, Song J, Liu X, Luo M, Ma X. Curcumin-induced global profiling of transcriptomes in small cell lung cancer cells. Front Cell Dev Biol 2020; 8: 588299
• 133 Liu WL, Chang JM, Chong IW, Hung YL, Chen YH, Huang WT, Kuo HF, Hsieh CC, Liu PL. Curcumin inhibits LIN-28A through the activation of miRNA-98 in the lung cancer cell line A549. Molecules 2017; 22: 929
• 134 Zhan JW, Jiao DM, Wang Y, Song J, Wu JH, Wu LJ, Chen QY, Ma SL. Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion. Thorac Cancer 2017; 8: 461-470
• 135 Ye M, Zhang J, Zhang J, Miao Q, Yao L, Zhang J. Curcumin promotes apoptosis by activating the p 53-miR-192–5 p/215-XIAP pathway in non-small cell lung cancer. Cancer Lett 2015; 357: 196-205
• 136 Jin H, Qiao F, Wang Y, Xu Y, Shang Y. Curcumin inhibits cell proliferation and induces apoptosis of human non-small cell lung cancer cells through the upregulation of miR-192–5 p and suppression of PI3K/Akt signaling pathway. Oncol Rep 2015; 34: 2782-2789
• 137 Zhang W, Bai W, Zhang W. MiR-21 suppresses the anticancer activities of curcumin by targeting PTEN gene in human non-small cell lung cancer A549 cells. Clin Transl Oncol 2014; 16: 708-713
• 138 Zhou C, Hu C, Wang B, Fan S, Jin W. Curcumin suppresses cell proliferation, migration, and invasion through modulating miR-21–5 p/SOX6 axis in hepatocellular carcinoma. Cancer Biother Radiopharm 2020; 3734
• 139 Zeng Y, Shen Z, Gu W, Wu M. Inhibition of hepatocellular carcinoma tumorigenesis by curcumin may be associated with CDKN1A and CTGF. Gene 2018; 651: 183-193
• 140 Wang H, Cai X, Ma L. Curcumin modifies epithelial-mesenchymal transition in colorectal cancer through regulation of miR-200c/EPM5. Cancer Manag Res 2020; 12: 9405-9415
• 141 Li B, Shi C, Li B, Zhao JM, Wang L. The effects of Curcumin on HCT-116 cells proliferation and apoptosis via the miR-491/PEG10 pathway. J Cell Biochem 2018; 119: 3091-3098
• 142 Zhu M, Zheng Z, Huang J, Ma X, Huang C, Wu R, Li X, Liang Z, Deng F, Wu J, Geng S, Xie C, Zhong C. Modulation of miR-34a in curcumin-induced antiproliferation of prostate cancer cells. J Cell Biochem 2019; 120: 15616-15624
• 143 Liu L, Fu Y, Zheng Y, Ma M, Wang C. Curcumin inhibits proteasome activity in triple-negative breast cancer cells through regulating p 300/miR-142–3 p/PSMB5 axis. Phytomedicine 2020; 78: 153312
• 144 Gallardo M, Kemmerling U, Aguayo F, Bleak TC, Muñoz JP, Calaf GM. Curcumin rescues breast cells from epithelial-mesenchymal transition and invasion induced by anti-miR-34a. Int J Oncol 2020; 56: 480-493
• 145 Yang J, Cao Y, Sun J, Zhang Y. Curcumin reduces the expression of Bcl-2 by upregulating miR-15a and miR-16 in MCF-7 cells. Med Oncol 2010; 27: 1114-1118
• 146 Sun M, Estrov Z, Ji Y, Coombes KR, Harris DH, Kurzrock R. Curcumin (diferuloylmethane) alters the expression profiles of microRNAs in human pancreatic cancer cells. Mol Cancer Ther 2008; 7: 464-473
• 147 Bi Y, Shen W, Min M, Liu Y. MicroRNA-7 functions as a tumor-suppressor gene by regulating ILF2 in pancreatic carcinoma. Int J Mol Med 2017; 39: 900-906
• 148 Zhao SF, Zhang X, Zhang XJ, Shi XQ, Yu ZJ, Kan QC. Induction of microRNA-9 mediates cytotoxicity of curcumin against SKOV3 ovarian cancer cells. Asian Pac J Cancer Prev 2014; 15: 3363-3368
• 149 Sun K, Jia Z, Duan R, Yan Z, Jin Z, Yan L, Li Q, Yang J. Long non-coding RNA XIST regulates miR-106b-5 p/P21 axis to suppress tumor progression in renal cell carcinoma. Biochem Biophys Res Commun 2019; 510: 416-420
• 150 Subramaniam D, Ponnurangam S, Ramamoorthy P, Standing D, Battafarano RJ, Anant S, Sharma P. Curcumin induces cell death in esophageal cancer cells through modulating Notch signaling. PLoS One 2012; 7: e30590
• 151 Sun C, Zhang S, Liu C, Liu X. Curcumin promoted miR-34a expression and suppressed proliferation of gastric cancer cells. Cancer Biother Radiopharm 2019; 34: 634-641
• 152 Qiang Z, Meng L, Yi C, Yu L, Chen W, Sha W. Curcumin regulates the miR-21/PTEN/Akt pathway and acts in synergy with PD98059 to induce apoptosis of human gastric cancer MGC-803 cells. J Int Med Res 2019; 47: 1288-1297
• 153 Sun Q, Zhang W, Guo Y, Li Z, Chen X, Wang Y, Du Y, Zang W, Zhao G. Curcumin inhibits cell growth and induces cell apoptosis through upregulation of miR-33b in gastric cancer. Tumour Biol 2016; 37: 13177-13184
• 154 Zhang X, Wang W, Zhu W, Dong J, Cheng Y, Yin Z, Shen F. Mechanisms and functions of long non-coding RNAs at multiple regulatory levels. Int J Mol Sci 2019; 20: 5573
• 155 Wang L, Cho KB, Li Y, Tao G, Xie Z, Guo B. Long noncoding RNA (lncRNA)-mediated competing endogenous RNA networks provide novel potential biomarkers and therapeutic targets for colorectal cancer. Int J Mol Sci 2019; 20: 5758
• 156 Bhan A, Soleimani M, Mandal SS. Long noncoding RNA and cancer: A new paradigm. Cancer Res 2017; 77: 3965-3981
• 157 Qi Y, Song C, Zhang J, Guo C, Yuan C. Oncogenic LncRNA CASC9 in cancer progression. Curr Pharm Des 2021; 27: 575-582
• 158 Wang W, Li Y, Zhi S, Li J, Miao J, Ding Z, Peng Y, Huang Y, Zheng R, Yu H, Qi P, Wang J, Fu X, Hu M, Chen S. LncRNA-ROR/microRNA-185-3 p/YAP1 axis exerts function in biological characteristics of osteosarcoma cells. Genomics 2021; 113: 450-461
• 159 Qin WW, Xin ZL, Wang HQ, Wang KP, Li XY, Wang X. Inhibiting lncRNA ROR suppresses growth, migration and angiogenesis in microvascular endothelial cells by up-regulating miR-26. Eur Rev Med Pharmacol Sci 2018; 22: 7985-7993
• 160 Fei D, Sui G, Lu Y, Tan L, Dongxu Z, Zhang K. The long non-coding RNA-ROR promotes osteosarcoma progression by targeting miR-206. J Cell Mol Med 2019; 23: 1865-1872
• 161 Shao J, Shi CJ, Li Y, Zhang FW, Pan FF, Fu WM, Zhang JF. LincROR mediates the suppressive effects of curcumin on hepatocellular carcinoma through inactivating Wnt/β-catenin signaling. Front Pharmacol 2020; 11: 847
• 162 Wang S, Chen W, Yu H, Song Z, Li Q, Shen X, Wu Y, Zhu L, Ma Q, Xing D. lncRNA ROR promotes gastric cancer drug resistance. Cancer Control 2020; 27: 1073274820904694
• 163 Yoshida K, Toden S, Ravindranathan P, Han H, Goel A. Curcumin sensitizes pancreatic cancer cells to gemcitabine by attenuating PRC2 subunit EZH2, and the lncRNA PVT1 expression. Carcinogenesis 2017; 38: 1036-1046
• 164 Qiu C, Li S, Sun D, Yang S. lncRNA PVT1 accelerates progression of non-small cell lung cancer via targeting miRNA-526b/EZH2 regulatory loop. Oncol Lett 2020; 19: 1267-1272
• 165 Yang J, Zhu D, Liu S, Shao M, Liu Y, Li A, Lv Y, Huang M, Lou D, Fan Q. Curcumin enhances radiosensitization of nasopharyngeal carcinoma by regulating circRNA network. Mol Carcinog 2020; 59: 202-214
• 166 Xu X, Zhang X, Zhang Y, Wang Z. Curcumin suppresses the malignancy of non-small cell lung cancer by modulating the circ-PRKCA/miR-384/ITGB1 pathway. Biomed Pharmacother 2021; 138: 111439
• 167 Yu H, Xie Y, Zhou Z, Wu Z, Dai X, Xu B. Curcumin regulates the progression of colorectal cancer via LncRNA NBR2/AMPK pathway. Technol Cancer Res Treat 2019; 18: 1533033819870781
• 168 Cai J, Sun H, Zheng B, Xie M, Xu C, Zhang G, Huang X, Zhuang J. Curcumin attenuates lncRNA H19-induced epithelial-mesenchymal transition in tamoxifen-resistant breast cancer cells. Mol Med Rep 2021; 23: 13
• 169 Liu T, Chi H, Chen J, Chen C, Huang Y, Xi H, Xue J, Si Y. Curcumin suppresses proliferation and in vitro invasion of human prostate cancer stem cells by ceRNA effect of miR-145 and lncRNA-ROR. Gene 2017; 631: 29-38
• 170 Liu G, Xiang T, Wu QF, Wang WX. Curcumin suppresses the proliferation of gastric cancer cells by downregulating H19. Oncol Lett 2016; 12: 5156-5162
• 171 Wang WH, Chen J, Zhang BR, Lu SJ, Wang F, Peng L, Dai JH, Sun YZ. Curcumin inhibits proliferation and enhances apoptosis in A549 cells by downregulating lncRNA UCA1. Pharmazie 2018; 73: 402-407
• 172 Gao L, Shao T, Zheng W, Ding J. Curcumin suppresses tumor growth of gemcitabine-resistant non-small cell lung cancer by regulating lncRNA-MEG3 and PTEN signaling. Clin Transl Oncol 2021; 23: 1386-1393
• 173 Pan JX, Chen TN, Ma K, Wang S, Yang CY, Cui GY. A negative feedback loop of H19/miR-675/VDR mediates therapeutic effect of cucurmin in the treatment of glioma. J Cell Physiol 2020; 235: 2171-2182
• 174 Wang Q, Fan H, Liu Y, Yin Z, Cai H, Liu J, Wang Z, Shao M, Sun X, Diao J, Liu Y, Tong L, Fan Q. Curcumin enhances the radiosensitivity in nasopharyngeal carcinoma cells involving the reversal of differentially expressed long non-coding RNAs. Int J Oncol 2014; 44: 858-864
• 175 Kanai M, Imaizumi A, Otsuka Y, Sasaki H, Hashiguchi M, Tsujiko K, Matsumoto S, Ishiguro H, Chiba T. Dose-escalation and pharmacokinetic study of nanoparticle curcumin, a potential anticancer agent with improved bioavailability, in healthy human volunteers. Cancer Chemother Pharmacol 2012; 69: 65-70
• 176 Salehi B, Del Prado-Audelo ML, Cortés H, Leyva-Gómez G, Stojanović-Radić Z, Singh YD, Patra JK, Das G, Martins N, Martorell M, Sharifi-Rad M, Cho WC, Sharifi-Rad J. Therapeutic applications of curcumin nanomedicine formulations in cardiovascular diseases. J Clin Med 2020; 9: 746
• 177 Mahmud M, Piwoni A, Filipczak N, Janicka M, Gubernator J. Long-circulating curcumin-loaded liposome formulations with high incorporation efficiency, stability and anticancer activity towards pancreatic adenocarcinoma cell lines in vitro. PLoS One 2016; 11: e0167787
• 178 Dende C, Meena J, Nagarajan P, Nagaraj VA, Panda AK, Padmanaban G. Nanocurcumin is superior to native curcumin in preventing degenerative changes in experimental cerebral malaria. Sci Rep 2017; 7: 10062
• 179 Chen C, Huang X, Cai H, Xu J. Anti-proliferation and anti-angiogenesis of curcumin-K30 solid dispersion. Zhong Nan Da Xue Xue Bao Yi Xue Ban 2010; 35: 1029-1036
• 180 Zhang HY, Sun CY, Adu-Frimpong M, Yu JN, Xu XM. Glutathione-sensitive PEGylated curcumin prodrug nanomicelles: Preparation, characterization, cellular uptake and bioavailability evaluation. Int J Pharm 2019; 555: 270-279
• 181 Teiten MH, Dicato M, Diederich M. Curcumin as a regulator of epigenetic events. Mol Nutr Food Res 2013; 57: 1619-1629
• 182 Soleimani V, Sahebkar A, Hosseinzadeh H. Turmeric (Curcuma longa) and its major constituent (curcumin) as nontoxic and safe substances: Review. Phytother Res 2018; 32: 985-995
• 183 Feng T, Wei Y, Lee RJ, Zhao L. Liposomal curcumin and its application in cancer. Int J Nanomedicine 2017; 12: 6027-6044