Natural compounds and strategies for fighting against drug resistance in cancer: a special focus on phenolic compounds and microRNAs

REVIEW Cellular and Molecular Mechanisms of Cancer Drug Resistance Natural compounds and strategies for fighting against drug resistance in cancer: a special focus on phenolic compounds and microRNAs Nina Petrović, 1,2 Ivana Z. Matić, 2 and Tatjana Stanojković 2 1 “VIN CA”Institute of Nuclear Sciences-National Institute of the Republic of Serbia, University of Belgrade, Belgrade, Serbia and 2 Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Belgrade, Serbia Abstract Bioactive phytochemicals, phenolic compounds, terpenoids, and alkaloids, exert antioxidative, anti-inflammatory, antigenotoxic, and anticancer effects, simultaneously showing minimal or no toxicity on normal, healthy cells. Phytochemicals targeting various signaling pathways and multiple mechanisms underlying intrinsic and acquired multidrug resistance (MDR) in cancer cells make them invaluable tools for the development of novel strategies for fighting against anticancer drug resistance in different types of cancer, which is one of the ultimate goals of modern oncology research. As MDR is described to be a simultaneous development of resistance to multiple drugs with different chemical structures, mechanisms of action, and targets it is not surprising that multiple factors, such as genetic and epigenetic changes, as well as noncoding RNAs, including microRNAs may significantly contribute to the development MDR in cancer cells, and its targeting and modulation of their expression to sensitize cells to treatment. This review implies that some natural compounds, such as curcumin, resveratrol, kaempferol, allicin, and quercetin, have the potential to interact with highly oncogenic and/or proinflammatory miRNAs, such as miR-21/155/663/146a, significantly influencing the response to cancer therapy. This article aims to point out how natural compounds may be used, accompanied by miRNAs mimics or miRNA inhibitors to treat specific types of cancer and its subtypes to overcome multidrug resistance. The main challenge is to determine the proper doses and concentrations of both miRNAs and compounds. cancer drug resistance; microRNA (miRNA); natural compounds INTRODUCTION Plant kingdom and metabolome are plentiful sources of secondary metabolites, which exert numerous health-beneficial biological, pharmacological, and medicinal properties. Every day, there is more and more progress in the isolation and characterization of natural compounds with a prominent potential in the fight against multidrug resistance (MDR) in cancer. Natural products act on multiple targets and can significantly contribute to overcoming resistance to cancer therapy. Natural compounds have already shown a prospective role in the fight against MDR. Currently, resistance to chemotherapy is one of the biggest problems in cancer therapy. MDR is the simultaneous development of resistance to multiple drugs with different chemical structures, mechanisms of action, and targets. Recent research has shown that genetic background and epigenetic mechanisms accompanied by the transcriptional and posttranscriptional regulation by noncoding RNAs, including microRNAs (miRNAs), long-noncoding RNAs (lncRNAs), and others, may contribute to and induce MDR phenotype in cancer cells (1–4). Various novel natural products isolated from animals, plants, and other organisms have enriched the chemical libraries and exerted anticancer effects. Compared with conventional synthetic molecules, they possess unique characteristics that confer advantages and disadvantages in anticancer drug discovery. Natural products have shown potential in reversing MDR in cancer cells, which could facilitate effective cancer therapy. Some of the most effective cancer treatments to date are natural products or compounds derived from natural products. The first natural anticancer compound was podophyllotoxin isolated from Podophyllum peltatum in 1947 (5). From then until today, patients use natural compounds as an essential part of the complementary approach. Since the popularity of using natural compounds in cancer treatment appears to be growing rather than declining, it is necessary to study natural compounds so that we can properly direct their future application in cancer therapy. On the other hand, to overcome the MDR, it is necessary to use multiple compounds in combination. Natural compounds are ideally suited for this application; they are active at concentrations that can be N. Petrovićand I. Z. Matićcontributed equally to this work. Correspondence: T. Stanojković([email protected]). Submitted 26 June 2024 / Revised 17 July 2024 / Accepted 7 May 2025 http://www.ajpcell.org 0363-6143/25 Copyright ©2025TheAuthors.LicensedunderCreative Commons Attribution CC-BY-NC-ND 4.0. Published by the American Physiological Society. C183 Am J Physiol Cell Physiol 329: C183–C199, 2025. First published May 15, 2025; doi:10.1152/ajpcell.00428.2024 Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. achieved in the organism, and their mild toxicity allows them to be used safely (6). Along with the growth of interest in natural products, there has been progress in the field of phytochemical investigation and isolation techniques to elucidate their structure. Over the years, secondary metabolites were specially examined. Thousands of secondary metabolites were isolated, their anticancer activity was examined, and leading substances that are the most interesting for new anticancer drugs were extracted from the crowded data (7,8). Phenolic compounds constitute one of the most numerous groups in the plant kingdom, with over 8,000 identified to date. The most abundantly occurring phenols in plants are flavonoids, phenolic acids, stilbenes, and lignans. Over 4,000 flavonoids have been identified to date, and in addition, 6,500 different flavonoids have been identified from plant sources (9,10). The most famous flavonoids that have been studied to date and whose anticancer activity has been widely investigated are curcumin and quercetin (11–14). It has been shown that several classes of alkaloids can also reverse MDR, such as matrine, tetrandrine, ligustrazine, neferine, dauricine, cepharanthine, solanine, and others (15– 20). These compounds were reported to inhibit the proliferation of various cancer cells through apoptosis and cell cycle arrest (21,22). They can also inhibit cancer cell migration, invasion, and adhesion by downregulating the expression of oncogenes (23–25). On the other hand, terpenes and terpenoids, such as ginsenosides, soil bastard saponin, limonoids, as well as sterols, have been heavily exploited in attempts to identify compounds that would have potent anticancer effects and help to overcome MDR (26–29). These compounds exert anticancer effects through the induction of apoptosis, inhibition of proliferation, metastasis, angiogenesis, and activation of immunity (30,31). Their use may contribute to reducing toxicity and improving chemosensitivity in cancer combination therapy (26,32). However, natural products show some problems, such as poor solubility, poor permeability, instability, and insufficient bioavailability in biological systems. New drug delivery strategies, such as nanotechnology, have attempted to overcome the problems, rediscovering new benefits associated with these natural products. Nanotechnology could be one of the ways to improve the pharmacokinetics and effects of natural products and improve their efficiency in cancer prevention and therapy. Further research to improve cancer therapy due to manyobstaclesiscertainlyimperative.Theaimofthis review was to provide a comprehensive overview of the ability of the most frequently used natural compounds, especially phenolic compounds, to modulate resistance to anticancer therapies, and their perspective and importance for developing new, more effective therapeutic options for the fight against cancer. CHEMOSENSITIZING EFFECTS OF PHENOLIC COMPOUNDS The plant phenolic compounds are secondary metabolites well known as multitarget anticancer bioactive phytochemicals, which may sensitize cancer cells to chemotherapy drugs or biologically targeted therapies (Fig. 1). RESVERATROL Resveratrol is a plant polyphenol found in grapes, red and white wines, berries, peanuts, and soy (33), well-recognized for its cancer-chemopreventive and cancer-therapeutic effects, including chemosensitization and radiosensitization effects (34,35). The inhibitory effect of resveratrol on P-gp and MRP1 transporter efflux function in the Caco-2 colorectal adenocarcinoma cells and P-gp overexpressing CEM/ ADR5000 doxorubicin-resistant leukemia cells had been demonstrated in addition to increased resistant cells sensitivity to doxorubicin (36). Resveratrol inhibited the activity of metabolic enzymes cytochrome P450 3A4 (CYP3A4) and glutathione S-transferase (GST), induced apoptosis in resistant cancer cells, and decreased expression levels of genescoding ABC transporters MDR-1,MRP1, and breast cancer resistance protein (BCRP), in addition to CYP3A4,GST, and Figure 1. Overview of the mechanisms of the most prominent anticancer phenolic compounds in overcoming multidrug resistance in cancer. NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER C184 AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. their regulatory gene-coding receptor hPXR in Caco-2 cells, confirming its suppressive effects on different mechanisms of cancer MDR (36). Increased sensitivity of MDR cancer cell lines to resveratrol, ABCB5-overexpressing HEK-293/ABCB5 cells (embryonic kidney), and mutation-activated epidermal growth factor receptor (EGFR) overexpressing U87.MGDEGFR glioblastoma cells, which may be explained by resveratrolcaused sirtuin 1 (SIRT1) overexpression, had been reported (37). Anticancer drug-sensitizing effects of resveratrol in breast cancer have been well documented in vitro and in vivo studies (38–41). Yang et al. (38) showed a synergistic effect of resveratrol and cisplatin on survival, migration, and invasion of triple-negative breast adenocarcinoma MDA-MB-231 cells through PI3K/AKT, Smad, NF-κB, JNK, and ERK; it increased the effect of cisplatin in MDA-MB-231 xenografts and reduced adverse effects. Resveratrol was effective in overcoming the resistance of HER-2 overexpressing SK-BR-3 breast cancer cells to docetaxel through downregulation of the HER-2-Akt signaling axis activated by docetaxel (39). The sensitization effect of resveratrol of breast cancer cells to poly (ADP-ribose) polymerase (PARP) inhibitor talazoparib mediated by inhibition of Akt pathway and autophagy flux, leading to impairment of double-strand break repair, has been also reported. The combination of resveratrol and talazoparib in breast cancer cells led to cell cycle progression dysregulation, p38MAPK-mediated apoptosis, induction of DNA damage, abnormal mitotic progression, reduced autophagosome formation, and postponed/inhibited autophagy flux (40). The resveratrol efficacy was confirmed in the in vivo preclinical SCID mouse breast cancer xenograft model (40). The incubation with resveratrol enhanced the effects of doxorubicin in breast cancer MCF-7 and MDA-MB-231 cells (41). Treatment with doxorubicin and resveratrol of breast cancer cells induced apoptosis (Bax:Bcl-2 and caspase-9), downregulated inflammation-associated proteins (NF-κB, COX-2), autophagy-associated proteins (LC3, Beclin-1), and redox regulator (Nrf2) (41). The efficacy of resveratrol, which can cross the blood-brain barrier, has been documented in glioblastoma, showing potential as a radiosensitizer and chemosensitizer (42). The treatment ofdoxorubicin-resistant U87MG/DOX glioblastoma cells reversed their sensitivity to doxorubicin by upregulating phosphatase and tensin homolog (PTEN) and downregulating PI-3K, Akt, and membrane transporter P-gp levels (43). The recent research also demonstrated the ability of resveratrol to increase the effect of temozolomide (TMZ) against A172 and LN428 glioblastoma cells, to effectively inhibit cell proliferation, migration, and induce apoptosis (44). Treatment with resveratrol and temozolomide reversed the sensitivity of LN428 glioblastoma cells to temozolomide, which could be attributed to the downregulation of O 6 -methylguanine-DNA methyltransferase (MGMT) and signal transducer and activatorof transcription 3 (STAT3) (44). Resveratrol has been recognized as a sensitizer of pancreatic cancer cells to gemcitabine (45). It inhibited lipid synthesis by downregulation of sterol regulatory element-binding protein 1 (SREBP1) and reversed the gemcitabine-induced stemness of pancreatic cancer in vitro and in vivo (45). Resveratrol has been proven to be effective in overcoming MDR resistance in human nonsmall cell and small cell lung cancer cells (46,47). In MDR human cell lines, SPC-A-1/CDDP resveratrol inhibited cell proliferation, induced apoptosis, and increased chemosensitivity to cisplatin, paclitaxel, and gefitinib (46). The anticancer efficacy of resveratrol was confirmed in nude mice implanted with SPC-A-1/ CDDP lung cancer cells. Moreover, resveratrol enhanced the sensitivity of H69AR small-cell lung cancer cells resistant to doxorubicin by inhibiting inflammatory mediators, STAT3/ VEGF pathway, and P-gp activity (47). Colorectal cancer may be also effectively chemosensitized by resveratrol by affecting multiple regulatory signaling pathways implicated in chemotherapy drug resistance and plasticity (48). The study by Chung et al. (49) showed that treatment with resveratrol reversed the sensitivity of resistant colorectal cancer HCT116 and DLD1 cells to 5-fluorouracil (5FU). When used in combination, resveratrol and 5-fluorouracil increased apoptosis of colorectal cancer cells, inhibited STAT3 and Akt signaling pathways, inhibited epithelial-mesenchymal transition (EMT), and reduced telomerase activity (49). APIGENIN The flavonoid that possesses the potential to be used as a part of combination therapy with anticancer drugs for various malignant diseases is flavone apigenin, found in many vegetables and fruits, such as grapes and apples, chamomile tea, red wine, and medicinal herbs (50). Recently published research showed the ability of apigenin to increase the sensitivity of breast adenocarcinoma MCF-7 cells resistant to doxorubicin by reducing the expression levels of transporter multidrug resistance-associated protein (MDR1) (P-gp) in resistant MCF-7 cells and inhibition of phosphorylation and activation of JAK2 and STAT3 (51). The downregulation of MRP1, MRP3, MRP5, and BCRP caused by apigenin in MCF-7 cells resistant to doxorubicin has been also reported (52). Apigenin proved its efficacy as a chemosensitizing compound against three-dimensional (3-D) spheroids of MDA-MB-231 breast cancer cells treated with apigenin and doxorubicin, induced increased DNA damage levels, and activated apoptosis through caspase-3 and caspase-9 (53). Sudhakaran et al. (53) reported that apigenin-induced sensitization of breast cancer spheroids to doxorubicin is partially mediated through RNAbinding protein: heterogeneous ribonuclear protein A2/B1 (hnRNPA2). Apigenin reduced gene expression levels of doxorubicin efflux transporters (ABCB1,ABCC1,ABCC4,andABCG2), regulated by hnRNPA2-dependent and independent mechanisms (53). Apigenin increased cisplatin-induced apoptosis in lung cancer A549 and NCI-H1299 cells (54). Treatment with apigenin and cisplatin of A549 cells triggered p53-dependent apoptosis mediated by activation of the Erk/MAPK signaling pathway (54). Furthermore, apigenin used with gefitinib had proved efficacy against EGFR mutant-resistant nonsmall cell lung cancer NCI-H1975 cells, which could be attributed to suppressive effects on c-Myc, HIF-1a, and EGFR, inhibition of AMPK pathway and autophagy flux, decreased glucose uptake, impaired metabolism leading to apoptosis (55). The study by Li et al. (56) demonstrated the ability of apigenin to increase the sensitivity of hypoxia-induced drug-resistant liver cancer to paclitaxel in vitro and in vivo through AKT/p-AKT pathway, HSP90, and HIF-1a. Chemosensitization properties of apigenin against hepatocellular cancer treated with sorafenib in in vitro (HepG2 and Huh7 cells) and in vivo settings (mice hepatocellular carcinoma model) had been reported (57). NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org C185 Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. LUTEOLIN Flavone luteolin is a flavonoid present in medicinal plants, fruits,andvegetables,suchasapples,oranges,lemons,grapes, carrots, celery, onion, spinach, oregano, and thyme, which is also well-known for its multiple mechanisms of anticancer effects (58,59). Luteolin inhibited growth, induced cell cycle arrest, and triggered apoptosis in MDR P-gp-expressing NCIADR/RES and BCRP-expressing MCF-7/MitoR cancer cell lines, while at the same time not inhibiting functions of the drug transporters (60). The antiproliferative and proapoptotic activities of luteolin were related to the generation of reactive oxygen species (ROS), DNA fragmentation, activation of the ATR/Chk2/ p53 signaling pathway, inhibition of NF-κB signaling pathway, activation of p38 pathway, and depletion of antiapoptotic proteins c-IAP1, claspin, survivin, and XIAP (60). This flavone showed promising properties to overcome MDR of multiple myeloma cells to bortezomib in vitro and in vivo by inhibition of TGF-b/Smad2/Smad3 pathway and through the autophagy pathway ALK5 levels, as well as reducing the amounts of ALDH1 þcells (61). The synergistic activity of luteolin and lowdose paclitaxel has been reported against esophageal cancer cells and xenograft models (62). Combined treatment with luteolin and paclitaxel suppressed cell growth, cell migration, induced apoptosis, and EMT; these effects were attributed to the activation of ROS/JNK signaling pathway (62). Luteolin showed chemosensitizing effects against tamoxifen-resistant MCF-7 breast cancer cells by suppressing the expression of cyclin E2 and cell progression from G1 to S phase (63). Furthermore, luteolin increased the effects of paclitaxel on breast MDA-MB-231 cells and lowered the expression of proteins associated with breast cancer stemness mediated through downregulating Nrf2, HO-1, Sirt3, Cripto-1, ABCG2, CD44, Oct4, and ALDH1 (64). A study by Wang et al. (65)reportedsensitization of cisplatin-resistant ovarian cancer CAOV3/DDP cells by luteolin, evident as enhancement of antiproliferative, proapoptotic, and anti-invasive effects that were confirmed in vivo. Luteolin increased the anticancer effects of cisplatin in hepatocellular carcinoma HepG2 and colorectal carcinoma HCT116 cells with wild-type p53, which were attributed to increasing JNK activation, p53 phosphorylation, and reduced protein ubiquitination and proteasomal degradation; this effect was also shown in vivo (66). QUERCETIN AND RUTIN Flavanol quercetin found in many fruits, vegetables, and medicinal plants, possesses anticancer and cancer-chemosensitizing properties. This flavanol has been shown to increase the sensitivity of pancreatic cancer cells to daunorubicin, gemcitabine, sulforaphane, doxorubicin, bromodomain, and extraterminal domain inhibitors, and the tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL), mediated by effects on regulation of oxidative and inflammatory signaling pathways, as reviewed by Hu et al. (67). Quercetin demonstrated the potential to overcome MDR in resistant gastric adenocarcinoma AGS-cyr61 cells and increased sensitivity to 5-fluorouracil and doxorubicin by decreasing CYR61, MRP1, and NF-κB p65 levels, induction of apoptosis, inhibition of cell migration, and downregulated epithelial-mesenchymal transition-related proteins (68). Zhou et al. (69) reported the ability of quercetin to overcome the P-gp-mediated MDR in colon cancer SW620/Ad300 cells and improve the sensitivity to doxorubicin mediated by inhibition of P-gp transport activity, inhibition of the expression of the glutamine transporter solute carrier family 1, member 5 (SLC1A5), and blocking D-glutamate and D-glutamine metabolism. In addition, quercetin exerted synergistic effects with 5-fluorouracil in drug-resistant colon cancer HCT-116 cells related to inhibition of the Nrf2/HO-1 pathway (70). Quercetin had also been shown to be effective in the reversal of sensitivity of doxorubicin-resistant MCF-7 breast cancer cells to doxorubicin, paclitaxel, and vincristine, which was explained by downregulating P-gp expression and eliminating breast cancer stem cells with CD44 þ /CD24  / low phenotype through inhibition of YB-1 protein nuclear translocation (71). The chemosensitizing effects of quercetin on prostate cancer cells to docetaxel have been demonstrated in vitro and in vivo (72,73). This effect was mediated by inhibition of P-gp expression, suppression of the mesenchymal and stem-like cell characteristics, and inhibition of activation of PI3K/Akt signaling pathways in LNCaP/R and PC-3/R prostate cancer cells (72). Sharma et al. (73)discovered that pretreatment of prostate cancer cells for 24 h with quercetin and treatment for another 24 h with low doses of docetaxel was the most effective in overcoming drug resistance in PC-3 and DU 145 prostate cancer cells. A quercetin glucoside rutin is also a promising anticancer flavonoid, which may be used in combination with chemotherapy drugs (74). Rutin increased the cytotoxicity of cyclophosphamide and methotrexate on breast adenocarcinoma MDA-MB-231 cells, inhibited the activity of P-gp and breast cancer resistance protein (BCRP), and reversed MDR of breast cancer cells (75). KAEMPFEROL Another flavonol compound, kaempferol, occurring in fruits and vegetables, might be useful for overcoming MDR and enhancing the effects of anticancer therapies. Kaempferol increased the sensitivity of 5-fluorouracil-resistant colorectal cancer HCT8-R cells to this drug and decreased glucose uptake and generation of lactic acid by inhibiting pyruvate kinase M2 (76). The chemosensitizing effect of kaempferol was also demonstrated in 5-fluorouracil-resistant colorectal adenocarcinoma LS-174T cells related to inhibition of ROS generation and modulation of JAK/STAT3, MAPK, PI3K/AKT, and NF-κB signaling pathways (77). Kaempferol decreased the expression levels of MDR genes ABCB1 and ABCC1 in acute promyelocytic leukemia HL-60 cells, upregulated apoptotic genes, and downregulated survival genes (PI3K,AKT,andBcl-2)(78). This flavonol sensitized ovary adenocarcinoma OVCAR-3 cells to cisplatin by downregulation of ABCC6 transporter and c-myc protooncogene (79). A recently published study showed that kaempferol alone or in combination with verapamil suppressed the expression of components of breast cancer stemness and chemoevasion pathways responsible for chemoresistance phenotype (SOX2, OCT4, NANOG, MDR1, and CD44) in MDA-MB231 and primary breast cancer stem cells (80). FLAVANOLS The chemosensitizing effects of flavanols (catechins, epicatechins, epigallocatechin, and epigallocatechin gallate), NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER C186 AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. abundant in black grapes, red wine, and green tea, have been studied as well (81). Flavanol epigallocatechin-3-gallate (EGCG) has been recognized for its prominent effectiveness in overcoming MDR in cancer by affecting multiple signaling pathways in vitro and in vivo (82). Epigallocatechin-3-gallate inhibited P-gp and BCRP activity, implicated in drug efflux in breast adenocarcinoma MCF-7 cells resistant to tamoxifen (83). The chemosensitizing action of epigallocatechin-3-gallate was reported in doxorubicin-resistant lung carcinoma A549 cells due to suppression of multidrug resistance signaling (MRP1, EGFR, and ERK), drug efflux, and enhancement of drug uptake, cell cycle arrest, and cell death, and modulation of antioxidant machinery and their regulators (84). The study by Toden et al. (85) demonstrated the ability of epigallocatechin-3-gallate to increase the sensitivity of resistant HCT116 and SW480 colon cancer cells to 5-fluorouracil, inhibit colon cancer stem cell formation, downregulate cancer stem cell markers (Oct4, Nanog), and suppress tumor growth in vivo. Epigallocatechin-3-gallate efficiently increased apoptosis in resistant esophageal cancer Eca109/ABCG2 cells induced by doxorubicin, downregulated ABCG2 expression, and increased drug concentration (86). This flavanol caused apoptosis and autophagy in cisplatin-resistant oral cancer cells and inhibited MDR1 and AKT/STAT3 signaling pathways (87). Its in vivo efficacy in multidrug-resistant oral carcinoma KBV200 xenografts against vincristine sulfate, which might be attributed to angiogenesis inhibition by VEGF downregulation, has been demonstrated (88). Liang et al. (89) showed the chemosensitizing activity of epigallocatechin-3-gallate in doxorubicinresistant liver cancer BEL-7404/DOX cells in vitro and in vivo through inhibition of P-gp and increasing intracellular doxorubicin concentration and downregulation of MDR1 expression. NARINGENIN AND NARINGIN Isoflavones naringenin and naringin are abundant in citrus fruits and possess the potential to enhance the effectiveness of anticancer drugs. Naringenin in combination with low concentrations of cisplatin increased cytotoxicity and anti-invasive effects in 3-D HeLa spheroids (90). Naringenin increased the cytotoxic activities of DNA-damaging anticancer drugs camptothecin, doxorubicin, 5-fluorouracil, cisplatin, etoposide, ellipticine, carboplatin, and cyclophosphamide against breast cancer HTB26 and colorectal cancer SW1116 cells (91). The chemosensitizing effect of naringin to doxorubicin had been demonstrated in the animal study by Ali et al. (92). Pretreatment of adult male Sprague–Dawley rats with naringin before treatment with doxorubicin increased sensitivity to doxorubicin and downregulated P-gp expression (92). GENISTEIN Isoflavone genistein, abundant in soybeans, possesses the ability to modulate ABC transporters (P-gp, MRP1, MRP2, MRP4, MRP5, and BCRP) (93). This phytoestrogen increased the sensitivity of A549 lung cancer cells to cisplatin and significantly suppressed tumor growth in vivo in the A549 xenograft mice model through suppression of the PI3K/Akt pathway (94). Genistein exerted a chemosensitizing effect on bladder cancer cells treated with hydroxycamptothecin in vitro and in vivo, activated ATM, and suppressed NEMO/ NF-κB/IKK/caspase signaling pathway (95). Soy isoflavone increased the sensitivity of diffuse large cell lymphoma WSUDLCL2 and WSU-DLCL2-SCID mouse xenograft to CHOP regimen (cyclophosphamide, doxorubicin, vincristine, and prednisone) and inhibited NF-κB binding to DNA (96). In contrast, Rigalli et al. (97) showed that genistein upregulated protein levels of ABCC1 and ABCG2 in MCF-7 breast cancer cells, accompanied by increased resistance to doxorubicin and mitoxantrone as well as upregulated ABCC1 protein levels in MDA-MB-231 cells without effect on resistance; genistein suppressed drug efflux in breast cancer cells. CURCUMIN Curcumin is recognized as a potent polyphenolic chemosensitizer, able to reverse MDR and enhance the sensitivity of resistant cancer cells to anticancer therapeutics (98). Curcumin effectively increased the sensitivity of breast cancer MCF-7, MDA-MB-231, SK-BR-3, and T47D cells to 5-fluorouracil mediated by downregulation of NF-κB in MDA-MB231 cells (99). The increase in sensitivity of cisplatin-resistant MCF-7/DDP breast cancer cells induced by curcumin had been reported as well; curcumin inhibited PI3K/AKT/mTOR pathway and CCAT1 expression and induced autophagy (100). Curcumin was reported to reverse MDR of colon cancer in vitro and in vivo (12,101). It increased cytotoxicity of vincristine, cisplatin, 5-fluorouracil, and hydroxycamptothecin in vincristine-resistant human colon cancer cell line HCT-8/ VCR, inhibited tumor growth in mice xenograft, and reduced the expression of P-gp (101). In addition, curcumin reversed resistance to oxaliplatin in resistant colorectal carcinoma HCT116/OXA, increased active caspase-3, and inhibited EMT through downregulation of TGF-b/Smad2/3 pathway in vitro and in vivo (12). Elevation of ROS was identified as one of the possible mechanisms underlying chemosensitizing effects of curcumin in colon cancer cells (102). The sensitivity increases in MRP5 overexpressing HEK293 (HEK293/MRP5) cells and two pancreatic cancer cell lines, PANC-1 and Mia-PaCa-2, when curcumin was appliedin combination with 5-fluorouracil was reported as well (103). The study by Sreekanth et al. (104) provided data about the chemosensitizing efficacy of curcumin in combination with paclitaxel in two animal cervical cancer models; curcumin downregulated NF-κB pathway and increased paclitaxel-induced proapoptotic effects (104). Curcumin also increased the effects of gemcitabine and irradiation in prostate adenocarcinoma PC-3 cells and PC-3 xenografts mediated by downregulation of MDM2 expression through modulation of PI3K/mTOR pathway (105). SILIBININ Flavonolignan silibinin is a major bioactive constituent of silymarin, extract obtained from seeds of milk thistle, Silybum marianum [L.] Gaertn., well recognized for the treatment of liver diseases, as well as its chemopreventive and chemosensitization activities (106). Silibinin has been reported to enhance the cytotoxic effects of doxorubicin in resistant MDA-MB-435/ DOX breast cancer cells mediated through induction of apoptosis through caspase-3, and inhibition of STAT3, AKT, and NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org C187 Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. ERK (107). In addition, silibinin exerted synergistic effects in combination with paclitaxel in resistant MCF-7/PAC breast adenocarcinoma cells (107). Silibinin reversed MDR in small cell lung cancer VPA17 cell line, which overexpressed P-gp, to etoposide and doxorubicin and showed a synergistic effect when applied in combination (108). The effectiveness of silibinin and paclitaxel was demonstrated in resistant A2780/taxol ovarian cancer cell line; silibinin increased apoptosis and G2/ M cell cycle arrest, suppressed P-gp and survivin expression, and decreased cell invasiveness (109). In the human gastric cancer cell line SGC-7901, silibinin increased the cytotoxicity of paclitaxel, induced prominent G2/M cell cycle arrest, and apoptosis through extrinsic pathway demonstrating synergistic effects (110). The overview of the mechanisms of phenolic compounds to overcome multidrug resistance in cancer cells is presented in Table 1. TARGETING MicroRNAs BY NATURAL PRODUCTS The strategies for miRNA molecule silencing or upregulating have been extensively researched over time, and they include inhibitory small molecules, RNA sponges, miRNA Zip molecules, miRNA mimics, anti-miRNA oligonucleotides, catalytic nucleic acids, exosomes, artificial DNA molecules, nanoparticles, as well as CRISPR-Cas9 technique (111, 112). Besides the use of artificial synthetic molecules, which show great potential, one of the most promising strategies may be the modulation of miRNAs by natural products and their derivatives, which can be used for the reduction of tumor progression and propagation, and for overcoming drug and chemotherapy resistance. The strategy of utilization of natural products from the modulation of miRNA levels may be one step closer to clinical practice utilization because natural products have been already approved by the Food and Drug Administration. MicroRNAs, as noncoding RNAs, are recognized as mediators of various disease formation and progression. Their differential expression is especially important in cancer research and treatment. MicroRNA represents level changes that influence response to cancer therapy, not only by its interaction with messenger RNAs (mRNAs), but through the interplay with other noncoding RNAs, such as circular RNAs (circRNAs), competing endogenous RNAs (ceRNAs), long noncoding RNAs (lncRNAs), and miRNA sponges (113). MicroRNA molecules can interact with multiple targets (114) andviceversa,canbethetargetofawidespectrumofcompounds and molecules (115). MicroRNAs are associated with the response to therapy and clinical outcomes. Petrovićet al. (116) have emphasized that miR-21/155/34a/146a/221/222/ 133/206 are associated with response to breast cancer, glioblastoma, and prostate cancerinvasive potential and response to treatment, (117–120), and that miR-156a and miR-155 levels change after the mechanic therapy of periodontitis (121). These findings emphasize the importance of miRNAs to be investigated as potential biomarkers of the response to therapy. MiRNA expression levels are sensitive to chemical compounds (122,123), radiation, natural products, herbal extracts (124,125), and compounds extracted from natural products in cancer, metabolic diseases, and inflammation (126,127). Regulation of miRNA levels with natural products and compounds during the treatment of various diseases may increase the efficiency of therapy. Some natural agents and plant extracts manifest their antitumor activities via modulating miRNA amounts and expression. Natural compounds can interact with pre-miRNA molecules and enzymes involved in miRNA maturation and processing, as well as directly bind to miRNA molecules, thus preventing them from binding to its targets, or can act indirectly (126). MicroRNAs AND PLANT EXTRACTS IN CANCER RESEARCH Various plant extracts have been shown to change miRNA expression levels in both ways, upregulating or downregulating them (125)(Table 2 and Fig. 2). For example, Olea europaea (OLE) extract from leaves was shown to increase miR-137/145/ 153/181b and let-7d expression levels and induce apoptosis of glioblastoma T98G, U-87MG, and U-138MG cells. OLE treatment was shown to improve response to temozolomide in T98G glioblastoma (128). Treatment with OLE extract, accompanied by temozolomide, induced a higher increase of miRNAs than temozolomide solely. Also, OLE temozolomide treatment reduced levels of their targets involved in cell death, reduced angiogenesis, and invasiveness (128). Hypericum perforatum extracts have also been extensively investigated as anticancer agents. Their anticancer potential, among other research, has been investigated against two-dimensional (2-D) and 3-D HeLa cell line models by Matićet al. (124). This research has shown that Hypericum perforatum L., collected from Samsun, Turkey, various plant partsand extract solvents differently influence miR128/193a-5p/335 signature in HeLa cells (124). Plant extracts contain numerous active compounds that can influence metabolite abundance, as well as gene activity, and thus protein synthesis. Mostly investigated natural products with the ability to change levels of miRNA molecules, associated with cancer research, inflammation, diabetes, metabolic, and cardiovascular diseases, are curcumin, resveratrol, and quercetin, accompanied by allicin. MicroRNA AND NATURAL COMPOUNDS AGAINST CANCER DRUG RESISTANCE CANDIDATES FOR NOVEL ANTICANCER THERAPEUTICS It is well-known that microRNAs can modulate chemotherapeutic drug resistance and interact with natural compounds (135)(Table 2 and Fig. 2). Phenolic compounds were shown to influence DNA methylation, chromatin remodeling, and miRNA expression changes. Phenolic compounds belonging to a class of curcuminoids, stilbenes (resveratrol), and flavonoids—such as curcumin, allicin, quercetin, epigallocatechin-3-gallate (EGCG), genistein, and proanthocyanidin—have been shown to actively contribute to various levels and aspects of epigenetic changes (136,137). EGCG was shown to elevate miR-485 expression levels in stem-like nonsmall cell lung cancer A549 cells resistant to cisplatin. Upregulation of miR-485 levels reduced stemness of A549 NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER C188 AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. Table 1. Summary of the mechanisms of phenolic compounds to overcome multidrug resistance in cancer Phenolic Compound Cancer Type Effect and Mechanism References Resveratrol Colon cancer and leukemia Inhibition of P-gp and MRP1 function, CYP3A4 and GST activity, activation of apoptosis, and decrease in the expression of genes coding MDR-1, MRP1, and BCRP,CYP3A4,GST, and hPXR, increased sensitivity to doxorubicin (36) Resveratrol Embryonic kidney and glioblastoma Increased MDR cell sensitivity, SIRT1 overexpression (37) Resveratrol Breast cancer Inhibition of cell survival, migration, and invasion, synergism with cisplatin, targets: PI3K/AKT, Smad, NF-κB, JNK, and ERK (38) Resveratrol Breast cancer Downregulation of the HER-2-Akt signaling pathway, overcoming docetaxel resistance (39) Resveratrol Breast cancer Inhibition of Akt pathway and autophagy flux, cell cycle effects, induction of DNA damage and apoptosis, resveratrol in combination with talazoparib (40) Resveratrol Breast cancer Apoptosis activation via Bax:Bcl-2 and caspase-9, downregulation: NFκB, COX-2, LC3, Beclin-1, and Nrf2, doxorubicin, and resveratrol (41) Resveratrol Glioblastoma PTEN upregulation, PI-3K, Akt, and membrane transporter P-gp downregulation, reversal of doxorubicin sensitivity (43) Resveratrol Glioblastoma Cell proliferation and migration inhibition, apoptosis activation, MGMT and STAT3 downregulation, reversal of temozolomide sensitivity (44) Resveratrol Pancreatic cancer Inhibition of lipid synthesis, SREBP1 downregulation, reversal of the gemcitabine sensitivity (45) Resveratrol Lung cancer Chemosensitivity increase, apoptosis induction, antiproliferative effect, inhibition of inflammatory mediators, STAT3/VEGF pathway, and P-gp, chemosensitivity to cisplatin, paclitaxel, gefitinib, and doxorubicin (46,47) Resveratrol Colorectal cancer Proapoptotic effect, inhibition of STAT3 and Akt pathways, epithelialmesenchymal transition inhibition, and antitelomeric effect, 5-fluorouracil sensitivity reversal (49) Apigenin Breast cancer Downregulation of MDR1 (P-gp), MRP1, MRP3, MRP5, and BCRP, JAK2 and STAT3 inhibition, doxorubicin sensitization (51,52) Apigenin Breast cancer Proapoptotic effects, DNA damage induction, downregulation of (ABCB1, ABCC1,ABCC4, and ABCG2), doxorubicin sensitization (53) Apigenin Lung cancer Proapoptotic effect through Erk/MAPK signaling pathway, combination with cisplatin (54) Apigenin Lung cancer Proapoptotic effect, inhibition of c-Myc, HIF-1a, EGFR, AMPK pathway, autophagy flux, and glucose uptake, apigenin, and gefitinib (55) Apigenin Liver cancer Induction of apoptosis, inhibition of HIF-1athrough AKT/p-AKT pathway, and HSP90, apigenin and paclitaxel (56) Luteolin Breast cancer, ovarian cancer Induction of apoptosis and cell cycle arrest, ROS production, DNA fragmentation, p38 and ATR/Chk2/p53 pathway activation, NF-κB pathway suppression, and reduction of c-IAP1, claspin, survivin, and XIAP (60) Luteolin Multiple myeloma Inhibition of TGF-bpathway and degradation of ALK5, overcoming MDR to bortezomib (61) Luteolin Esophageal cancer Proapoptotic effect, inhibition of cell proliferation, migration, and EMT, activation of mitochondrial apoptotic pathway through activation of ROS/JNK pathway, synergism with paclitaxel (62) Luteolin Breast cancer Cell cycle arrest, cyclin E2 inhibition, combination with tamoxifen; stemness-targeted breast cancer—decrease in: Nrf2, HO-1, Sirt3, Cripto-1, ABCG2, CD44, Oct4, and ALDH1—paclitaxel (63,64) Luteolin Ovarian cancer Apoptosis induction, proliferation, migration, and invasion inhibition, synergism with cisplatin (65) Luteolin Hepatocellular and colorectal cancer p53 stabilization through increasing JNK activation, combination with cisplatin (66) Quercetin Pancreatic cancer Increased drug sensitivity, regulation of oxidative and inflammatory pathways (67) Quercetin Gastric adenocarcinoma Proapoptotic effect, downregulation of CYR61, MRP1, and NF-κB p65, EMT-related proteins (68) Quercetin Colon cancer Inhibition of: P-gp transport activity, SLC1A5, D-glutamate and D-glutamine metabolism, Nrf2/HO-1 pathway (69,70) Quercetin Breast cancer Chemosensitivity reversal, P-gp expression suppression, inhibition of YB1 nuclear translocation (71) Quercetin Prostate cancer Increased apoptosis, inhibition of P-gp expression, inhibition of activation of PI3K/Akt signaling pathways, combination with docetaxel (72) Rutin Breast cancer Inhibition of activity of P-gp and BCRP (75) Kaempferol Colorectal cancer Chemosensitization to 5-fluorouracil, JAK/STAT3, MAPK, PI3K/AKT, and NF-κB pathways modulation (76,77) Kaempferol Leukemia Upregulation of apoptotic genes, downregulation of ABCB1 and ABCC1, PI3K,AKT, and Bcl-2 (78) Kaempferol Ovarian cancer Suppression of ABCC6 and c-Myc, sensitization to cisplatin (79) Kaempferol Breast cancer Suppression of SOX2, OCT4, NANOG, MDR1, and CD44, with verapamil (80) Continued NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org C189 Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. cisplatin-resistant cells. Furthermore, the reduction of miR-485 levels by inhibitors boosted stemness, whereas proper doses of EGCG lowered stemness, indicating that proper dose and consumption of EGCG may be utilized shortly to overcome resistance to cisplatin chemotherapy (129). Furthermore, EGCG upregulated tumor suppressive miR-34a/145/200c in colorectal carcinoma, and induced chemosensitivity of CRC cells to 5-fluorouracil (85). According to Zhou et al. (138), EGCG diet in nude mice with tobacco carcinogen-induced lung cancer, 12 microRNAs were over-represented, and 9 were under-represented, which were involved in cancer signaling pathways, among others. Curcumin can alter miRNAs in an epigenetic manner by interacting with methyl groups of miRNA gene promoters (126). In the case of miR-203, curcumin releases and unlocks its expression transcription by promoter demethylation (139). Curcumin was shown to modulate levels of miR-9/19/34a/181/192-5p and miR-21 molecule (140,141), showing its potential to be used as an anticancer agent and to reverse resistance to chemotherapy. It has been shown that curcumin sensitizes U-87 MG malignant glioma cells to temozolomide by upregulating miR146a and inhibiting NF-κBsignaling(130). The difference in 67 miRNA expression levels was shown among MCF-7 sensitive, resistant, and curcumin-treated doxorubicinresistant cells. In the same study, it has been also shown that higher levels of miR-29b-1-5p decreased the effect of curcumin treatment and sensitizing MCF-7 cells to doxorubicin. Curcumin affects miRNA expression levels and has the potential to help overcome drug resistance in breast cancer cells. In addition, miRNA levels could affect curcumin effectiveness, and the synergy of doxorubicin and curcumin inhibits breast cancer cell proliferation and progression (131). Allicin, although not a phenolic compound, was noteworthy to be mentioned in terms of combining effect with miRNA in overcoming resistance to cancer drugs. Allicin is an organosulfur compound, mostly found in garlic, was described to have antioxidant, antibacterial, and antitumor effects, and that among others, can reduce propagation of the two gastric cancer cell lines AGS and HGC27 by inhibiting invasion and migration by increasing level of tumor suppressive miR-383-5p, and decreasing the components of erb-b2 receptor tyrosine kinase 4 (ERBB4) oncogene singling pathway (142). Also, allicin has been shown to induce upregulation of miR-486-3p, which increases the sensitivity of temozolomide-resistant U251-TR cells through O 6 -methylguanine-DNA methyltransferase (MGMT) downregulation (132). According to this finding, the authors have suggested that allicin can be proposed as an additive to therapy with TMZ to improve the patients’survival rates, and also in combination with miR-486-3p as its target (132). Table 1.—Continued Phenolic Compound Cancer Type Effect and Mechanism References Epigallocatechin3-gallate Breast cancer Inhibition of P-gp and BCRP activity (83) Epigallocatechin3-gallate Lung cancer Overcoming MDR to doxorubicin, inhibition of MRP1, EGFR, ERK, drug efflux, and modulation of redox stress signaling (84) Epigallocatechin3-gallate Colorectal cancer Suppression of cancer stem cell markers (Oct4, Nanog), combination with 5-fluorouracil (85) Epigallocatechin3-gallate Esophageal cancer Decrease in ABCG2 expression and increased adriamycin levels (86) Epigallocatechin3-gallate Oral cancer Apoptosis, autophagy, suppression of MDR1, and AKT/STAT3 (87) Epigallocatechin3-gallate Liver cancer Inhibition of P-gp and MDR1 expression, doxorubicin accumulation (89) Naringenin Cervical cancer Cytotoxicity activity and anti-invasive effects (90) Naringenin Breast and colorectal cancer Stronger cytotoxic effects when combined with anticancer drugs (91) Genistein Lung cancer PI3K/Akt pathway inhibition, chemosensitization to cisplatin (94) Genistein Bladder cancer ATM activation, NEMO/NF-κB/IKK/caspase pathway inhibition (95) Genistein Lymphoma Increased sensitivity to CHOP, NF-κB binding suppression (96) Curcumin Breast cancer Chemosensitization to 5-fluorouracil, NF-κB downregulation (99) Curcumin Breast cancer Autophagy, inhibition of PI3K/AKT/mTOR pathway and CCAT1 expression, chemosensitization to cisplatin (100) Curcumin Colon cancer Chemosensitizing effects to anticancer drugs, downregulation of P-gp, downregulation of TGF-b/Smad2/3 pathway-mediated inhibition of EMT (101,102) Curcumin Pancreatic cancer Chemosensitizing effects to 5-fluorouracil (103) Curcumin Cervical cancer Chemosensitizing effects to paclitaxel, proapoptotic effects, NF-κB pathway downregulation (104) Curcumin Prostate cancer Combination with gemcitabine and irradiation, PI3K/mTOR pathway modulation, suppression of MDM2 expression (105) Silibinin Breast cancer Increased sensitivity to doxorubicin, apoptosis, caspase-3 activation, STAT3, AKT, and ERK inhibition (107) Silibinin Lung cancer MDR reversal to etoposide and doxorubicin (108) Silibinin Ovarian cancer Apoptosis, cell cycle arrest, anti-invasive effects, downregulation of P-gp and surviving, combination with paclitaxel (109) Silibinin Gastric cancer Apoptosis, cell cycle arrest, synergism with paclitaxel (110) BCRP, breast cancer resistance protein; EGFR, epidermal growth factor receptor; MDR, multidrug resistance; MGMT, O 6 -methylguanine-DNA methyltransferase; PTEN, phosphatase and tensin homolog; ROS, reactive oxygen species; SIRT1, sirtuin 1; SREBP1, sterol regulatory element-binding protein 1; STAT3, signal transducer and activator of transcription 3. NATURAL COMPOUNDS AGAINST DRUG RESISTANCE IN CANCER C190 AJP-Cell Physiol doi:10.1152/ajpcell.00428.2024 www.ajpcell.org Downloaded from journals.physiology.org/journal/ajpcell (147.091.198.002) on November 20, 2025. A combination of quercetin and 5-fluorouracil treatment of Caco-2 and HCT-116 colon cancer cell line showed a synergistic effect on apoptosis induction. The combination of these two compounds significantly decreased levels of miR27a, an oncomiRNA involved in the promotion of colon cancer cell proliferation. Reduction of miR-27a levels led to suppression of miR-Wnt/b-catenin signaling and significantly lowered cell growth (133). A chemically modified derivative of quercetin, 7-O-geranylquercetin (GQ), was shown to enhance the sensitivity of MCF-7-adriamycin-resistant breast cancer cells through upregulation of miR-451. Overexpression of miR-451 in turn lowered P-glycoprotein, and multidrug resistance-associated protein (MDR1), as well as on mice xenograft model indicating that quercetin-based synthetic derivative and miR-451 have additive effects against overcoming doxorubicin resistance, and that the better effect of silencing is accomplished when both agents are present, GQ and miR-451 (134). Furthermore, it has been shown that miR-155 was significantly upregulated in BRCA1 methylated HCC-38 and UACC3199 cells compared with BRCA1 mutation-containing breast cancer cell lines, both triple-negative and estrogen receptorpositive MDA-MB-231 and HCC-1937 cells, indicating that miR-155 acts as an “epi”miRNA (143). In this research, it has been shown that curcumin-induced demethylation of BRCA1 promoter, restored BRCA1 activity, which in turn reduced miR-155 levels in HCC-38 cells, unlike in HCC-1937 cells, meaning that curcumin has the potential to silence miR-155 through in cells with hypermethylated BRCA1methylated cells but not in cells containing BRCA1 mutation. Also, these results indicate that curcumin can reduce the oncogenic effects of miR-155 in specific cell types, highlighting its antitumor potential (143). According to this, some natural agents undoubtedly influence epigenome remodeling. Curcumin also alters levels of miRNAs miR-30c/200b/200c/ 22/101/27 in colorectal, lung, gastric, and thyroid cancer, and miR-21, which was downregulated after curcumin treatment in lung, hepatocellular, and breast cancer (144). Besides the curcumin, miR-155 was shown to be a potential target of resveratrol, as well. According to Su et al. (145), miR-155-5p was significantly upregulated in MGC803, SGC7901, and AGS cell lines and gastric carcinoma tissue samples compared with normal GES-1 line and paracancerous noncancerous tissue, which was reversed in cell lines after the treatment with resveratrol who inhibited cell proliferation and growth, and reduced miR-155 expression levels. Another study has shown that resveratrol interacts with miR-21 via activation of phosphatase and tensin homolog (PTEN) expression in colon cancer cells, whereas in prostate cancer cells via restoration of suppressor programmed cell death 4 (PDCD4)(137). The influence of resveratrol on miRNA is associated with inflammation and cancer by upregulation of miR-663, whose target genes are part of inflammatory and cancer pathways, including atherosclerosis as well (146). Considering that miR-663 is shown to have a large number of targets, and that resveratrol induces and restores its expression in a dose-dependent manner, the authors proposed treatment with a low dose for a longer Table 2. Natural compounds targeting miRNA levels against cancer drug resistance Extract/Natural Compound MicroRNA How to Overcome Resistance/Induce Sensitivity Descriptions References Olea europaea leaf extract (OLE) miR-137, miR-145, miR-153, miR-181b, let-7d :Treatment with OLE and temozolomide gives better results than temozolomide solely in terms of cell death and invasiveness enhances sensitivity to temozolomide (synergistic effect) against glioblastoma cells T98G, U-138MG, and U-87MG (128) Epigallocatechin-3-gallate (EGCG) miR-145, miR-200c, miR-34a :Upregulated tumor-suppressive miRNAs in HCT116 and SW480 colorectal cancer fluorouracil-resistant cells and sensitized them to 5FU (85) miR-485 :Overexpression of miR-485 induced by EGCG treatment of lung cancer A549 reduced stemness, responsible for resistance to cisplatin in EGCG-miR485 dose-dependent manner (129) Curcumin miR-146a :Curcumin sensitizes glioblastoma cells to temozolomide via miR-146a upregulation (130) miR-29b-1-5p ;Liposomal curcumin changes miRNA levels in MCF-7 breast cancer cells. Higher miR-29b-1-5p levels decrease the effect of curcumin on sensitizing MCF-7 cells to doxorubicin (131) Allicin miR-486-3p :Allicin induces sensitivity to temozolomide by upregulating miR-486-3p and inhibition of 6-methylguanineDNA methyltransferase in resistant U251-TR glioblastoma cells (132) Quercetin miR-27a ;Quercetin together with 5-fluorouracil synergistically induced apoptosis of Caco-2 and HCT-116 colon cancer cells. Quercetin may have the potential to sensitize colon cancer cells to 5-fluorouracil (133) 7-O-geranylquercetin (GQ) miR-451 :GQ-induced miR-451 upregulation enhanced sensitivity of MCF-7-adriamycin-resistant breast cancer cells to doxorubicin (134) The up arrow suggests that upregulation of particular miRNA may be considered for the improvement of the treatment, enhancement of sensitivity to the drug, and/or overcoming drug resistance. 5FU, 5-fluorouracil. 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