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Review

Polyphenols and Chronic Myeloid Leukemia: Emerging Therapeutic Opportunities

by
Claudia Moriello
1,
Chiara De Rosa
2,
Stefania D’Angelo
3,* and
Perrone Pasquale
3,*
1
Department of Experimental Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy
2
Department of Clinical Medicine, School of Medicine and Surgery, University of Naples Federico II, 80131 Naples, Italy
3
Department of Medical, Movement, and Wellbeing Sciences, Parthenope University of Naples, 80133 Naples, Italy
*
Authors to whom correspondence should be addressed.
Hemato 2025, 6(3), 28; https://doi.org/10.3390/hemato6030028
Submission received: 2 July 2025 / Revised: 1 August 2025 / Accepted: 14 August 2025 / Published: 15 August 2025
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Abstract

Background/Objectives: Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by the BCR–ABL fusion gene, whose constitutive tyrosine kinase activity drives leukemogenesis. Although tyrosine kinase inhibitors (TKIs) have revolutionized treatment, drug resistance and leukemic stem cell persistence remain major challenges. Natural compounds such as polyphenols have shown potential in modulating key oncogenic pathways in CML. Results: Polyphenols such as resveratrol, quercetin, curcumin, and epigallocatechin gallate (EGCG) demonstrated significant antiproliferative and pro-apoptotic effects in CML cell lines, including imatinib-resistant models. These effects were mediated through the modulation of signaling pathways, including PI3K/Akt, STAT5, and MAPK; inhibition of BCR–ABL expression; induction of oxidative stress; and the enhancement of apoptosis via mitochondrial and caspase-dependent mechanisms. Some polyphenols also showed synergistic activity with TKIs, potentiating their efficacy and overcoming resistance. Conclusions: Preclinical evidence supports the role of polyphenols as potential adjuvants in CML therapy, particularly in drug-resistant contexts. Their pleiotropic molecular actions and low toxicity profile make them promising candidates for integrative oncology. Nonetheless, clinical translation requires further investigation through well-designed trials assessing efficacy, safety, and pharmacokinetics.

1. Introduction

Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of the Philadelphia chromosome (Ph) and the BCR–ABL fusion protein [1]. This disease serves as a paradigm for understanding the molecular mechanisms of carcinogenesis and for the development of targeted therapies. Despite significant therapeutic advances achieved with tyrosine kinase inhibitors (TKIs), drug resistance and the persistence of leukemic stem cells (LSCs) remain major clinical challenges.
CML originates from a pluripotent hematopoietic stem cell that acquires a reciprocal translocation between chromosomes 9 and 22, resulting in the formation of the Ph chromosome and the consequent production of the constitutively active BCR–ABL1 tyrosine kinase [2]. This altered protein triggers an aberrant signaling cascade that promotes uncontrolled proliferation, inhibits apoptosis, and disrupts cell adhesion and immune response [3]. The clinical management of CML has been revolutionized by TKIs; however, approximately 20–30% of patients develop resistance or intolerance, and LSCs, often refractory to TKIs, constitute a pathological reservoir that is difficult to eradicate [4].
Polyphenols, a class of bioactive compounds of plant origin, have garnered increasing attention for their antioxidant, anti-inflammatory, and antitumor properties [5,6,7]. Recent scientific evidence suggests that these compounds may represent a complementary therapeutic strategy in the treatment of CML by modulating molecular mechanisms involved in cell proliferation, apoptosis, and BCR–ABL expression [8].
In particular, polyphenols such as resveratrol, quercetin, curcumin, and epigallocatechin gallate have been investigated for their ability to inhibit leukemic cell growth in preclinical models. They exert their effects through the modulation of signaling pathways such as PI3K/Akt, STAT5, and MAPK, which are frequently dysregulated in CML. Some of these compounds also exhibit synergistic effects with TKIs, enhancing their efficacy and overcoming certain forms of drug resistance. Moreover, their antioxidant activity helps to reduce the burden of reactive oxygen species (ROS), which are often elevated in leukemic cells, thereby mitigating oxidative stress associated with disease progression [9]. Interest in polyphenols is further reinforced by their abundance in the Mediterranean diet, a dietary pattern known for its protective effects against various chronic diseases, including cancer [10].
Among the various alternative approaches explored to overcome the limitations of TKI therapy, polyphenols stand out due to their multifaceted biological activities, low toxicity profile, and ability to target multiple oncogenic pathways simultaneously. Unlike many synthetic agents, polyphenols can modulate both BCR–ABL-dependent and independent mechanisms, addressing not only drug resistance but also the persistence of LSCs. Importantly, their relevance extends beyond TKI-resistant contexts: polyphenols have shown promising activity in general CML models, supporting their potential role in disease prevention, cytoreduction, and long-term disease control. Moreover, their ability to enhance the efficacy of existing TKIs without adding significant side effects makes them particularly appealing as adjunct therapies.

2. Chronic Myeloid Leukemia: Clinical and Molecular Characteristics

CML is a myeloproliferative neoplasm arising from the clonal transformation of a hematopoietic stem cell, characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation t(9;22)(q34;q11) and the consequent formation of the BCR–ABL fusion gene [11].
During chromosomal translocation, the ABL gene on chromosome 9 may break at one of three sites. However, in all cases, the alternative first exons (1b, 1a) of ABL are spliced out. The BCR gene on chromosome 22 contains three major breakpoint cluster regions: the major (M-BCR), minor (m-BCR), and micro (μ-BCR) [12,13,14].
The BCR–ABL gene encodes a chimeric 210-kDa protein (p210 BCR–ABL) with constitutive tyrosine kinase activity. It contains the BCR coiled-coil domain and ABL’s SH3, SH2, and kinase domains. Loss of ABL’s regulatory cap domain leads to constitutive kinase activation [15]. Two major isoforms of BCR–ABL exist: the p210 form, typically associated with CML and some cases of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), and the p190 form, more commonly found in Ph+ ALL [16].
BCR–ABL activates STAT, RAS, RAF, JNK, MYC, and AKT, promoting proliferation and survival. Members of the Src family kinases, especially Hck, play a key role in coupling BCR–ABL to STAT5 activation. It recruits inactive Hck via SH3/SH2, facilitating STAT5 interaction. BCR–ABL phosphorylates Hck, which then activates STAT5 via Tyr699/694 [17,18].
Persistent activity increases ROS, causing DNA damage and resistance [9]. Rac2 disrupts mitochondrial function via MRC-cIII, raising ROS in stem/progenitor cells. ROS derived from MRC-cIII promote oxidative DNA damage, triggering genomic instability and resulting in chromosomal aberrations and BCR–ABL mutations conferring TKI resistance [19]. Additionally, BCR–ABL alters metabolism and the marrow microenvironment to support leukemia [20]. In particular, it triggers a Warburg-like effect, with increased glucose uptake and lactate secretion [21].
Importantly, BCR–ABL was one of the first tyrosine kinases identified as directly involved in the pathogenesis of a human malignancy. Its kinase activity is critical for both the initiation and maintenance of the leukemic phenotype, and mutations impairing enzymatic function abolish its transforming potential, thereby blocking neoplastic proliferation [22].
Within the bone marrow microenvironment, leukemic progression is associated with dynamic alterations in stromal populations, including the expansion of arteriolar endothelial cells, chondrocytes, and mesenchymal stromal cells (MSCs), and the loss of sinusoidal endothelial and osteo-associated cells (Figure 1) [23].
Globally, the incidence of CML is estimated at 0.7–1.0 cases per 100,000 individuals annually, with a median age at diagnosis of 57–60 years and a male-to-female ratio of 1.2–1.7 [24,25].
CML typically progresses through three clinical phases: chronic, accelerated, and blast crisis. Chronic phase often has mild or no symptoms like fatigue, splenomegaly, and leukocytosis [26,27].
Progression to advanced phases brings more blasts, cytopenias, and resistance. It is driven by additional mutations, gene inactivation, or BCR–ABL amplification. The blast phase mimics acute leukemia and is associated with poor prognosis [28]. Common side effects include chronic fatigue, metabolic disturbances, gastrointestinal symptoms, skin rash, and cardiovascular dysfunction. Long-term adherence to therapy may also pose challenges for some patients [29].
In this context, there is growing interest in integrative approaches, including the use of natural bioactive compounds such as polyphenols. Due to their antioxidant and regulatory properties, polyphenols may help mitigate chronic oxidative stress induced by both the disease and its treatment, improving therapy tolerability and potentially reducing the risk of disease progression.

3. Polyphenols: Structure and Biological Functions

Polyphenols are a broad and heterogeneous class of plant-derived organic compounds, characterized by the presence of one or more aromatic rings directly bound to hydroxyl groups (–OH), which confer high reactivity towards ROS [30]. In plants, polyphenols act as secondary metabolites involved in defense against environmental stress, pathogens, and UV radiation [31]. In the human diet, they are widely found in fruits, vegetables, legumes, whole grains, tea, red wine, extra virgin olive oil, and other Mediterranean diet components [32,33,34].
Structurally, polyphenols can be grouped into main subclasses, including flavonoids, phenolic acids, stilbenes, and tannins. Flavonoids are the most abundant and include compounds such as quercetin, catechins, anthocyanins, and isoflavones [35]. They share a common C6–C3–C6 backbone and their biological activity is influenced by the degree and position of hydroxylation and methylation [36]. For example, hydroxyl groups on aromatic rings generally enhance bioactivity, while methylation can reduce it, except in some flavonols, where it may increase stability and efficacy [37].
Phenolic acids, such as gallic and caffeic acid, are simpler structures and often act as biosynthetic precursors for more complex polyphenols. Their anti-AGE activity is closely related to their hydroxylation patterns [38].
Stilbenes, including resveratrol and pterostilbene, have shown antioxidant, anti-inflammatory, and anticancer properties. Resveratrol, found in grapes and red wine, is particularly studied for its capacity to modulate redox balance and signaling pathways relevant to cancer [39,40]. Stilbenes have specific acid dissociation constants (pKa) affecting their biological activity [41].
Tannins are high molecular weight polyphenols, classified into hydrolyzable tannins (e.g., ellagic acid) and condensed tannins (proanthocyanidins). These compounds are abundant in berries, tea, and wine, and contribute to antioxidant activity through radical scavenging and metal chelation (Figure 2) [42,43].
Polyphenols exert antioxidant effects through several mechanisms: neutralizing free radicals via electron donation, chelating pro-oxidant metals like iron and copper, inhibiting oxidative enzymes (e.g., NADPH oxidase), and regenerating endogenous antioxidants such as glutathione and vitamin E [44].
Beyond direct radical scavenging, polyphenols modulate cellular redox homeostasis by activating Nrf2 (nuclear factor erythroid 2-related factor 2), a transcription factor that induces the expression of antioxidant enzymes such as catalase, superoxide dismutase, and glutathione peroxidase [45,46]. Under basal conditions, Nrf2 is inhibited by Keap1, but polyphenols can relieve this inhibition and promote the nuclear translocation of Nrf2. Moreover, they regulate the bioavailability of iron, limiting ROS formation through Fenton reactions [47].
Numerous epidemiological, preclinical, and clinical studies have documented the health benefits of polyphenols, especially in cardiovascular protection [48]. They improve endothelial function, stimulate nitric oxide (NO) production, reduce low-density lipoprotein (LDL) oxidation, inhibit platelet aggregation, and modulate vascular inflammation [49].
In recent years, hydroxytyrosol, a phenolic compound abundant in extra virgin olive oil, has gained interest for its cardioprotective properties [50,51]. It reduces the exposure of phosphatidylserine on erythrocyte membranes, a key event in programmed red blood cell death (eryptosis) [52,53,54,55]. By inhibiting eryptosis, hydroxytyrosol may help preserve erythrocyte integrity and longevity, potentially protecting against oxidative stress-related hematologic and cardiovascular disorders [56,57].
Many polyphenols cross the blood–brain barrier and show protective effects against neurodegenerative diseases such as Alzheimer’s and Parkinson’s [58,59]. Clinical studies with phytochemicals like quercetin, caffeine, and ginkgolides reveal anti-inflammatory, antioxidant, and neuroprotective effects, mitigating neuroinflammation, neuronal oxidation, and synaptic dysfunction [60].
At the metabolic level, polyphenols contribute to glycemic control by inhibiting digestive enzymes, enhancing insulin sensitivity, and modulating glucose uptake and hepatic output, thereby supporting the prevention of type 2 diabetes [61,62].
Lastly, polyphenols have shown strong anti-inflammatory and antimicrobial properties. They inhibit proinflammatory pathways like NF-κB, reduce cytokine production (e.g., TNF-α, IL-6), and promote beneficial gut microbiota, selectively enhancing commensal bacteria such as Lactobacillus and Bifidobacterium while inhibiting pathogens [63].
In oncology, including hematologic malignancies such as chronic myeloid leukemia, polyphenols show antiproliferative, pro-apoptotic, and chemosensitizing properties [64,65].

4. Scientific Evidence for Polyphenols in the Treatment of Chronic Myeloid Leukemia

CML represents a paradigmatic oncological model in which the introduction of targeted therapies has revolutionized treatment. However, the emergence of resistance and the side effects of conventional drugs call for the exploration of alternative or complementary therapeutic strategies. In this context, polyphenols, known for their antioxidant and pro-apoptotic properties, are emerging as promising bioactive compounds [66,67]. A review that summarizes the available evidence on the effect of polyphenols in CML is therefore essential to identify new treatment pathways and to promote targeted clinical studies.
In a study by Luzi et al. the in vitro effects of resveratrol on the apoptotic pathway in human K562 and acute lymphoblastic (HSB-2) cells were investigated. Treatment with resveratrol in both cell types significantly and irreversibly inhibited their growth, which was associated with extensive apoptosis and an increase in hypodiploid cells. Resveratrol-induced apoptosis was associated with the increased expression of Bax and a marked release of cytochrome c from the mitochondria. Interestingly, K562 cells showed a basal glutathione content 10 times higher than that of HSB-2 cells, which increased after 24–48 h of exposure to resveratrol, along with an increase in glutathione reductase and peroxidase activity. These data are highly encouraging for the use of these natural substances in the treatment of specific pathologies such as CML [68]. Supporting these results, further studies have investigated the multiple effects of resveratrol on leukemic cells.
A study by Alhawamdeh et al. also explored the effects of resveratrol on apoptosis, cell cycle regulation, and DNA fragmentation in K562 cells. The compound induced a time-dependent reduction in cell viability, with IC50 values decreasing from 282.2 µM at 24 h to 107.1 µM and 102.4 µM at 48 and 72 h, respectively. Its pro-apoptotic activity was confirmed by marked DNA fragmentation in 55 ± 5% of treated cells, which was absent in control cells. Gene expression analysis showed an upregulation of pro-apoptotic genes (BCL-2, AIF, BAX, VDAC1) and a slight downregulation of genes associated with cell survival (CASP3, PGC1α, NDUFA9, Cyclin-D1, p53), suggesting a dual role of resveratrol in inducing apoptosis and inhibiting survival signals [8].
Further investigating the efficacy of resveratrol under the conditions of drug resistance, Can et al. evaluated its effect on both imatinib-sensitive and resistant K562 cells (K562/IMA-3). The concentrations of resveratrol required to inhibit cell growth by 50% (IC50) were found to be 85 and 122 μM, respectively. The loss of mitochondrial membrane potential increased 1.91, 7.42, and 14.73 times in K562 cells and 2.21, 3.30, and 7.65 times in K562/IMA-3 cells in response to increasing concentrations of resveratrol (10–100 μM). Caspase-3 activity also showed a dose-dependent increase, with apoptosis rates reaching 58.7% in K562 cells and 43.3% in K562/IMA-3 cells treated with 100 μM resveratrol. These results suggest the potential usefulness of resveratrol even in cases of primary or acquired resistance to imatinib [69].
In addition to its direct effects on the cell cycle and apoptosis, resveratrol also acts on specific molecular pathways. In particular, histone H2AX phosphorylation has been proposed as a crucial event in resveratrol-induced apoptosis. Treatment of K562 cells with concentrations between 20 and 100 μmol/L induced apoptosis and phosphorylation of H2AX at Ser139 in a dose- and time-dependent manner, while simultaneously reducing histone H3 phosphorylation at Ser10. Resveratrol activated the MAPK family members p38 and JNK, while blocking ERK activation. Pharmacological or genetic inhibition of p38 and JNK reduced H2AX phosphorylation and apoptosis induced by treatment. H2AX overexpression amplified the apoptotic response, whereas Ser139 mutation or H2AX silencing conferred resistance, suggesting an essential role for H2AX phosphorylation at Ser139 [70].
Another relevant molecular target is STAT5, a transcription factor constitutively activated in several neoplasms, including CML. The study by Li et al. showed that resveratrol inhibits STAT5 activation in K562 and KU812 cell lines, indicating possible therapeutic utility also through this pathway [71].
It has also been observed that resveratrol acts through AMPK activation and p62/SQSTM1 expression mediated by JNK, as reported by Puissant et al., adding further insight into its cytotoxic effects [72].
Among the mechanisms of therapy resistance, the high expression of heat shock protein 70 (Hsp70) is a key factor in CML. Resveratrol has shown the ability to suppress Hsp70 at the transcriptional and protein levels, with a reduction in heat shock factor 1 (HSF1) activity, suggesting that Hsp70 downregulation may enhance chemosensitivity [73].
The efficacy of resveratrol is amplified when combined with other chemotherapeutic agents such as imatinib mesylate or arsenic trioxide. In combination with imatinib mesylate, it resulted in a greater inhibition of cell growth and an increased apoptotic rate compared to single-agent treatment [74]. Similarly, resveratrol enhanced the pro-apoptotic effect of arsenic trioxide, suggesting a potential use in targeting early leukemic cells [75].
Other polyphenols beyond resveratrol also show promising effects. Quercetin, in particular, has shown significant anti-leukemic activity in CML cells. In in vitro models with the K562 cell line, the combination of quercetin and curcumin induced synergistic apoptosis, characterized by increased ROS levels, glutathione reduction, and a loss of mitochondrial membrane potential. The apoptotic action occurred mainly via the mitochondrial pathway, with cytochrome c release and activation of caspase-9 and PARP. The molecular mechanism involves the coordinated modulation of multiple pathways: the p53 pathway; inflammation (NFκB); the TGFα growth factor pathway, including cell cycle regulatory genes such as p21, p27, BTG2, and FAS; and the downregulation of AKT1 and IFNγ. Furthermore, in a comparison of eight polyphenols (quercetin, chrysin, apigenin, emodin, aloe-emodin, rhein, cis-stilbene, and trans-stilbene) on hematologic cells, quercetin, emodin, and cis-stilbene proved the most potent, with IC50 values in the 8–33 μM range for quercetin. Even more resistant cell lines, such as KG 1a and K562, responded significantly, suggesting efficacy even in resistant contexts [76].
Another study showed that quercetin displayed significant activity against imatinib-sensitive and resistant K562 cells, with IC50 values of 85 and 122 μM, respectively. The 100 μM dose induced apoptosis in 58.7% of the sensitive K562 cells and 43.3% of the resistant ones. The effect was mediated by mitochondrial potential loss and caspase-3 activation, encouraging its use as a potential adjuvant strategy in TKI resistance cases [77].
Curcumin has also shown promising results both in vitro and in vivo. In K562 cells, treatment with 20–40 μM resulted in a dose-dependent reduction of BCR–ABL mRNA by 20–45%; this effect was mediated by increased miR-196b, known to suppress BCR–ABL. Curcumin also affects the PTEN/AKT pathway through the downregulation of miR-21, leading to increased miR-21 export in exosomes and the inhibition of leukemic growth. Moreover, the authors studied curcumin’s effects on a CML xenograft in SCID mice. Data showed that animals treated with curcumin developed smaller tumors compared to control mice [78].
Recent studies have shown that curcumin, in nanomicellar formulations, reduces BCR–ABL expression in imatinib-sensitive and resistant cells (fold change ≈ 0.54–0.50), and induces apoptosis in K562 [79]. One study compared curcumin sensitivity between chronic (K562) and acute (HL-60) myeloid lines. K562 showed greater sensitivity, with vitality reduction < 80% at 10 μM and mortality peaks up to 90% with treatment. However, caspase activation was more incomplete in K562, suggesting differences in the mechanisms of action [80].
Khatamsaz et al. also showed that curcumin, particularly a curcumin-based nanodrug, induced apoptosis in CML K562 cells. IC50 values for curcumin and the nanodrug were 50 and 25 μg/mL, respectively. Apoptosis in the K562 cell line occurred 48 h after treatment with 25 μg/mL curcumin and 12.5 μg/mL nanodrug. The increased cytotoxicity of curcumin and the nanodrug was directly related to drug concentration and administration time. Interestingly, the nanodrug showed greater cytotoxic effects on cell viability and stimulated more apoptosis than curcumin alone [81].
A study by Jia et al. also showed that curcumin inhibited K562 cell viability in a dose- and time-dependent manner. Moreover, curcumin-induced cell death was associated with apoptosome complex formation, mitochondrial membrane potential collapse, and caspase-3 activation. Curcumin treatment also induced Bid cleavage and reduced Bcl-2 protein expression. Surprisingly, despite these apoptotic features, the authors demonstrated that curcumin stimulated autophagy, as evidenced by the immunoreactivity of microtubule-associated protein light chain 3. Curcumin also increased Beclin-1 protein levels. Overall, these results suggested that curcumin induces both autophagic and apoptotic death in K562 cells [82].
Another widely studied natural polyphenol in oncology is (−)-epigallocatechin-3-gallate (EGCG), the main catechin in green tea. A study by Della Via et al. showed that EGCG, a gallate ester obtained from gallic acid condensation with the (3R)-hydroxyl group of (−)-epigallocatechin, has multiple effects on signaling pathways and enzymatic activity, which may enhance apoptosis and suppress cell proliferation, invasion, angiogenesis, and metastasis in tumors. Specifically, hematologic analysis in this study revealed that EGCG treatment reversed leukocytosis, anemia, and thrombocytopenia and prolonged the survival of PML/RARα mice. Notably, EGCG reduced immature leukemia cells and promyelocytes in the bone marrow while increasing mature myeloid cells, probably by inducing cell differentiation. Additionally, EGCG has been reported to inhibit PIN1, a peptidyl isomerase overexpressed and/or overactivated in human tumors, described as a key target in PML/RARα. Overall, the data in this study supported further evaluation of EGCG in clinical studies on acute myeloid leukemia [83].
Xiao et al. also studied EGCG’s effect on the growth of Bcr/Abl+ CML cell lines, including imatinib-resistant lines and primary CML cells. The results revealed that EGCG could inhibit cell growth and induce apoptosis in CML cells. The mechanisms involved include inhibition of the Bcr/Abl oncoprotein and regulation of its downstream pathways p38 MAPK/JNK and JAK2/STAT3/AKT. In conclusion, the data showed EGCG’s anti-CML effects in Bcr/Abl+ cells sensitive and resistant to imatinib, particularly in cells with the T315I mutation [84].
An epidemiological study also showed that green tea consumption is associated with a reduced risk of hematopoietic neoplasms. In particular, the authors demonstrated the activation of acid sphingomyelinase induced by EGCG and the clustering of lipid rafts in CML cells. The ASM inhibitor desipramine significantly reduced EGCG-induced cell death. Protein kinase Cδ, a well-known kinase, plays an important role in ASM activation. Furthermore, the authors observed EGCG-induced phosphorylation of protein kinase Cδ at Ser664. Importantly, EGCG-induced ASM activation was significantly reduced by the pre-treatment of CML cells with the soluble guanylate cyclase inhibitor NS2028, suggesting that EGCG induces ASM activation via a cyclic guanosine monophosphate (cGMP)-dependent pathway. Indeed, pharmacological inhibition of a negative cGMP regulator enhanced EGCG’s anti-CML effect. These results indicated that EGCG-induced cell death occurs through the cGMP/ASM pathway in CML cells [85].
An additional study by Iwasaki et al. demonstrated that EGCG predominantly causes necrotic-type cell death through a caspase-independent mechanism in CML, K562, and C2F8 cells, whereas imatinib induces typical apoptotic cell death. Moreover, this caspase-independent cell death partially mediated the release of apoptosis-inducing factor and the serine protease HtrA2/Omi from the mitochondria to the cytosol. Furthermore, EGCG enhanced the imatinib-induced cell death, resulting in additive cell death in K562 cells, and EGCG alone effectively reduced the viability of imatinib-resistant K562 cells. The authors therefore suggested that catechin is a potential candidate as an antitumor agent causing cell death in CML cells via a caspase-independent mechanism [86].
EGCG has also been studied in combination with ponatinib, a drug used in the treatment of CML. This study also aimed to detect changes in the expression levels of genes related to cell cycle regulation after the combination of ponatinib and EGCG in the CML K562 cell line. The IC50 values for ponatinib and EGCG were 87.13 nM and 50 μM respectively, and the combination showed a synergistic effect. Cyclin D1 and CDC25A were downregulated by ponatinib–EGCG by 2.49 and 2.63 times, respectively. TGF-β2 was upregulated 4.57 times. The authors suggested that EGCG could synergistically cooperate with ponatinib’s growth inhibitory activity against CML cells. Furthermore, according to the authors, apoptosis mediated by ponatinib–EGCG may be associated with the upregulation of the TGF-β2 gene and the downregulation of the cyclin D1 and CDC25A genes [87].
Finally, epidemiological evidence supports the rationale for the use of additional polyphenols in the prevention and treatment of CML. Anthocyanin-rich extracts (cyanidin 3-rutinoside, delphinidin) reduced the proliferation of murine Ph+ ALL cells (BM185), reaching efficacy comparable to standard agents such as imatinib [88].
Triterpenoids, particularly a pentacyclic derivative of gypenoside (compound 1c), also showed an inhibition of ABL1 (IC50 ≈ 9.3 μM) and improved selectivity compared to imatinib on normal cells. Notably, compound 1c exhibited a different inhibitory profile against eight kinases compared to imatinib. The interaction between the ATP binding site of ABL and compound 1c was examined via molecular docking studies, revealing a binding mode distinct from that of imatinib and next-generation inhibitors. Additionally, compound 1c suppressed downstream BCR–ABL signaling. This study suggested that plant extracts could be a source for CML treatment and offer a strategy to overcome drug resistance to known BCR–ABL inhibitors [89]. The polyphenolic tri-vanillic compound (13c) also inhibited the phosphorylation of JAK2V617F and BCR–ABL; downregulating P STAT3/5, Mcl-1, and c-Myc; and inducing apoptosis in CML cells [90].
Interestingly, while some clover species are known for beneficial effects in human diseases, little is known about the activity of the forage plant Trifolium repens. However, a 2020 study showed that its phytochemical components, specifically its isoflavonoid-rich fraction, exhibited strong cytotoxic effects in CML K562 cells, with IC50 values of 1.67 and 0.092 mg/mL, respectively. Cell growth arrest was associated with the total inhibition of BCR–ABL/STAT5 and activation of the p38 signaling pathways. Conversely, these strong cytotoxic effects did not occur in normal cells. These results suggested that developing new compounds derived from phytochemical molecules in Trifolium could lead to the identification of new therapeutic agents active against CML [91].
Carnosic acid, an important polyphenol mainly isolated from the well-known spice and medicinal plant Rosmarinus officinalis, also showed antitumor effects in CML. Specifically, in this study using the KBM-7 cell line, carnosic acid demonstrated significant antitumor activity against KBM-7 CML cells with an IC50 of 25 μM. The antitumor activity was due to apoptosis induction and cell cycle arrest. Additionally, carnosic acid inhibited the proliferation and invasion of KBM-7 CML cells, which could be mainly attributed to the downregulation of microRNA-780 expression, as indicated by quantitative RT-PCR analysis. Overall, the authors proposed that carnosic acid could prove to be a potential lead compound in CML treatment [92].
A 2019 study aimed to manipulate the apoptotic pathway of tumor necrosis factor-related apoptosis-inducing ligand using hydroxychavicol, a polyphenol extracted from Piper betel leaves, to induce apoptosis in TRAIL-resistant CML cells. This ligand, a member of the cytokine superfamily, induces apoptosis in various tumor cells through activation of the extrinsic apoptotic pathway but shows little to no cytotoxicity toward normal cells. However, some tumor cells are intrinsically resistant to TRAIL-mediated apoptosis, a challenge in establishing TRAIL as a potential chemotherapeutic drug. When imatinib-resistant K562 cells were treated with hydroxychavicol, they became sensitive to TRAIL. It was observed that hydroxychavicol reduced the expression of anti-apoptotic proteins XIAP and FLIP, while expression of the TRAIL receptors DR4 and DR5 remained unchanged. Data from this study demonstrated that the combined treatment with TRAIL and hydroxychavicol represents a promising alternative therapeutic approach for treating leukemia resistant to imatinib and TRAIL [93].
Collectively, preclinical evidence indicates that polyphenols act on multiple molecular targets in CML: from microRNA modulation to regulation of the cell cycle and caspases, as well as influencing resistance to TKIs. Synergistic combinations of polyphenols may reduce necessary doses, improve efficacy, and mitigate resistance, opening innovative therapeutic perspectives. However, valid clinical translation is still lacking; well-designed clinical trials are needed to validate these compounds as nutraceutical supports or co-therapeutic agents in CML (Table 1).

5. Discussion

The collected preclinical evidence consistently demonstrates the effectiveness of polyphenols, particularly resveratrol, quercetin, curcumin, and EGCG, in significantly modulating the proliferation and survival of CML cells, including cell lines resistant to TKIs such as imatinib [94]. Their effects are mediated through multiple and converging mechanisms: the induction of mitochondrial apoptosis, the inhibition of key oncoproteins (such as BCR–ABL and STAT5), regulation of the cell cycle, and the activation of cellular stress pathways (MAPK, AMPK, JNK) [71,90].
In particular, resveratrol stands out for its robust pro-apoptotic activity, mediated by cytochrome c release, caspase-3 activation, and histone H2AX phosphorylation, as well as its ability to overcome resistance mechanisms related to Hsp70 overexpression and mitochondrial dysfunction [70]. Its effects also extend to the transcriptional regulation of pro- and anti-apoptotic genes, highlighting a potential epigenetic or signal transduction role in modulating the cellular response.
Similarly, quercetin shows synergistic activity with other polyphenols and chemo-targeted agents, exerting cytotoxic effects even on drug-resistant cell lines. The coordinated involvement of pathways related to ROS, inflammation and cell cycle regulation (p21, p27) suggests a broad spectrum of action, which could also prove useful in combination with conventional therapies or personalized approaches [77,95].
Curcumin, in addition to confirming its pro-apoptotic and anti-proliferative activity, displays unique characteristics, including the ability to induce autophagic cell death and modulate the expression of onco-miRNAs (such as miR-21 and miR-196b), strengthening the hypothesis that its effects are linked to fine-tuned regulation of the molecular networks within leukemic cells. Nanomicellar formulations of curcumin have further enhanced its bioavailability and therapeutic efficacy, offering a promising rationale for clinical development [78,82].
Finally, EGCG is notable for its ability to induce non-conventional cell death through caspase-independent necrotic mechanisms, the activation of acid sphingomyelinase, and modulation of the cGMP pathway. Its synergistic effect with imatinib and its activity against mutant lines (e.g., T315I) reinforce its therapeutic relevance, suggesting it may serve as a valuable adjuvant or alternative strategy, particularly in refractory cases [83,85].
Despite the consistency and biological plausibility of these preclinical findings, the translational impact of polyphenols in the clinical setting remains limited. No clinical trials have yet been initiated in CML patients to test the efficacy of these compounds, and this gap underscores several challenges that still need to be addressed. First, although the results are promising, they are still preliminary and largely restricted to in vitro and selected in vivo models, which do not fully capture the complexity of the disease in humans. Furthermore, the limited bioavailability, rapid metabolism, and systemic instability of many polyphenols significantly reduce their therapeutic potential in clinical contexts, unless advanced delivery systems or structural modifications are employed.
Another critical limitation concerns the lack of standardized formulations and dosing regimens, which hampers the reproducibility of results and complicates the design of interventional studies. Additionally, the pleiotropic nature of polyphenols, while advantageous from a mechanistic standpoint, introduces difficulties in identifying specific molecular targets and clinically measurable endpoints, which are essential for drug development and regulatory approval.
Taken together, these factors help explain the absence of clinical trials to date and highlight the need for a more integrated approach, combining pharmaceutical innovation with translational research, in order to unlock the full therapeutic potential of polyphenols in CML.

6. Conclusions

Polyphenols represent a class of bioactive compounds of great interest in the treatment of CML, due to their ability to selectively modulate key processes such as apoptosis, proliferation, oxidative stress, and oncogenic signaling. The collected preclinical evidence indicates significant potential, both as monotherapy and in combination with TKIs, particularly in resistant or refractory cases.
The integration of polyphenols into standard therapeutic protocols could represent an evolution in CML management, promoting a more personalized and less toxic approach. However, to support their clinical integration, well-designed translational and clinical studies will be necessary to assess their efficacy, safety, pharmacokinetics, and drug interactions.
In conclusion, further investigation into the role of polyphenols in CML opens new therapeutic perspectives and strengthens the concept of integrated oncology, in which natural compounds can effectively complement conventional treatments, improving patients’ quality of life and treatment adherence.

Author Contributions

Conceptualization: S.D. and P.P.; methodology: C.M., S.D. and P.P.; data curation: S.D., C.D.R. and C.M.; validation: P.P. and S.D.; resources: S.D.; writing—original draft preparation: S.D. and P.P.; writing—review and editing: C.M., S.D. and P.P.; visualization: S.D. and P.P.; supervision: S.D.; project administration: S.D.; funding acquisition: S.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research work was supported by grants from NextGenerationEU in the framework of PRIN 2022 (project code 2022J2NT4L)—CUP I53D23004490006 (S.D.).

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding authors.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

AGEAdvanced glycation end product
CMLChronic myeloid leukemia
EGCG(−)-epigallocatechin-3-gallate
LSCLeukemic stem cell
MSCMesenchymal stromal cell
MRC-cIIIMitochondrial respiratory chain complex III
NONitric oxide
Nrf2Nuclear factor erythroid 2-related factor 2
ROSReactive oxygen species
TXNIPThioredoxin-interacting protein
TKITyrosine kinase inhibitor

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Figure 1. Schematic representation of the reciprocal translocation between chromosomes 9 and 22 resulting in the BCR–ABL fusion gene. The chimeric BCR–ABL protein exhibits constitutive tyrosine kinase activity, aberrantly activating multiple intracellular signaling pathways. This leads to uncontrolled cell proliferation, apoptosis inhibition, genomic instability and altered cell adhesion, promoting oncogenic transformation, and the persistence of LSCs and MSCs.
Figure 1. Schematic representation of the reciprocal translocation between chromosomes 9 and 22 resulting in the BCR–ABL fusion gene. The chimeric BCR–ABL protein exhibits constitutive tyrosine kinase activity, aberrantly activating multiple intracellular signaling pathways. This leads to uncontrolled cell proliferation, apoptosis inhibition, genomic instability and altered cell adhesion, promoting oncogenic transformation, and the persistence of LSCs and MSCs.
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Figure 2. The three main categories of polyphenols include flavonoids divided into flavonols, flavones, flavanols, flavanones, anthocyanins, and isoflavones; non flavonoids, divided into phenolic acids, lignans, and stilbenes; and tannins, divided into hydrolyzable tannins and condensed tannins.
Figure 2. The three main categories of polyphenols include flavonoids divided into flavonols, flavones, flavanols, flavanones, anthocyanins, and isoflavones; non flavonoids, divided into phenolic acids, lignans, and stilbenes; and tannins, divided into hydrolyzable tannins and condensed tannins.
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Table 1. Main effects of polyphenols in MCL model systems.
Table 1. Main effects of polyphenols in MCL model systems.
PolyphenolMain EffectsMechanisms of Action
ResveratrolProliferation inhibition, apoptosis induction↑ Bax, ↑ cytochrome c, ↓ mitochondrial membrane potential, ↑ caspase-3, ↑ H2AX (Ser139), ↓ H3 (Ser10), STAT5 inhibition, ↑ p38/JNK, ↓ ERK, AMPK/p62 activation, ↓ Hsp70
QuercetinApoptosis induction, ↑ ROS, ↓ glutathione, ↓ mitochondrial membrane potential↑ cytochrome c, caspase-9, PARP, p53, NFκB, TGFα modulation, ↑ p21, p27, BTG2, FAS, ↓ AKT1, IFNγ
Curcumin↓ BCR–ABL mRNA, apoptosis, autophagy↑ miR-196b, ↓ miR-21, PTEN/AKT pathway modulation, apoptosome activation, Bid cleavage, ↑ Beclin-1
EGCGApoptosis, necrosis-like death, ↑ survival↓ BCR–ABL, ↑ p38/JNK, ↓ JAK2/STAT3/AKT, ↑ acid sphingomyelinase, ↑ PKCδ, caspase-independent cell death
AnthocyaninsCell growth inhibitionReduced Ph+
Triterpenoids↓ ABL1, ↓ phosphorylated STAT3 and STAT5, ↓ Mcl-1, ↓ c-MycNew binding mechanism with ABL1, ABL1 kinase selectivity
Trifolium repensCytotoxic effect, BCR–ABL inhibition↓ STAT5, ↑ p38
Carnosic acidApoptosis, ↓ invasiveness↓ miRNA-780
HydroxychavicolSensitization to TRAIL↓ XIAP, ↓ FLIP, DR4/5 unmodified
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Moriello, C.; De Rosa, C.; D’Angelo, S.; Pasquale, P. Polyphenols and Chronic Myeloid Leukemia: Emerging Therapeutic Opportunities. Hemato 2025, 6, 28. https://doi.org/10.3390/hemato6030028

AMA Style

Moriello C, De Rosa C, D’Angelo S, Pasquale P. Polyphenols and Chronic Myeloid Leukemia: Emerging Therapeutic Opportunities. Hemato. 2025; 6(3):28. https://doi.org/10.3390/hemato6030028

Chicago/Turabian Style

Moriello, Claudia, Chiara De Rosa, Stefania D’Angelo, and Perrone Pasquale. 2025. "Polyphenols and Chronic Myeloid Leukemia: Emerging Therapeutic Opportunities" Hemato 6, no. 3: 28. https://doi.org/10.3390/hemato6030028

APA Style

Moriello, C., De Rosa, C., D’Angelo, S., & Pasquale, P. (2025). Polyphenols and Chronic Myeloid Leukemia: Emerging Therapeutic Opportunities. Hemato, 6(3), 28. https://doi.org/10.3390/hemato6030028

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