Izuegbuna Ogochukwu O.- Department of Haematology, Ladoke Akintola University of Technology (LAUTECH) Teaching Hospital, Ogbomoso, Nigeria
Polyphenols are one of the largest plant-derived natural product and they play an important role in plants’ defense as well as in human health and disease. A number of them are pleiotropic molecules and have been shown to regulate signaling pathways, immune response and cell growth and proliferation which all play a role in cancer development. Hematological malignancies on the other hand, are cancers of the blood. While current therapies are efficacious, they are usually expensive and with unwanted side effects. Thus, the search for newer less toxic agents. Polyphenols have been reported to possess antineoplastic properties which include cell cycle arrest, and apoptosis via multiple mechanisms. They also have immunomodulatory activities where they enhance T cell activation and suppress regulatory T cells. They carry out these actions through such pathways as PI3K/Akt/mTOR and the kynurenine. They can also reverse cancer resistance to chemotherapy agents. In this review, i look at some of the molecular mechanism of action of polyphenols and their potential roles as therapeutic agents in hematological malignancies. Here i discuss their anti-proliferative and anti-neoplastic activities especially their abilities modulate signaling pathways as well as immune response in hematological malignancies. I also looked at clinical studies done mainly in the last 10–15 years on various polyphenol combination and how they enhance synergism. I recommend that further preclinical and clinical studies be carried out to ensure safety and efficacy before polyphenol therapies be officially moved to the clinics.
Introduction
Hematological malignancies can be defined as a heterogenous group of cancers of blood cells and blood-forming tissues such as bone marrow and lymph nodes. They can be classified as leukemia (acute and chronic), lymphoma (Non-Hodgkin and Hodgkin) and myeloma. According to the GLOBOCAN 2020 report, hematological malignancies accounted for more than one million cancer cases (1). The diversity of their incidence and pathogenesis depends on their subtypes, which are broadly classified as lymphoid and myeloid according to the world health organization (WHO) classification of tumors of hematopoietic and lymphoid tissue (2). More than 400,000 cases and 300,000 deaths of leukemia were reported in 2018 and 2020 (1, 3).
The incidence of hematologic malignancies (HM) varies across regions and is also based on subtypes, age, gender, co-morbidities and socioeconomic status. While the incidence rate of some HM like chronic myeloid leukemia (CML) has decreased, the incidence of others like chronic lymphocytic leukemia (CLL) has increased in some countries (4). Co-morbidities like HIV increase the risk of HM (5). In the modern era of effective anti-retroviral therapy, the incidence rate of HM is still higher, and the 5-year survival rate is also significantly lower than the general population (6).
For the past few decades, most especially in the 21st century, there has been an explosion of knowledge and innovative technologies in the field of oncology which has resulted in newer and more effective therapies, especially in the field of hemato-oncology. Some of these recent therapies are targeted therapies, which make use of synthetic molecules and antibodies to target specific protein molecules and receptors in tumor growth and signaling pathways. This in most cases leads to fewer off-target activities and adverse effects. There are, however, the cost-to-benefit issues. Barnes and colleagues reported that ibrutinib a novel oral Bruton’s tyrosine kinase (BTK) inhibitor that has shown significant efficacy in the management of CLL was not cost-effective as initial therapy (7). The targeted therapies such as BTK inhibitors have shown clinical benefits in some groups of patients e.g., patients with del17p, and are used most often in these groups of patients, but response rates vary. Idelalisib an oral phosphatidylinositol 3-kinase delta isoform (PI3Kδ) has shown substantial activity in patients with CLL, however, the complete remission rate is comparatively low. In a clinical trial study of treatment-naïve older patients (median age, 71 years) with CLL treated with idelalisib and rituximab, the overall response rate (ORR) was 97% and the complete response rate was 19% (8). Acalabrutinib is a selective, next-generation covalent BTK inhibitor in another trial was shown to have an overall response rate was 97% and a complete response of 7% (9). The complete remission rate of the targeted therapies mentioned in CLL is low compared to a chemoimmunotherapy regimen with a complete remission rate of 72% (10). While most of the targeted therapies are target-specific e.g., Bcr-Abl oncoprotein in CML, most tumors are known to activate multiple signaling pathways and adopt/facilitate various resistance mechanisms to targeted drugs. Chemotherapies on the other hand, due to their adverse toxicities which often are severe and reduce the quality of life of patients are avoided in certain clinical settings. Such adverse effects include hematological toxicity, nephrotoxicity, hepatotoxicity, neurological toxicity, etc. Indeed chemotherapies are being systematically phased out.
Due to the challenges posed by these treatments natural products such as polyphenols are being regarded as ideal alternatives with comparable efficacy, safety and less toxicity profiles (11, 12). In a concerted effort at finding directed at finding alternative treatment options in HM, phytochemicals most especially polyphenols provide some interesting applications in this regard. Phytochemicals are plant-derived compounds that have been used in the prevention and treatment of many diseases. They are non-nutrient bioactive chemical compounds produced by plants to enhance their resistance to microbes as well as aid the repulsion of some predators (13). Polyphenols have been extensively studied both in vivo and in vitro in different cancers (14, 15). They are a large family of about 10,000 compounds having at least one aromatic ring with one or more hydroxyl functional groups attached (14). Natural polyphenols are a large group of plant secondary metabolites ranging from small molecules to highly polymerized compounds (16). They are biologically active compounds with activities against various chronic diseases. They are readily found in foods and beverages of plant origin including fruits, vegetables, spices, soy, nuts, coffee, tea, and wine). Regular consumption of polyphenol-rich diets has been associated with many health benefits. This includes a reduction in cardiovascular events (17, 18), modulation of anti-inflammatory pathways (19), and also in cancer prevention (20).
While their activities are in no doubt, the major challenge to their use in clinical practice is their low oral bioavailability. This is a result of low stability and poor pharmacokinetics which limits their bioavailability when they undergo hepatic phase I/II metabolism before reaching systemic circulation. Thus, the development of a delivery system that favors improved biological activities of polyphenols with better stability is of utmost importance for their clinical use. The activities of polyphenols in HM reveal some interesting applications especially their ability to modulate several signaling pathways such as PI3K and key proteins like NF-kB. The objective of this review is to discuss the chemistry, and biological activities of polyphenols on HM and explore some delivery systems that can enhance their efficacy for use in clinical practice.
Chemistry of polyphenols
Polyphenols are a diverse class of secondary metabolites that are derivatives of shikimic acid and phenylpropanoid – the shikimate biosynthesis pathway (Figure 1). This biochemical pathway serves for the production of polyphenolic compounds in bacteria, fungi and plants by converting the simple carbohydrate molecules (resulting from the pentose phosphate pathway and glycolysis) into phenylalanine and tryptophan (21). Shikimic acid is named after the highly toxic Japanese shikimi (Illicium anisatum) flower from which it was first isolated (22). Shikimic acid is a key intermediate of the shikimate biosynthesis pathway and acts as a precursor in the synthesis of the drug oseltamivir phosphate (Tamiflu), a neuraminidase inhibitor that acts against such viruses as the avian influenza virus H5N1, and the human influenza virus H1N1 (23). The shikimate pathway in micro-organisms is responsible for the production of aromatic amino acids L-phenylalanine (L-Phe), L-tyrosine (L-Tyr), and L-tryptophan (L-Trp) (24, 25). However, in plants, these aromatic acids though important for protein synthesis, also serve as precursors for diverse secondary metabolites that are important for plant growth (26). The principal aromatic phenolic compounds synthesized from L-Phe and L-Tyr are cinnamic acids and esters, coumarins, phenylpropenes, chromones (C6-C3), stilbenes, anthraquinones (C6-C2-C6), chalcones, flavonoids, isoflavonoids, neoflavonoids (C6-C3-C6), and their dimers and trimers, respectively (C6-C3-C6)2,3, lignans, neolignans (C6-C3)2, lignans (C6-C3)n, aromatic polyketides, or diphenylheptanoids (C6-C7-C6).
Figure 1. Shikimic acid pathway.
Flavonoids
Flavonoids are a large class of polyphenolic secondary metabolites found in fruits, grains, vegetables, flowers, and certain beverages. They play a variety of roles in plants, and are responsible for the color and aroma of flowers and fruits as well as protect plants from different biotic and abiotic stresses especially ultraviolet (UV) light (27). They may also function against frost hardiness, drought resistance, heat acclimatization and freezing tolerance (28, 29). Thus, they have potential applications in the nutraceutical, pharmaceutical, cosmetic and biotechnology industries. Flavonoids can be divided into six subclasses based on chemical structures: anthocyanidins, flavanones, flavonols, isoflavones, flavone, and flavan-3-ol (30) (Figure 2 and Table 1). The glycosylated flavonols are the most widely distributed in the diet (31). On the other hand, flavonoids account for about 60% of all natural polyphenols (14).
Figure 2. Chemical structures of some polyphenols.
Table 1. The major classes of dietary flavonoids.
Currently, there are about 15,000 naturally occurring flavonoid compounds (31). Flavonoids generally consist of a benzopyrone core skeleton which is characterized by the presence of 15 carbon atoms as the base skeleton, organized in the form C6–C3–C6 (A + C – B) (two benzenic rings A and B) and linked by a unit of three carbons that may or not form a third-ring structure (pyran ring C). Flavonoids occur in various forms in nature; they come as either O-glycosides or C-glycosides which play a role in their bioactivities (32). They also occur as aglycones or can be hydroxylated or methylated (33).
Flavones
Flavones are a class of flavonoids commonly found in some food and fruits giving a yellow or orange color. Their chemical structure is characterized by a double bond between C3 and C4, a keto group at C4, and no substitution in C3. Flavones have emerged as important metabolites that are involved in plant signaling and defense (34). They are also involved in protection against UV light (35) and oxidative stress (36); allelopathy (37); lignification (38) and pathogen resistance (39). Some of the better-known flavones include luteolin, wogonin, apigenin, tangeretin and chrysin.
4’,5,7-Trihydroxyflavone, also known as apigenin which can be synthesized through a two-step pathway is present in black and green tea (40). Apigenin has been shown to have some good activities against leukemia cell lines including suppression of cell proliferation, induction of cell cycle arrest and induction of apoptosis in leukemia cell lines (41, 42). Also, apigenin when combined with etoposide or cyclophosphamide-induced apoptosis via the mitochondrial pathway, increases the expression of pro-apoptotic cytochrome c, SMAC/DIABLO, and HTRA2/OMI, which promoted caspase-9 and -3 activation (43). Interestingly, apigenin has low intrinsic toxicity to normal cells.
Flavonols
Flavonols are a class of flavonoids that have the 3-hydroxyflavone backbone; having a double bond between positions 2 and 3 and an oxygen (a ketone group) in position 4 of the C ring, like flavones from which, however, they differ in the presence of a hydroxyl group at the position 3 (IUPAC name: 3-hydroxy-2-phenylchromen-4-one). They are distinct from flavanols like catechins. They are colorless molecules found mainly in the skin and leaves of fruits and vegetables since their biosynthesis is stimulated by light. The majority of flavonols exist as O-glycosides and rarely as C-glycosides (44). They are also very diverse in methylation and hydroxylation patterns along with flavones; they are perhaps the largest subgroup of flavonoids in fruits and vegetables (27). Some fruits and vegetables rich in flavonol include elderberry juice, rocket lettuce, red onions, fresh cranberries, fresh figs, apples, fresh capers, dried parsley and tea. The consumption of flavonols is found to be associated with a wide range of health benefits including antioxidation (45), anti-inflammatory (46), and anti-obesity (47) and reduced risk of vascular disease. The major flavonols that are well-studied include kaempferol, quercetin, fisetin, isorhamnetin, and myricetin. Recent studies have shown that flavonol has good anticancer activities including against leukemia (48). Quercetin has been shown to induce cell death via downregulation of VEGF/Akt signaling pathways and mitochondria-mediated apoptosis in AML cells (49). The cell death is caspase-dependent apoptosis, and this also depends on the decrease of mitochondria membrane potential (MMP) and Bcl-2 proteins induced by quercetin. Kaempferol was shown to decrease cell viability in tested acute promyelocytic cell lines with an associated decrease in Akt, BCL2, ABCB1, and ABCC1 genes expression, while the expression of CASP3 and BAX/BCL-2 ratio were significantly increased (50). Recently, an O-methylated flavonol was shown to target multiple kinases that play critical roles in survival signaling in AML, including FLT3, MNK2, RSK, DYRK2 and JAK2 (51). Thus, it can be developed as a novel therapeutic for drug-resistant acute myeloid leukemias.
Flavan-3-ol
Flavan-3-ol also known as flavanol or dihydroflavonols are the 3-hydroxy derivatives of flavanones. Flavan-3-ol are considered the most complex subclass of flavonoids, ranging from the simple monomers to the oligomeric and polymeric proanthocyanidins. In the monomeric form, they have two chiral centers at C2 and C3 which give rise to four isomers for each level of B-ring hydroxylation (52) and also the absence of a double bond between C-2 and C-3. Unlike other flavonoids, they rarely exist as glycosides in plants (53) flavanols are found in common foods, including cereals, legumes, fruits, vegetables, forages, hops, beers, red wine, tea, cocoa, grapes, and apples. They are known to exhibit health benefits including acting as antioxidants, anticancer, cardioprotective, anti-microbial, anti-viral, and neuroprotective agents. Some of the well-known flavan-3-ol include: (+)-catechin; (+)-gallocatechin; (–)-epicatechin; (–)-epigallocatechin; (–)-epicatechin 3-gallate; (–)-epigallocatechin 3-gallate; theaflavin; theaflavin 3-gallate; theaflavin 3′-gallate; theaflavin 3,3′-digallate; and thearubigins (54). A few of the health benefits of flavan-3-ol include: acute promyelocytic cell lines treated with various concentrations of catechin significantly reduced their proliferation, and induced cell apoptosis, in association with mitochondria damage, ROS production and caspase activation (55). Epigallocatechin 3-gallate (EGCG) inhibited multiple myeloma cell line U266 proliferation and induced apoptosis by targeting EZH2 and modulating the mitochondrial apoptosis pathway (56). In a similar experiment, EGCG treatment reversed leucocytosis, anemia and thrombocytopenia, and prolonged survival of PML/RARα mice; in combination with all-trans retinoic acid (ATRA) yielded increased expression of CD15 marker (57).
Flavanones
Flavanones are an important group of flavonoids also called dihydroflavones. They have two benzene rings, A–B bound by a dihydropyrone ring C, with chirality at C3 of the C ring, and no double bond between C-2 and C-3 which is the only difference between flavones and flavanones (27). They occur mainly as the S- or (–)-enantiomer with the C-ring attached to the B-ring at C-2 in the α-configuration (58). Like some other groups of flavonoids, flavanones also do occur as hydroxyl, glycosylated, and O-methylated derivatives. They are generally found in almost all citrus fruits and are responsible for the bitter taste of their juice and peel (59). Some examples of flavanones include Hesperitin, naringenin and eriodictyol. Flavanones found in citrus have some pharmacological activities including anti-inflammatory (60), and antioxidation (27). Some flavanones have been reported to possess anticancer properties through the regulation of some key pathways (61).
Isoflavones
Isoflavones are a distinct group of flavonoids that have the B-ring attached at C-3 rather than at the C-2 position of the pyran ring, a feature that distinguishes them from flavones are found almost exclusively in leguminous plants where they play a role in plant-microbe interactions (62). Isoflavones are also known to act as phytoalexins in plants i.e., compounds produced by the plants during stress or pathogen attacks (63). They are often referred to as phytoestrogens because of their similarity to 17-β-estradiol. Isoflavones may occur as aglycons or as glycosides (64), but their biological activity is from their aglycones (65). Sources of isoflavone include soybeans, chickpeas, fava beans, pistachios, peanuts, and other fruits and nuts (66). Examples of isoflavone include Genistein (7,4’-dihydroxy-6-methoxy isoflavone), daidzein (7,4’-dihydroxyisoflavone), glycitein (7,4’-dihydroxy-6-methoxy isoflavone), biochanin A (5,7-dihydroxy-4’-methoxy isoflavone), and formononetin (7-hydroxy-4′-methoxy isoflavone). Isoflavones are known to have health benefits which can also be seen in the increased number of isoflavone-containing nutritional health products. Some of these health benefits include the prevention of osteoporosis (59, 67), cardiovascular diseases (68), antioxidation and anti-inflammatory (69). It also has chemopreventive and chemotherapeutic roles, especially in hormone-dependent cancers (70). In a recent meta-analysis, the consumption of soy isoflavones was reported to reduce the risk of breast cancer in pre-menopausal and post-menopausal women (71). Genistein and daidzein inhibited cell migration, invasion, proliferation and sphere formation, and induced cell cycle arrest and apoptosis in metastatic ovarian cancer models (72). Genistein is also reported to have an antiproliferative effect on leukemia (73), lymphoma (74) and myel2oma (69, 75).
Phenolic acids
Phenolic acids are aromatic acids consisting of an aromatic ring with one or more hydroxy or methoxy groups. Phenolic acids are divided into two major subgroups: hydroxybenzoic and hydroxycinnamic acid. Hydroxycinnamic acid is more abundant than hydroxybenzoic acid. Hydroxycinnamic acids are secondary metabolites derived from phenylalanine and tyrosine and they all have a C6C3 carbon skeleton with a double bond in the side chain that may have a cis or a trans configuration. They may be present as free carboxylic acids or in bound forms as amides, esters or glycosides (76). Hydroxycinnamic acids share a similar pathway of production with the likes of lignins, 89 coumarins, lignans, stilbenes, chalcones, anthocyanins and flavonoids (77). They are well-distributed in most plants including many species that are consumed as food or processed into beverages. They are abundant in fruits, vegetables, cereals, legumes, soybeans, coffee, and tea (77, 78). The most common hydroxycinnamic acids are ferulic, caffeic, p-coumaric, and sinapic acids (79). On the other hand, hydroxybenzoic acids have a general structure of C6-C1. They can be found in some foods like red fruits, onions and black radish, etc. (21). Examples of hydroxybenzoic acids are gallic, vanillic, syringic, 2,3-dihydroxybenzoic acid (Pyrocatechuic acid), 2,5-dihydroxybenzoic acid (Gentisic acid), 3,4-dihydroxybenzoic acid (Protocatechuic acid), 3,5-dihydroxybenzoic acid (α-Resorcylic acid) and 3-monohydroxybenzoic acid (33, 80). Phenolic acids have many health benefits. These include anti-inflammatory and antioxidative actions (81, 82), antidiabetic (83), and hepatoprotective (84), and antineoplastic (85, 86). Caffeic acid (3,4-dihydroxycinnamic acid) phenethyl ester (CAPE) is reported cytotoxic and anti-proliferative actions on RPMI 8226, H929, U266 and ARH77 cell lines, and also synergises with bortezomib in growth inhibition and reduction of NF-kB binding activity and IL6 levels (87). In preclinical studies, caffeic acids and its analogues have also been reported to downregulate specificity protein 1 and IKZF1-IRF4-MYC axis in myeloma cells including cell lines resistant to immunomodulatory drugs lenalidomide and pomalidomide (88). Gallic acid (3,4,5-trihydroxy benzoic acid) was observed to significantly induce apoptosis in AML cell lines via a caspase-dependent pathway in a dose-dependent manner and augment some chemotherapy agents’ efficacy (89). It is also reported to induce apoptosis in the Jurkat cell line (90).
Stilbenoids
Stilbenoids are non-flavonoid polyphenols just like the lignans, coumarins and xanthones (91). They are hydroxylated derivatives of stilbene with a C6–C2–C6 structure. Stilbenoids can be either monomers or polymers. They do exist as aglycones or glycosidic conjugates and can be further processed by methylation, glucosylation and prenylation (92). Like isoflavones, stilbenoids are regarded as plant phytoalexins (92, 93). They are found in some foods such as grapes, rhubarb, passion fruit, berries, white tea and red wine (94, 95). Stilbenoids demonstrate various health benefits, including antioxidant, anti-inflammatory (96), anti-microbial activities (97) and anti-neoplastic (98, 99). In leukemia, a stilbenoid tyrosine kinase inhibitor was once reported to inhibit the proliferation of the Jak2-V617F expressing human erythroleukemia in a caspase-dependent manner as well as the cleavage of PARP (100).
Molecular activities of polyphenols
From a clinical point of view, hematological malignancies (HM) are generally incurable. While therapeutic options have improved, disease relapse and resistance are rather not uncommon. Chemotherapy and immunotherapy remains the mainstay of treatment, but not without their associated side effects. For example, treatment with CD19 chimeric antigen receptor (CAR) T cells the most recent approved innovative therapy for patients with lymphoid malignancies, especially with relapsed/refractory disease (101) is not without serious adverse effects. Its high therapeutic response rate is accompanied by serious side effects such as cytokine release syndrome (CRS) and severe neurotoxicity termed immune effector cell-associated neurotoxicity syndrome (ICANS) (102). In a recent multicenter observational study of patients treated with CD19-targeted CAR T-cell therapy for relapsing lymphoma, 43% developed neurotoxicity and more than half of the patients (64%) had grade 1–2 severity and 34% had grade 3–4; a further 80% developed CRS (103). These side effects along with the fact that some patients do not respond to CAR T cell therapy or relapse after remission underscore the need for newer therapies. One potential source of therapeutics can be polyphenols; albeit some of the pathways and strategies muted to enhance CAR T cell therapy are already known targets of polyphenols (104).
Like many approved antineoplastic drugs, polyphenols target different molecular pathways that are involved in carcinogenesis. Some of these targets are involved in cell signaling, proliferation and survival, cellular stress response, apoptosis, etc. For example, mutations in some components of the NF-kB pathway especially its regulators like NFKB2, TRAF2, TRAF3, CYLD, NFKB1, TACI, NIK, REL, NFKB2, IKBA, CYLD, NEMO, etc., that are involved in both the canonical and non-canonical pathway plays a role in multiple myeloma development (105, 106). Resveratrol, a stilbenoid is reported to prevent the ubiquitination of NEMO and IKK-mediated NF-κB activation (107), and mangiferin, a xanthone, is observed to cause a decrease in the expression of phosphorylated NF-κB-inducing kinase (NIK) (108). With their various actions similar to other approved drugs, polyphenols represent prospective therapeutic options for hematological malignancies.
The phosphatidylinositol 3-kinase/protein kinase B pathway
The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) and the mammalian target of rapamycin (mTOR) signaling is one of the most important intracellular pathways. It is involved in the control of many physiological cellular processes as well as the development of malignancies through cell growth, proliferation, and survival (109) (Figures 3, 4). They also play a role in metabolism. The activation of the PI3K/AKT pathway reprograms cellular metabolism through increased activities of nutrient transporters and metabolic enzymes in cancer cells (110). The activation of the PI3K/AKT signaling is downstream of a network of receptor tyrosine kinases (RTKs), cytokine receptors, integrins, and G protein-coupled receptors (GPCRs). Thus, the PI3K is divided into three classes I, II, and III made up of catalytic and regulatory domains. There are four Class I PI3K isoforms subdivided into Class IA PI3K (PI3K α, β, and δ) and class IB PI3K (PI3K γ); three Class II PI3K isoforms (PI3KC2α, C2β, C2γ) and a single Class III PI3K (111). The Class IA are dimers made up of a regulatory subunit p85 (p85α, p55α, p50α, p85β, p55γ), and a catalytic subunit (p110α, p110β, p110δ). The Class IB also a dimer comprise of the regulatory subunits (p101 or p84) and the catalytic subunit p110γ (112, 113). While PI3Kα and PI3Kβ are ubiquitously expressed in different tissues, PI3Kγ is expressed in T lymphocytes (114), whereas PI3K γ is mainly expressed in B lymphocytes and its precursors (115). When PI3K is activated, it stimulates the phosphorylation of its phospholipid substrate phosphatidylinositol 4,5-bisphosphate (PIP2) to produce the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 then recruits a subset of signaling proteins with pleckstrin homology (PH) domains to the membrane, including 3-phosphoinositide-dependent protein kinase (PDK1) and AKT, resulting in its phosphorylation at threonine-308 and activation (116).
Figure 3. Pl3K/Akt/mTOR pathway.
Figure 4. Targeting Pl3K/Akt/mTOR with different outcomes.
AKT exist in three isoforms: AKT1, AKT 2, and AKT3. AKT is known to phosphorylate a diverse group of downstream substrates including forkhead box protein O (FOXO), glycogen synthase kinase-3 (GSK-3), and Bcl-2 associated death promoter (BAD). It inhibits the proline-rich AKT substrate of 40 kDa (PRAS40) and tuberous sclerosis complex 2 (TSC2) through inhibition of the GTPase activity of the TSC1/TSC2 complex, thereby activating mTOR complex 1 (mTORC1) through the RAS homologue enriched in brain (RHEB) (117, 118). MTORC exist in two different protein complexes form which are mTORC1 and mTORC2. mTORC1 can be directly inhibited by the natural product rapamycin (119). mTORC1 complex consists of a catalytic subunit mTOR, regulatory-associated protein of mTOR (RAPTOR), mammalian lethal with SEC13 protein 8 (MLST8), and the regulatory proteins PRAS40 and DEP domain-containing mTOR-interacting protein (DEPTOR). mTORC1 plays a key role in cell growth through some substrates that include ribosomal S6 kinase-1 (S6K-1) and eukaryote translation initiation factor 4E binding protein-1 (4EBP-1) (120). mTORC1 also regulate other substrates like unc-51-like autophagy-activating kinase 1 (ULK-1), a key regulator of autophagy, transcription factor EB (TFEB), a regulator of lysosome biogenesis, and Grb-10, an insulin-receptor binding protein (121, 122).
The constitutive activation of the PI3K pathway is rather common in hematological malignancies (123, 124) and certain PI3K isoforms are expressed mainly in hematopoietic cells. This gave room for the development and approval of novel PI3K inhibitors and research into other novel ones.
Polyphenols and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin
The PI3K/Akt/mTOR pathway is seen as a prime target because of its frequent activation in many cancers including hematological malignancies (125, 126). Several in vitro and in vivo studies have shown that this pathway has direct effects on multiple cellular functions as earlier mentioned. PI3K signaling is reported to affect every step of carcinogenesis, and it is also shown to be a prognostic factor as well as a predictor of response to chemotherapy (127). Thus, this pathway is targeted in various studies using small molecules and natural products (128). Several polyphenols including quercetin, curcumin, resveratrol, apigenin, etc., are known to exert some antineoplastic actions through several mechanisms including the PI3K/Akt/mTOR pathway. The treatment of the flavonoids isorhamnetin, genkwanin and acacetin against some breast cancer cell lines decreased the levels of PI3Kγ-p110, phospho-PI3K, phospho-AKT, phospho-mTOR, phospho-p70S6K, and phospho-ULK in them, thus showing their potential as an inhibitor of the PI3K/Akt/mTOR pathway (129). Currently, there are about four approved PI3K inhibitors (113), two mTORC1 inhibitors (130) and no Akt inhibitor (131) for the management of cancers. While there haven’t been many studies on the effect of polyphenols on the PI3K/Akt/mTOR pathway in hematological malignancies, a few done shows their efficacy. Quercetin has been reported to modulate AKT signaling leading to attenuation of cell survival, inflammation, and angiogenesis in lymphoma-bearing mice (132). Constitutive activation of Akt has been observed in various types of leukemia (133, 134) which is responsible for the anti-apoptotic mechanisms. Apigenin has been noted to inactivate Akt with concomitant down-regulation of Mcl-1 and Bcl-2 which results in apoptosis (42). Curcumin treatment of pre-B ALL cell lines with various translocations induced dephosphorylation of the constitutive phosphorylated AKT/PKB and downregulation of IAPs (135). In primary CLL B cells, curcumin was also observed to inhibit the constitutive activation of pro-survival pathways including Akt (136).
Some of these effects of the attenuation of the PI3K/Akt/mTOR pathway are autophagy and apoptosis.
Autophagy
Autophagy is a cellular mechanism that leads to intracellular degradation of cell components and organelles through a lysosome-dependent regulated mechanism in order to adapt to metabolic stress and survival (137). Autophagy is controlled by a group of autophagy-related genes (Atg genes) as well as several proteins that play a role in the regulation of initiation of autophagy including mTOR which acts as a sensor for growth factors and nutrient availability. Thus, PI3K/Akt/mTOR pathway is a negative regulator of autophagy (138, 139). Polyphenols are known to induce autophagy in leukemic cells. Resveratrol has been shown to be an autophagic modulator in MOLT-4 and HL-60 cells (140). It also induces autophagy in imatinib-sensitive (IM-S) and resistant (IM-R) K562 cells (141). The polyphenols emodin, cis-stilbene, apigenin and rhein have been reported to induce autophagy of myeloid (K562 cells) and lymphoid leukemia cells (CCRF-CEM) (142). Curcumin has also been shown to have inhibitory effects on leukemia by inducing autophagy. A study by Guo et al. discovered that curcumin induces autophagic cell death in human Philadelphia chromosome-positive acute lymphoblastic leukemia SUP-B15 cells via activating RAF/MEK/ERK pathway (143). Pi3k is known to regulate MEK/ERK signaling (144); ERK and Akt are known to activate MTORC1 signaling thus, promoting autophagy (145). Curcumin use has also been associated with the autophagic death of the CML cell line K562 cells (146). A curcumin derivative has also been shown to induce autophagy in the THP-1 cell line (147). Polyphenols have so far demonstrated the ability to induce autophagy in hematological malignancies.
Apoptosis
Apoptosis is a form of cell death. It is divided into two, namely: the extrinsic pathway, which is dependent on caspase 8 activation and mediated by death receptors; and the intrinsic pathway which is caspase 9-dependent and mediated by mitochondria (148). Dysregulations have been identified in these two pathways which are associated with pathogenesis, prognosis and resistance to standard chemotherapeutic agents. Several studies have shown that the deregulation of apoptosis is a common and causative event in hematologic malignancies and has prognostic significance (149, 150). The death receptors are members of the tumour necrosis factor receptor (TNFR) family including Fas (CD95), tumor necrosis factor α receptor 1 (TNFR1), tumor necrosis factor α ligand-receptor 1(TRAIL-R1, DR4), tumor necrosis factor α ligand-receptor 2 (TRAIL-R2, DR5), DR3, and DR6. Death-inducing ligands e.g., FasL/CD95 ligand (CD95L), tumor necrosis factor α ligand (TNFα) initiate the extrinsic pathway by interactions with the death receptors. Adaptor proteins are then recruited to the Fas-associated death domain (FADD) and TNF receptor-associated death domain (TRADD) on the death receptor. Inactive forms of some caspase protease families (procaspase 8 and 10) are recruited, forming a “death-inducing signaling complex” (DISC), and resulting in the activation of caspases 8 and 10 (151). There is also the activation of caspase 3, 6, and 7 which lead to apoptotic cell death (148).
The intrinsic pathway on the other hand is a form of regulated cell death initiated by a balance between the proapoptotic and anti-apoptotic BCL-2 family proteins within mitochondria. A series of molecular events involving intrinsic stimuli and BCL-2 family proteins form the mitochondrial outer membrane permeabilization (MOMP) complex resulting in the release of cytochrome c, a second mitochondria-derived activator of caspase (SMAC) and mitochondrial serine protease (Omi). The release of cytochrome c leads to its binding of apoptotic protease-activating factor-1 (APAF-1) and dATP, to form an apoptosome which in turn activates caspase 9. In the process of apoptosome formation, SMAC and Omi inhibit inhibitors of apoptosis proteins (IAP) which are endogenous inhibitors of caspase function (152, 153). Activation of apoptotic caspase 9 shall then lead to the activation of downstream “executioner” caspases.
The complex nature of apoptosis requires that it be closely regulated. Several signaling pathways have been shown to impact apoptosis. The most notable is the phosphatidylinositol 3′-kinase (PI3K) pathway (154). Activated PI3K activates PKB/Akt which leads to the expression of anti-apoptotic genes through the activation of nuclear factor κB (NF-κB) (155). It also influences pro-apoptotic gene expression by inactivating the forkhead superfamily transcription factors AFK and FKHRL1. Activation of Akt is known to inhibit apoptosis through the upregulation of bcl-2 expression (156, 157) and the inhibition of bad (158, 159). Another regulator of apoptosis is the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway which regulates the activity of the bcl-2 family of proteins (160). It is also involved in the ubiquitination of pro-apoptotic proteins BIM, BAD, BIK, etc., for degradation (161, 162).
Several polyphenols have been shown to induce apoptosis in hematological cancers (163). Curcumin treatment of B Pre-ALL cell lines causes downregulation of cIAP1 and XIAP (135). Gossypol a polyphenol isolated from the seed, roots, and stem of the cotton plant (Gossypium sp.) and originally used as a herbal drug in China (164) is known as a bcl-2 inhibitor as well as inducing autophagy in Burkitt lymphoma cells (165, 166). Gossypol compounds have hence been tried in some small clinical trials to determine efficacy (167, 168). Piceatannol induces a Fas/FasL upregulation in U937 cells (169). Resveratrol is observed to sensitize carfilzomib-induced apoptosis through the upregulation of SMAC, and downregulation of SIRT1, a positive modulator of survivin (170). Resveratrol also induced apoptosis in K562 cells through the activation of p38 and JNK, and the inhibition of ERK; it also increased caspase 3 cleavage as well as the expression of bim (171). In the treatment of multiple myeloma cells with bortezomib and gambogenic acid, a prenylated xanthone was observed to induce apoptosis via the activation of PARP cleavage, P53, Caspase-3 cleavage and Bax and inhibition of Bcl-2 expression (172). Curcumin also synergises with carfilzomib to significantly downregulate the nf-kb pathway (173). In a recent clinical study, Ramakrishna et al. showed that oral administration of up to 8 g of curcumin daily to MM patients is well tolerated and can decrease the paraprotein load, free light chains, bone turnover, and% plasma cell dyscrasia (174). Zaidi et al. reported similar activities of curcumin in a multiple relapsed MM patient on curcumin (175). quercetin and kaempferol derivatives have been shown to induce activation of caspase-3, -8 and -9, subsequent cleavage of PARP, and significantly suppressed XIAP, cIAP-1 and cIAP-2 in a dose-dependent manner along with the upregulation of proteins (Bax and Bad), and downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL) and cytochrome c release (176).
These studies provide considerable evidence that polyphenols can induce apoptosis in hematological cancers, through the activation of death receptors, upregulation of pro-apoptotic proteins and induction of caspase 8, 3, and 9. Moreso, PI3K/Akt/mTOR pathway is an important pathway for the growth, survival and chemoresistance of leukemic cells. It is targeted especially in lymphoproliferative neoplasms (113, 177). Polyphenols can therefore be attractive candidates for this pathway in the management of hematological malignancies.
Cell cycle
The cell cycle is a complex process that involves numerous regulatory proteins that direct the cell through a specific sequence of events culminating in mitosis and the production of two daughter cells. It is a fundamental step in the growth, development and maintenance of living things. It has two basic stages it passes through to divide and produce new cells. These are the interphase (the S phase, where cells duplicate their DNA contents through DNA replication; the G1 phase, where cells synthesize mRNA and proteins in preparation for mitosis; G2 phase, a period of rapid protein synthesis. It is a point in the G2 phase of the cell cycle where cells become arrested in response to DNA damage) (178, 179); M (Mitotic) phase, chromosome segregation and cell division take place at this phase (consists of prophase, metaphase, anaphase and telophase). The cell cycle is a closely-controlled process by a family of serine/threonine protein-dependent kinases known as cyclin-dependent kinases (CDKs) (180) (Figure 5). Their regulatory subunits are known as cyclins and are involved in the regulation of CDK’s activities. CDK activities are also regulated by endogenous CDK inhibitors. There are two families of CDK inhibitors, the inhibitor of cyclin-dependent kinase 4 (INK4) family and the CDK interacting protein/kinase inhibitory protein (Cip/Kip) family (181, 182). The INK4 family includes p15 (INK4b), p16 (INK4a), p18 (INK4c), and p19 (INK4d), whilst the Cip/Kip family includes p21 (Cip1/Waf1), p27 (Cip2), and p57 (Kip2) (183, 184). They play a role in the inhibition of the CDK-cyclin complexes, thereby halting the cell cycle progression. Some other proteins play a role in the cell cycle. These are proto-oncogenes and they fall into two categories: gain-of-function mutations in proto-oncogenes, which enhance cell growth and division; and loss-of-function mutations in tumor suppressor genes that inhibit unhindered cell growth and cell cycle checkpoint activation among other things (185). The loss of function mutations includes the p53 and retinoblastoma (Rb) protein (186) while the gain of function mutations include K-ras and Bcr-abl protein (187). The Rb family of proteins play a key role in the regulation of the cell cycle progression from the G1 to S phase. This function is achieved through the negative regulation of the E2F transcription factors and the binding to histone deacetylases and chromatin remodeling complexes. Mitogenic signaling leads to the activation of CDKs, especially CDK 4 and 6 which phosphorylates and inactivates Rb protein leading to E2F activation and its target genes (188). The p53 protein is an important element in cell cycle regulation and apoptosis. It is called the guardian of the genome because of its role in tumor initiation. It performs multiple regulatory functions by receiving information, modulating and relaying the information, and carrying out multiple downstream signals such as cellular senescence, cell metabolism, inflammation, autophagy, and other biological processes which control the survival and death of abnormal cells (189, 190). Mdm2 and MdmX are negative regulators of p53. Mdm2 promotes Lys ubiquitination at the C-terminus, targeting p53 for proteasomal degradation (191). Due to its central regulatory role in tumor development, it is known as a tumor suppressor protein (192, 193). The p53 protein is reported to be the most mutated gene in most human cancers with a frequency of about 50% (194), however, it has a low incidence in hematological malignancies (195, 196).
Figure 5. The cell cycle.
Polyphenols and cell cycle arrest
The cell cycle has been observed as one key area for cancer cell proliferation. The cyclins and CDKs play an important role in the cell cycle and are known to be up or downregulated in several cancers including lymphomas and leukemias (197). Resistance to chemotherapy has been linked to the G0 phase of the cell cycle as well as the overexpression of some cyclins in cancers (198–200). Given the importance of the cyclins and CDKs for cell cycle control, these make attractive targets for chemotherapeutic intervention in hematological malignancies. Busa et al., reported that palbociclib, a breast cancer-approved CDK4/6 inhibitor suppressed AML in patient-derived Xenograft (201). Thus, G0/G1 phase and cyclin D1 are potential targets for the management of hematological malignancies (202, 203). Polyphenols and polyphenol-rich extracts have equally shown potential as cell cycle inhibitors (204, 205). Shih et al. showed that the polyphenol fraction of jelly fig (Ficus awkeotsang Makino) achenes caused G2/M cell cycle arrest in U937 cells (206). Resveratrol has been reported to arrest cell cycle progression in HL-60 leukemia cells by inducing the overexpression of cyclins A and E (207). Resveratrol has also been reported to inhibit cell cycle progression among other activities in acquired drug-resistant cancer cell lines including leukemia (208). Punicalagin, quercetin and delphinidin also induced G0/G1 and S phase cell cycle arrest in Jurkat, MOLT-3, HL-60, THP-1 and KG-1a leukemia cell lines (209, 210). Pomegranate juice has also been muted to exert some antileukemic effects; this was reported in a 44-year-old Caucasian man who was diagnosed with a T cell lymphoblastic lymphoma but had spontaneous remission without any chemotherapy treatment. The patient admitted to regularly drinking pomegranate juice, during the period after diagnosis. However, there was a tumor recurrence. Pomegranate juice extracts could be speculated to have caused the initial spontaneous remission (211). The pleiotropic molecule curcumin has been shown to induce G1 phase arrest in HL-60 cells and G2/M phase arrest in K562 cells (212), upregulate p21 and inhibit cyclin D1 in ML-2 and OCI-AML5 cells (213), and downregulation of cyclin D1, downregulation MDM2 and increase in p53 in multiple myeloma cell line (214). Quercetin, apigenin, emodin, rhein and cis-stilbene have all been shown to act synergistically with doxorubicin and etoposide to cause S and/or G2/M phase cell cycle arrest in lymphoid leukemia cell lines (215). 5-fluorouracil when combined with quercetin, apigenin and rhein caused a synergistic decrease in ATP levels, and induction of cell-cycle arrest in leukemia cell lines (216). The chalcone butein has also been shown to markedly downregulate the protein expression levels of CDK4, CDK6, cyclin D1, cyclin D2, cyclin E and phospho-pRb in HTLV-1-infected T cells, both in vitro and in vivo suggesting its therapeutic potentials in ATLL (217). It is thus evident that polyphenols are capable of both reducing CDKs, whilst increasing p53, resulting in cell cycle arrest and highlighting their therapeutic potential in preventing cell cycle progression and cell division in hematological malignancies.
The kynurenine pathway
The kynurenine pathway (KP) is a metabolite pathway that is involved in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+) (218). Tryptophan is the starting block of the pathway and 99% of it is catabolised in this pathway, if not incorporated into proteins via protein synthesis (Figure 6) (219). The conversion of tryptophan to kynurenine is mediated by either indoleamine 2,3-dioxygenase (IDO) or by tryptophan 2,3-dioxygenase (TDO) as rate-limiting enzymes. The KP is involved in the depletion of serum tryptophan and its conversion to biologically active metabolites. These metabolites include kynurenic acid, 3-hydroxykynurenine, anthranilic acid, xanthurenic acid, picolinic acid and quinolinic acid (Figure 7). These metabolites, along with the enzymes responsible for their production, have implications in a plethora of disease states. Chief among these enzymes are the rate-limiting enzymes that aid the conversion of tryptophan to kynurenine, indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). IDO is a heme-containing enzyme physiologically expressed in a number of tissues and cells. IDO is encoded by the IDO1 gene located on chromosome 8. IDO1is primarily regulated at the transcriptional level, and the regulatory proteins involved are (i) NF-KB (220), (ii) the aryl hydrocarbon receptor (AhR) (221, 222), and (iii) CTCF (223). Endogenous NO production can cause proteasomal degradation of IDO1 (224), but IFN-gamma can upregulate mRNA expression (225). IDO1 and its cognate tryptophan metabolites have been described to have immunomodulatory properties. Kynurenine can control T-cell immune responses especially through the generation of FoxP3+ T regulatory cells via AhR binding (226, 227); 3-hydroxykynurenine aids the depletion of CD4(+) T, CD8(+) T, B lymphocytes and induce the action of regulatory T cells (228); 3-Hydroxyanthranilic acid has immunomodulatory effects on macrophages and lymphocytes through the inhibition of PI3K/Akt/mTOR and NF-κB activation (229, 230) and inhibit Th1 and Th2 cells and increase the percentage of regulatory T cells; quinolinic acid is known to confer resistance to cancers (231); picolinic acid suppresses proliferation and metabolic activity of CD4 + T cells (232).
Figure 6. Kynurenine pathway.
Figure 7. Cheemical structure of kynurenine pathway metabolites.
IDO1 activity has been associated with many diseases including hepatitis B infection (233), malaria (234), psychiatric disorders (235), atherosclerosis (236) as well as cancer and the immune escape often observed in tumors (237, 238). IDO1 was originally thought to be an anti-cancer molecule because of its ability to deplete the tryptophan needed for cell metabolism and growth. However, the immunosuppressive ability has shown it is more of a pro-cancer molecule. IDO1 is overexpressed in more than 50% of tumors (239) including hematological malignancies. Like in solid tumors, hematological malignancies are known to create an immunosuppressive environment to foster immunological tolerance of cancer cells. IDO1 has been described as one of the ways used for immunosuppression in several hematological tumors. While its mechanism is not well understood, increased IDO1 and kynurenine are associated with the inhibition of NK cell function (129, 240), activation of T regulatory cells (241); and recruitment and activation of myeloid-derived suppressor cells (MDSCs) (242). All these foster the immune escape of cancer cells. AML cells, but not normal hematopoietic stem cells (HSCs), have been shown to constitutively express IDO1 (243) which in turn causes an increase in circulating CD4 + CD25 + FOXP3 + t cells in AML patients. A recent systematic review by Wells et al. shows that IDO expression in AML is associated with poor prognosis (244) and measurement of IDO and its kynurenine metabolites may be incorporated into prospective prognostic algorithms (245). It also confers a poor prognosis in childhood AML (246, 247). In CLL, kynurenine-treated CLL cells are more resistant to the apoptotic effect of venetoclax, a bcl-2 inhibitor (248). While pro-inflammatory mediators such as tumor necrosis factor-alpha (TNF-α) can induce an increase in IDO activity by acting synergistically with IFN-γ (249), anti-inflammatory cytokines such as interleukin (IL)-10 inhibit IDO activity (250). There is an association between IDO1 expression and cyclooxygenase (COX)-2. Studies have shown that the COX-2 inhibitor celecoxib inhibits IDO-mediated immune tolerance through regulatory T cells as well as suppresses the Interferon-γ-Induced expression of indoleamine 2,3-dioxygenase (IDO) in human leukemia cell lines (251, 252). Thus, suggesting the use of COX-2 inhibitors as potential drugs to circumvent IDO1-mediated immune tolerance in AML. From previous studies, it is known that anti-inflammatory compounds like salicylic acid slow down Th-1 type immune response, slowing down tryptophan breakdown (253). Coffee extracts were also reported to prevent tryptophan breakdown, essentially preventing the effects of kynurenine and other metabolites (254). In recent studies, several flavonoids including baicalein, mangiferin, EGCG, curcumin, etc., have been reported to correct the Th17/Treg imbalance restoring immunocompetence of effector T-cells (255).
The effect of IDO1 and kynurenine metabolites cannot be understated, especially their role in tumor immunology. Preclinical studies in a mouse model show that IDO inhibitor, DL-methyltryptophan suppresses tumor growth and peritoneal dissemination, and increases the efficacy of chemotherapeutic agents (256). Polyphenols are able to regulate these actions and thus can act as an adjunct in cancer immunotherapy (257, 258). Resveratrol has been shown to regulate IDO1 in a JAK/STAT1- and PKCδ-dependent manner (259). Curcumin also inhibited IDO1 in a JAK/STAT1- and PKCδ-dependent manner and also reversed IDO-mediated suppression of T-cell responses (260). However, curcumin does downregulate IDO expression via a COX-2/PGE2-dependant pathway (261). EGCG has been shown to inhibit the transcriptional activities of IDO promoters, IFN-stimulated response element and IFN-γ activation sequence, activated by STAT1 phosphorylation as well as the enzymatic activity of IDO1 (262). This is in contrast to flavones such as apigenin, baicalein, chrysin, and wogonin which inhibit the enzymatic activity of IDO-1 but not mRNA expression (263). Furthermore, EGCG inhibited the expression of COX-2 and the production of Prostaglandin E(2) (264).
Studies have suggested that IDO inhibition could be used therapeutically in cancer treatment especially AML (265). One study showed the use of the IDO inhibitor, 1-methyl tryptophan (1MT) with adriamycin in AML caused significant inhibition of blast cell proliferation and a significant increase in lymphocyte counts when used alone (266). Nakamura et al. also showed that a combination of 1MT and cyclophosphamide is an effective treatment for IDO-positive lymphoma in a model mouse by reducing Tregs and breaking tumor tolerance (267). However, failure of phase III clinical trial (ECHO-301/KN-252) where Epacadostat an IDO inhibitor in combination with anti-PD-1 antibody pembrolizumab was used in metastatic melanoma patients did not demonstrate improved progression-free survival and OS and thus terminated early (268, 269) have pushed for a re-think on the clinical benefits of IDO inhibitors in cancer. However, indoximod, another IDO inhibitor in phase 1 clinical trial was shown to be well-tolerated and induced a high rate of complete remission with MRD-negativity in newly diagnosed AML patients (270). In phase II clinical trial of patients with advanced melanoma, indoximod in combination with pembrolizumab was well tolerated and showed antitumor efficacy that was worth further evaluation (271). A phase II clinical trial of indoximod with chemotherapy and radiotherapy in pediatric cancer patients is currently ongoing (NCT04049669). Other targets of the kynurenine pathway are being muted for cancer immunotherapy such as TDO inhibitors (272) and AhR inhibitors (273). Another proposed option is the use of COX2 inhibitors since COX2 enhance the expression of IDO1 in tumors (274, 275). Polyphenols do inhibit COX-2 in cancer cells (276, 277) Celecoxib have also been shown to exert antineoplastic activity in AML cell lines (278) as well as in CML cell line (279). Polyphenols can be used as immunomodulatory agents in combination with some established therapies to attenuate the kynurenine pathway or enhance cellular immunity in hematological malignancies. In a clinical study of elderly AML patients, green tea was reported to exert an immunomodulatory effect in combination with low-dose cytarabine (280). Various studies have shown that the expression of IDO1 in AML portends a poor prognosis (244, 281, 282). Targeting hematological malignancies with IDO1 or COX2 polyphenolic inhibitors may be another therapeutic option.
Polyphenols in hematological malignancies: Clinical studies
Preclinical studies have shown the efficacy of various polyphenols such as curcumin, apigenin, EGCG, quercetin, resveratrol, etc., in cancer. They have been studied extensively both in vitro and in vivo by various groups and found to have good activity against different types of cancer. However, clinical studies using natural products including polyphenols are still in infancy and are often targeted at improving the efficacy of standard chemotherapy and also reducing the adverse reactions from chemotherapy. Most clinical trials are however, targeted at solid tumors (33). This may be because of the successes recorded in the non-phytochemical-based therapies especially the immune-based ones (283). The Food and Drug Administration (FDA) from 2011 to 2021 approved 52 new drug registrations for hematological malignancies; 29 of them were for small molecule drugs and 23 of them were for macromolecules (284). Flavopiridol (Alvocidib) a plant-derived semisynthetic flavone that acts as a cyclin-dependent kinase inhibitor was given an orphan drug designation in CLL, but subsequent studies showed it has significant activity against CLL as well as significant toxicities (285). Some other phase II studies as a combination therapy in AML showed it had higher rates of complete remission and a similar toxicity profile when compared to chemotherapy-only treatment (286, 287). In a recent phase II trial of three novel regimens against AML, the flavopiridol combination therapy regimen had a higher response rate than the other two regimens showing it could be pursued for further clinical development (288). Recently, a novel flavopiridol formulation was developed which showed improved pharmacokinetics and efficacy against AML both in vitro and in vivo (289). This shows the potential of polyphenols in leukemia management.
In multiple myeloma, curcumin and curcumin analogs in clinical trials were reported to have significant activity and clinical response (290). In a cohort study of 52,000 adults followed for 13 years, the consumption of green tea was observed to be inversely proportional to the risk of total hematological malignancies especially AML (291). The use of polyphenols in the management of light chain amyloidosis is considered with some interest. A case of improvement in cardiac symptoms of AL amyloidosis in a patient purposely drinking high amounts of green tea have been reported (292, 293).
Some clinical trials on these are still on (NCT01511263, NCT02015312) (294). Similarly, in a phase I and phase II clinical trial with CLL patients (Rai stage 0 to II), green tea extracts with doses ranging from 400 to 2,000 mg showed a good tolerance, as well as a decline in both the absolute lymphocyte count and in lymphadenopathy (295–297). In a cohort of 11 patients with various indolent lymphomas (CLL, follicular lymphoma (FL), Waldenstrom macroglobulinemia (WM), monoclonal gammopathy of undetermined significance (MGUS), and splenic Marginal zone lymphoma (MZL) who were given two bags of green tea daily and followed up, there was a clinical response with improvement in biomarkers and lymphadenopathy (298). In the IDEAL trial, the use of caloric restriction and increased intake of proteins and polyphenol-rich diets boosted the effectiveness of chemotherapy in acute leukemia patients (299). PIM1 kinase positive CLL patients were given quercetin therapy (500 mg twice daily) in a study; clinical response along with zero toxicity were noted (300). In a recent phase I trial, combretastatin a stilbene from the African Bushwillow Combretum caffrum was added to cytarabine in relapsed/refractory AML and it showed an overall response rate of 19% with a significantly longer overall survival in those that achieved a complete remission (301).
Despite the various drawbacks, it is evident that polyphenols are safe for human clinical trials and can serve some purpose in the management of hematological malignancies. These compounds should be considered serious candidates and efforts should be intensified to set up a well-planned clinical trial to consider them for approval.
Delivery system for polyphenols
The roles polyphenols play in cell regulation and cancer formation cannot be understated. They along with other phytochemicals are usually the mainstay of traditional herbal medicine. Wherein polyphenols are an important source of possible therapeutic agents, their major drawbacks are their bioavailabilities and pharmacokinetics. Oral administration of polyphenols has varying absorption potential according to their chemical nature. The presence of functional groups can also affect polyphenol absorption. Overcoming these challenges is needed to get polyphenols into the clinics. One of the ways attempted to overcome this challenge is the synthesis of polyphenol analogs. Analogs have been shown to improve compound stability and their bioavailability (302). The curcumin analog EF24 and EF31have been shown to have increased bioavailability (303) and with good anticancer activity (304, 305). Another set of curcumin analogs GO-Y078 and GO-Y030 were discovered to be 7 to 12-fold more potent growth inhibitors for myeloma cells, and 6- to 15-fold more powerful suppressors of IRF4, JAK/STAT3, PI3K/AKT, and NF-κB pathways than curcumin (306). EGCG synthetic analogs are also known to possess anticancer activities through several mechanisms (307). Thus, polyphenol analogs are one of the ways to improve their bioavailability and efficacy.
Nanotechnology is a promising tool to enhance the efficacy and delivery of drugs. The use of nanotechnology is expected to solve the problem of bioavailability and bioactivities of polyphenols by reducing particle size as a drug. A curcumin chitosan nanoparticle developed was found to have a tenfold increase of curcumin over native curcumin (308). A number of FDA-approved nanodrugs are on the market including vyxeos liposomal used in the management of AML and marqibo for the management of ALL (309). Thus, the aspect of the use of polyphenol-laden nanoformulations as anticancer therapies is a possibility. Curcumin nanodisks have been reported to induce apoptosis in mantle cell lymphoma and with improved bioavailability (310). Resveratrol nanoformulations in combination with standard chemotherapies have been tested across various cancers both in vitro and in vivo with good bioavailability and bioactivity reported (311, 312). Thus, resveratrol-based nanoformulations are being seen as a viable option in cancer treatment (313). A nano-drug delivery system with folic acid-functionalized EGCG showed good bioavailability and enhanced toxicity to ovarian cancer cells both in vitro and in vivo (314) showing potential as a treatment option.
Conjugated antibodies for cancer therapy are a well-developed strategy. They are composed of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker. They target the specificity of a monoclonal antibody to reach target antigens expressed on cancer cells for the delivery of a potent cytotoxic payload. To date, nine conjugated antibodies have been approved by the FDA and more than 80 conjugated antibodies are under clinical development worldwide (315). Examples include inotuzumab ozogamicin a recombinant humanized IgG4 conjugated antibody used in the management of B cell precursor ALL (316). Ozogamicin is the drug conjugate, a natural product from the class of calicheamicins (a class of enediyne antitumor antibiotics derived from the bacterium Micromonospora echinospora). Polyphenol antibody conjugate is also a strategy to deliver drugs to cancer cells. Polyphenol antibody conjugate is also known to improve bioavailability as well as efficacy. Nirachonkul et al. showed that anti-CD123-curcumin-loaded PLGA/poloxamer nanoparticles (anti-CD123-Cur-NPs) exhibited more cytotoxicity than curcumin-loaded PLGA/poloxamer nanoparticles (Cur-NPs) in leukemia stem cells (317). In another experiment, antibody-coupled curcumin was 230-fold more effective in eliminating B16F10 melanoma cells in vitro, and in vivo compared to curcumin alone, and also more efficacious than antibodies against the melanoma surface antigen Muc18 (318). These results show that the conjugation of some polyphenols can be efficacious against some hematological malignancies and can be explored further in clinical trials.
Hybrid combinations, a term coined by Wagner and Efferth in 2017 can be described as a combination of synthetic drugs with chemically defined constituents from plants (secondary metabolites) aiming to increase the pharmacological activity of the formulation and simultaneously reduce the toxic side-effects of the drugs (319). The synergy created by the hybrid combinations increases chemotherapy cytotoxicity and overcome resistance through their multi-target actions (320). Quite many hybrid combinations have been described for various cancer therapies (321). The combination of a chemotherapy formulation of cysteamine-modified cadmium tellurium (Cys-CdTe) quantum dots coloaded with daunorubicin and gambogic acid (GA) nanoparticles displayed a dose-dependent antiproliferative activity on multidrug-resistant lymphoma Raji/DNR cells in vitro and in vivo (322). Also, the curcumin-thalidomide hybrid combination was tested on MM1S, RPMI18226 and U266 human multiple myeloma (MM) cells and observed to generate higher levels of ROS after treatment and other biological activities compared to curcumin alone (323). Similarly some polyphenols especially apigenin have been noted to enhance the efficacy of alkylating agents in leukemia cell lines (324). Hybrid combinations have shown potential, and have even led to the creation of integrative oncology programs in some universities (325).
Future perspectives
This review have shown the potentials of polyphenols and their viability as either alternatives or complimentary options in the management of hematological malignancies. More attention are being focused on polyphenols in recent times probably because of their dexterity and pleiotropic effects. This interest can be seen in the number of recent research articles published over the past two decades. For example, between 1966 and 2004 only four scientific studies were published on gambogic acid, but since 2004 more than 370 reports for its general medicinal applications have been published of which about 260 are on cancers (326). This increased interest have led to additional studies of gambogic acid as a combination therapy with bortezomib to determine efficacy in multiple myeloma (327, 328). A phase II clinical trial also noted its dosage and safety profile in malignant tumors (329), and the fact that it does not cause bone marrow suppression was a plus (330). Unfortunately, like other polyphenols bioavailability is low, thus limiting its clinical potentials (331). In order to improve its clinical efficacy, several delivery systems such as micelles, nanoparticles and structural modifications are being deployed for greater availability (332, 333).
Lately, targeting the immune system have gained much grounds in the management of cancers in general and immune-based therapies are readily available for cancer treatment. The immunomodulatory activities of polyphenols are well documented (334, 335), and they are seen as possible immunoadjuvants (257). For example, apigenin have been shown to reduce the expression of PD-L1 in melanoma cells (336) as well as in K-ras mutant lung carcinoma in vivo (337). A curcumin analog bisdemethoxycurcumin in combination with an anti-PD-L1 antibody was able to cause an increase in CD8 + T cells as well as reduce PD-1 expression in an in vivo mouse model of bladder cancer (338).
Given the complexity of hematological malignancies, the use of combination therapies that target multiple signaling pathways is a standard management practice. Polyphenol fits in well for such combination therapies. However, improving their bioavailability is necessary to achieve their full potentials. It is hoped that one or more of the polyphenols will pass through phase III clinical trials sucessfully and find its way to the clinics.
Conclusion
Taking into account the advances in the areas of pharmacotherapy and hematological cancer research, it is evident that polyphenols have an important role to play hematological malignancies which I propose can come in the form of combination chemotherapy (339) or maintenance therapy (340). However, before polyphenol-based cancer therapies can be deployed to the clinics, further pre-clinical studies and clinical trials would be needed to be done to validate their use. This will ensure safety and standards in the clinical settings.
Author contributions
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Conflict of interest
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Keywords: polyphenols, hematological malignancies, signaling pathways, apoptosis, immunomodulation, combination therapy, clinical trials
Citation: Izuegbuna OO (2022) Polyphenols: Chemoprevention and therapeutic potentials in hematological malignancies. Front. Nutr. 9:1008893. doi: 10.3389/fnut.2022.1008893
Received: 01 August 2022; Accepted: 02 September 2022;
Published: 26 October 2022.
Edited by:
Pasquale Crupi, Council for Agricultural and Economics Research (CREA), ItalyReviewed by:
Mahdieh Darroudi, Mashhad University of Medical Sciences, IranHafiz Makeen, Jazan University, Saudi Arabia
Copyright © 2022 Izuegbuna. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ogochukwu O. Izuegbuna, b2dvaXp1QGdtYWlsLmNvbQ==; orcid.org/0000-0001-8395-8967