The Anti-Leukemic Activity of Natural Compounds

<jats:p>The use of biologically active compounds has become a realistic option for the treatment of malignant tumors due to their cost-effectiveness and safety. In this review, we aimed to highlight the main natural biocompounds that target leukemic cells, assessed by in vitro and in vivo experiments or clinical studies, in order to explore their therapeutic potential in the treatment of leukemia: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). It provides a basis for researchers and hematologists in improving basic and clinical research on the development of new alternative therapies in the fight against leukemia, a harmful hematological cancer and the leading cause of death among patients.</jats:p>

section_content: Cancer is one of the leading causes of death worldwide and a major challenge for the public health system [1]. The incidence of cancer is constantly increasing and is estimated to increase by 70% over the next 20 years [2]. 

Conventional anticancer therapies have limited efficacy and are associated with many side effects, such as hepatotoxicity, myelosuppression, or tumor lysis syndrome [3]. Chemotherapy and radiation therapy are frequently correlated with side effects, such as hair loss, loss of appetite, diarrhea, vomiting, liver damage, and neurological disorders [4]. Therefore, it is necessary to find new therapeutic approaches with high efficacy and fewer side effects. The main treatments used in leukemia are radiotherapy, hyperthermia, and chemotherapy. Conventional drug treatment is associated with cytotoxicity and systemic side effects. Therefore, efforts in cancer treatment are focused on finding strategies that can specifically target tumor cells without affecting normal cells [5]. Understanding the molecular mechanisms involved in hematologic cancers is useful in developing of the new therapeutic strategies that target various molecular abnormalities. Recently, there has been an increase in molecularly targeted therapies approved by the FDA in various types of leukemia, but there are insufficient data on the use of these drugs. Thus, in the case of AML, several agents are available for various clinical stages, but the best response rates were obtained by combining new molecularly-targeted treatments with conventional induction chemotherapy [6]. However, the patients experience short-term nausea/vomiting, diarrhea, hair loss, mouth sores, infection, rash; and for the long-term, organ dysfunction, chemobrain, fatigue, neuropathy, as well as resistance of leukemia cells to chemotherapy drugs [7] [8] [9], highlighting the need for the development of less toxic and targeted therapies. trates bone marrow, blood, and other tissues [40]. Additionally, leukemic cells show an increase proliferative capacity and altered hematopoietic differentiation [41]. 

Although most patients with AML experienced partial remission after conventional treatment, such as chemotherapy, they face a number of problems, such as the risk of recurrence, malignant cell resistance, and side effects that diminish the therapeutic value of these treatments [42]. Recurrence is common and the chances of survival are lower for a long term in most cases [43]. 

The main difficulty in the treatment of AML is chemoresistance, and CD34 + AML cells indicate poor prognosis and resistance to spontaneous apoptosis [44]. The emergence of multidrug resistance (MDR) in chemotherapeutic agents is an important obstacle in the treatment of AML. The discovery of new therapeutic agents that can be used to overcome MDR is becoming a challenge in clinical practice [37]. 

To date, polyphenols having cytotoxic effect on AML cells were identified [45]. Deng et al. (2017) demonstrated that luteolin extracted from Reseda odorata L., inhibited the growth of leukemic cell lines by inducing apoptosis through blocking of the RSK1 pathway, as well as by inhibiting their ability to migrate [46]. Other studies demonstrated a selective inhibitory activity against Fms-like tyrosine kinase 3 (FLT3), a highly expressed tyrosine kinase receptor in patients with AML and induced a strong cytotoxic effect in MV4-11 leukemic cells [47]. 

Quercetin has been shown to have an antitumor effect in various experimental models using tumor cell lines, including AML [48] [49] [50]. The antitumor activity of quercetin has been correlated with its ability to inhibit proliferation and induced cell death in AML cells [48, 51]. Quercetin induced AML cell apoptosis through Fas-mediated extrinsic pathways [51] and mitochondrial-derived intrinsic pathways [48]. It also had antitumor effect in acute T-cell lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) [52, 53]. 

Delphinidin showed antiproliferative effects against human acute promyelocytic leukemia (APL) NB4 cell line, a subtype of acute myeloid leukemia. Delphinidin had a cytotoxic effect on NB4 cells, induced activation of caspase-8 and -9 and -3 and decreased Bid expression and mitochondrial membrane potential (∆Ψm). Delphinidine-induced cytotoxicity was more pronounced in NB4 cells compared to normal peripheral blood mononuclear cells (PBMNCs) [54]. 

Genistein has been shown to have antiproliferative activity on tumor cells, being an alternative therapy for the treatment of patients with AML [55]. 

Parthenolide induced specific toxicity to leukemic cells and leukemic stem cells (LSCs) without causing damage to normal hematopoietic cells [56]. Parthenolide has been shown to be effective in inducing specific apoptosis to LSCs in AML. Due to poor bioavailability, the antileukemic activity of parthenolide has not been demonstrated in vivo [57, 58]. In order to increase water solubility, parthenolide analogs have been developed [59] that showed high bioavailability and bioactivity in vivo [57]. The chemically modified parthenolide analog, dimethylamino-parthenolide, showed an oral bioavailability of ~70% compared to intravenous administration in experimental models performed in mice and dogs and an improvement in the selective eradication of AML and of their progenitor stem cells [57]. 

Martínez-Castillo et al. (2018) studied the effects of curcumin in two cell lines derived from chronic and acute myeloid leukemia, respectively, HL-60 and K562 cells. K562 cells showed a higher sensitivity to cytostatic and cytotoxic effects of curcumin compared to HL-60 cells. Curcumin induced G1 phase blockade in HL-60 cells and G2/M phase blockade in K562 cells. Curcumin induced apoptosis in cell lines derived from chronic and acute myeloid leukemia by distinct cellular mechanisms. Thus, curcumin-induced apoptosis in HL-60 cells was caspase-dependent, whereas in K562 cells, they underwent apoptosis in a caspase-independent manner [60]. 

Boswellic acid acetate, a 1:1 mixture of α-boswellic acid acetate and β-boswellic acid acetate, isolated from Boswellia carterri, showed cytotoxic effects against six myeloid leukemia cell lines. This cytotoxic effect was mediated by the induction of apoptosis. Over 50% of cells underwent apoptosis after treatment with 20 mg/mL boswellic acid acetate for 24 h [61]. 

The main pharmacological effects exerted by natural compounds against acute myeloid leukemia (AML) are summarized in Table 1. 

The natural compounds with anti-tumoral activity against acute mieloid leukemia (AML) by in vitro and in vivo experiments or synergic activity with antineoplastig drugs, are summarized in Figure 1. 

dependent kinase 6; Rb-retinoblastoma protein; SCF-stem cell factor; mTOR-mechanistic target of rapamycin; MNCmononuclear cells; ATP-adenosine triphosphate; Akt-protein kinase B; CAPE-caffeic acid phenyl ester; PARPpoly(ADP-ribose) polymerase; BNML-Brown Norway rats with acute myeloid leukemia; pLKB1-phosphorylated liver kinase B1; SIRT1-Sirtuin 1; IL-6-interleukin 6; CSC-cancer stem cell; Shh-sonic hedgehog; Gli-1-glioma-associated oncogene homolog 1; HDACIs-histone deacetylase inhibitors; PTER-pterostilbene; MMP-mitochondrial membrane permeabilization; ERK1/2-extracellular signal-regulated kinase 1/2; JNK1/2-c-Jun N-terminal protein kinase 1/2; MAPKs-mitogen-activated protein kinases; Z-VAD-FMK-carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]fluoromethylketone; LMP-lysosomal membrane permeabilization; AKBA-3-O-acetyl-11-keto-β-boswellic acid; DR4 and DR5-death receptors 4 and 5; NADPH-nicotinamide adenine dinucleotide phosphate; ROS-reactive oxygen species; PTL-parthenolide; bcCML-blast crisis CML; LSCs-leukemia stem cells; Ara-C-cytarabine; RARα-retinoic acid receptor α; p-Akt-Akt phosphoration; WT1-Wilms' tumor 1 gene. 

The natural compounds with anti-tumoral activity against acute mieloid leukemia (AML) by in vitro and in vivo experiments or synergic activity with antineoplastig drugs, are summarized in Figure 1.
section_name: Introduction

section_content: Chronic myeloid leukemia (CML), BCR-ABL1-positive, also known as chronic myelogenous leukemia, is defined as a myeloproliferative neoplasm consisting predominantly of proliferating granulocytes [ 83]. This has an incidence of 1-2 cases per 100,000 adults [ 84]. Approximately 95% of patients with CML have t (9; 22) translocation (q34; q11. 2) [ 85]. CML affects both peripheral blood and bone marrow [ 83]. 

Fusion of the Abelson gene (ABL1) on chromosome 9 with the cluster breakpoint region (BCR) on chromosome 22 generates the oncoprotein BCR-ABL, an active tyrosine
section_name: Natural Compounds in Chronic Myeloid Leukemia (CML)

section_content: In vitro HL-60 and THP-1 cells and primary leukemia cells from AML patients -induced cytotoxicity in AML cell lines and primary leukemia cells from AML patients ↓ cyclin A and cyclin B1 in AML cell lines -induced apoptosis, caspase activation, and PARP cleavage in AML cell lines -induced autophagy but not autophagic cell death in AML cell lines -OSU-A9-mediated cytotoxicity and hypophosphorylation of Akt were dependent on the generation of ROS -suppressed the growth of THP-1 xenograft tumors and prolonged the survival of tumor-bearing athymic nude mice [82] In vivo athymic nude mice

Legend: ↑ increased/up-regulated; ↓ decreased/down-regulated; RSK1-ribosomal S6 kinase 1; RSK (ribosomal S6 kinase); Bad-Bcl-2-associated death promoter; KIBRA-kidney/brain protein; EGCGepigallocatechin-3-gallate; HL-60-human promyelocytic leukemia; DAPK2-death-associated protein kinase 2; 67LR-67 kDa laminin receptor; ATRA-all-trans retinoic acid; VEGFR2-vascular endothelial growth factor receptor 2; PI3K/Akt signaling pathway-phosphatidylinositol 3-kinase/protein kinase B signaling pathway; DNMTs-DNA methyl transferases; STAT3-signal transducer and activator of transcription 3; HDACs-histone deacetylases; TRAIL-apoptosis-inducing ligand; mRNA-messenger ribonucleic acid; NF-κB-nuclear factor-κB; Bcl-2-B-cell lymphoma-2; Bcl-xL-B-cell lymphomaextra-large; Mcl-1-myeloid cell leukemia 1; Bax-Bcl-2-associated X protein; CDK2-cyclin-dependent kinase 2; CDK6-cyclin-dependent kinase 6; Rb-retinoblastoma protein; SCF-stem cell factor; mTOR-mechanistic target of rapamycin; MNC-mononuclear cells; ATP-adenosine triphosphate; Akt-protein kinase B; CAPE-caffeic acid phenyl ester; PARP-poly(ADP-ribose) polymerase; BNML-Brown Norway rats with acute myeloid leukemia; pLKB1-phosphorylated liver kinase B1; SIRT1-Sirtuin 1; IL-6-interleukin 6; CSC-cancer stem cell; Shh-sonic hedgehog; Gli-1-glioma-associated oncogene homolog 1; HDACIs-histone deacetylase inhibitors; PTER-pterostilbene; MMP-mitochondrial membrane permeabilization; ERK1/2-extracellular signal-regulated kinase 1/2; JNK1/2-c-Jun N-terminal protein kinase 1/2; MAPKs-mitogen-activated protein kinases; Z-VAD-FMK-carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone; LMP-lysosomal membrane permeabilization; AKBA-3-O-acetyl-11-keto-β-boswellic acid; DR4 and DR5-death receptors 4 and 5; NADPH-nicotinamide adenine dinucleotide phosphate; ROS-reactive oxygen species; PTL-parthenolide; bcCML-blast crisis CML; LSCs-leukemia stem cells; Ara-C-cytarabine; RARα-retinoic acid receptor α; p-Akt-Akt phosphoration; WT1-Wilms' tumor 1 gene.
section_name: OSU-A9

section_content: Chronic myeloid leukemia (CML), BCR-ABL1-positive, also known as chronic myelogenous leukemia, is defined as a myeloproliferative neoplasm consisting predominantly of proliferating granulocytes [83]. This has an incidence of 1-2 cases per 100,000 adults [84]. Approximately 95% of patients with CML have t (9; 22) translocation (q34; q11. 2) [85]. CML affects both peripheral blood and bone marrow [83]. 

Fusion of the Abelson gene (ABL1) on chromosome 9 with the cluster breakpoint region (BCR) on chromosome 22 generates the oncoprotein BCR-ABL, an active tyrosine kinase that induces cytokine-independent cell proliferation, which causes excessive accumulation of myeloid cells in hematopoietic tissues [86]. The Bcr-Abl oncoprotein activates several downstream pathways, responsible for inducing cell proliferation, loss of adhesion, cell differentiation blocking, and inhibition apoptosis [87, 88]. 

The main pharmacological effects exerted by natural compounds against chronic myeloid leukemia (CML) are summarized in Table 2. 

The natural compounds with anti-tumoral activity against chronic myeloid leukemia (AML) by in vitro and in vivo experiments, are summarized in Figure 2.
section_name: Natural Compounds in Chronic Myeloid Leukemia (CML)

section_content: Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive malignant blood disorder [ 112]. Currently, the T-ALL treatment protocols include high doses of chemotherapeutics, which have significant toxic side effects [ 113, 114]. Natural products with various biological activities and specific selectivity have served as important sources of antitumor agents that have been developed for clinical use [ 115]. 

Anthocyanins, a subclass of flavonoids, are glycosides of anthocyanidins [ 116]. Blueberries are an important source of anthocyanins [ 117]. Anthocyanins showed, antimutagenesis and anti-carcinogenesis activity [ 118, 119]. They have been shown to have a strong antitumor effect by inducing a pro-apoptotic mitochondrial-mediated response [ 120]. 

Anthocyanins from blueberry extract (Antho 50) induced apoptosis in Jurkat cells by decreasing the expression of Polycomb group proteins. This effect was mediated by an increase in intracellular ROS and depolarization of the mitochondrial membrane [ 117]. In another study, two anthocyanins extracted from blackcurrant juice, delphinidin-3-Oglucoside and delphinidin-3-O-rutinoside, induced apoptosis in human Jurkat leukemic cells [ 121]. Additionally, blackcurrant juice and blackcurrant extract inhibited ↓ the viability of of leukemic cells -induced apoptosis of peripheral blood lymphocytes isolated from human CLL patients via mitochondrial pathway -induced the activation of proapoptotic Bax ↓ the expression of antiapoptotic Bcl-2 protein -released cytochrome c from mitochondria into cytosol -activated caspase-3, subsequently leading to the activation of apoptosis of B-CLL cells [90] Quercetin

In vitro K-562 cells -induced apoptosis in K-562 cells -abrogated K-562 cells proliferation ↓ genes expression of HSP70, Bcl-X(L), and FOXM1 -improved Bax, caspase-3, and caspase-8 expression [91] Quercetin In vitro KBM7 cells -inhibited KBM7 cell proliferation -induced cell apoptosis -blocked cell cycle at G1 phase ↓ the mRNA and protein expression of Smoothened and Glioma1 (Gli1) ↓ Bcl-2 and cyclin D1 ↑ p53 and caspase-3 expression -inhibited Hh signaling and its downstream targets in the KBM7 cells [92] Quercetin and curcumin K562 cells -induced changes in several genes in 10 different pathways related to cell proliferation, apoptosis, cell cycle, inflammation, hypoxia, and oxidative stress
section_name: Natural Compounds in Acute Lymphoblastic Leukemia (ALL)

section_content: ↑ ROS levels in CML cells -inhibited NF-κB activation in CML cells -inhibited cell proliferation and arrested cell cycle of CML cells in G0 and G2 phases, correlated with down-regulation of cyclin D1 and cyclin A [111] Legend:↑ increased/up-regulated; ↓ decreased/down-regulated; Bax-Bcl-2-associated X protein; Bcl-2-B-cell lymphoma-2; B-CLL-B-cell chronic lymphocytic leukemia; HSP70-70 kilodalton heat shock proteins; Bcl-xL-B-cell lymphoma-extra-large; FOXM1-Forkhead box protein M1; Gli1-Smoothened and Glioma1; mRNA-messenger ribonucleic acid; Hh-Hedgehog; CDKN1B-cyclin-dependent kinase inhibitor 1B; Akt 1-protein kinase B 1; IFN-γ-interferon-gamma; BTG2-BTG anti-proliferation factor 2; CDKN1A-cyclin-dependent kinase inhibitor 1A; FAS-Fas cell surface death receptor; CFU-Mixcolony-forming unit-mix; BFU-E-burst-forming unit-erythroid; CFU-GM-granulocyte-macrophage colony-forming unit; LTC-IC-long-term culture initiating cell; AIF-apoptosis inducing factor; JAK2-Janus kinase 2; STAT3-signal transducer and activator of transcription 3; AKT-protein kinase B; MAPK-mitogen-activated kinase; JNK-c-Jun N-terminal kinase; ASM-acid sphingomyelinase; cGMP-cyclic guanosine monophosphate; CHES1-checkpoint suppressor 1; PI3K-phosphatidylinositol 3-kinase/protein kinase B; SQSTM1-sequestosome 1; PTEN-tumor suppressor gene phosphatase and tensin homolog; VEGF-vascular endothelial growth factor; miR-196b-microRNA 196b; PARP-poly(ADP-ribose) polymerase; IM-imatinib; PEITC-phenethyl isothiocyanate; Raf-1-proto-oncogene, serine/threonine kinase; ERK1/2-extracellular signal-regulated kinase 1/2; PKC-protein kinase C; ROS-reactive oxygen species; MDR-1-multidrug resistance mutation; MRP-1-multidrug resistance-associated protein 1; NF-κB-nuclear factor-κB; DMAPT-dimethyl amino parthenolide.
section_name: ↓ viability of CML bulk and progenitor cells -induced cell death in CML cells

section_content: Acute T-cell lymphoblastic leukemia (T-ALL) is an aggressive malignant blood disorder [112]. Currently, the T-ALL treatment protocols include high doses of chemotherapeutics, which have significant toxic side effects [113, 114]. Natural products with various biological activities and specific selectivity have served as important sources of antitumor agents that have been developed for clinical use [115]. 

Anthocyanins, a subclass of flavonoids, are glycosides of anthocyanidins [116]. Blueberries are an important source of anthocyanins [117]. Anthocyanins showed, anti-mutagenesis and anti-carcinogenesis activity [118, 119]. They have been shown to have a strong antitumor effect by inducing a pro-apoptotic mitochondrial-mediated response [120]. 

Anthocyanins from blueberry extract (Antho 50) induced apoptosis in Jurkat cells by decreasing the expression of Polycomb group proteins. This effect was mediated by an increase in intracellular ROS and depolarization of the mitochondrial membrane [117]. In another study, two anthocyanins extracted from blackcurrant juice, delphinidin-3-Oglucoside and delphinidin-3-O-rutinoside, induced apoptosis in human Jurkat leukemic cells [121]. Additionally, blackcurrant juice and blackcurrant extract inhibited proliferation, induced cell cycle arrest in the G2/M phase, and apoptosis in Jurkat cells. These effects have been associated with increased expression of p73 and caspase 3, Akt and Bad dephosphorylation, and down-regulation of UHRF1 and Bcl-2 [121]. 

The main pharmacological effects exerted by natural compounds against acute lymphoblastic leukemia (ALL) are summarized in Table 3. 

The natural compounds with anti-tumoral activity against acute lymphoblastic leukemia (ALL) by in vitro and in vivo experiments or antagonizing activity against cytotoxicity of antineoplastic drugs, are summarized in Figure 3.
section_name: Natural Compounds in Acute Lymphoblastic Leukemia (ALL)

section_content: Chronic lymphocytic leukemia (CLL) is the most common type of hematologic cancer in the western countries (22-30%) [ 134, 135]. CLL is a monoclonal lymphoproliferative disorder characterized by the proliferation and accumulation of morphologically mature, but immunologically dysfunctional B-cell lymphocytes [ 136]. CLL B cells interact with their microenvironment, and B cell survival is enhanced by contact with bone marrow stromal cells. Therefore, the lifespan of B cells increases, causing their abnormal accumulation [ 137]. The main sites of the disease include peripheral blood, spleen, lymph
section_name: Natural Compounds in Chronic Lymphocytic Leukemia (CLL)

section_content: In vitro Jurkat and Molt-4 cells -inhibited proliferation, induced apoptosis, and activated autophagy in T-ALL cell lines -antileukemic effect against peripheral blood lymphocyte cells in patients with ALL -inhibited phospho-GSK3β S9 protein levels to inactivate Wnt signaling -suppressed β-catenin protein levels
section_name: Gambogic acid

section_content: Chronic lymphocytic leukemia (CLL) is the most common type of hematologic cancer in the western countries (22-30%) [134, 135]. CLL is a monoclonal lymphoproliferative disorder characterized by the proliferation and accumulation of morphologically mature, but immunologically dysfunctional B-cell lymphocytes [136]. CLL B cells interact with their microenvironment, and B cell survival is enhanced by contact with bone marrow stromal cells. Therefore, the lifespan of B cells increases, causing their abnormal accumulation [137]. The main sites of the disease include peripheral blood, spleen, lymph nodes, and bone marrow [136]. It mainly affects adults [138]. 

Although there are many therapeutic protocols, CLL is still an incurable disease [138]. Current treatment options include conventional chemotherapy, monoclonal antibodies, and hematopoietic transplantation [139]. These standard treatment methods are not sufficient to eliminate all CLL cells and have a number of side effects. Additionally, standard treatment promotes the development of resistance to treatment and most treated patients relapsed. Therefore, it is necessary to develop new therapeutic strategies that could eliminate apoptosis-resistant CLL cells. Recently, there has been a growing interest in the use of agents derived from natural compounds for cancer therapy [140]. 

Bcl-2 plays a key role in regulating cellular responses to treatment due to its proand anti-apoptotic properties [141]. The anti-apoptotic protein Bcl-2 is overexpressed in several hematological malignancies, including CLL. This overexpression is considered to be responsible for defective apoptosis in CLL [142]. 

The effects of polyphenols on cell proliferation, gene regulation, and apoptosis have been studied on several cancer cell lines [143]. Alhosin et al. (2015) demonstrated that a standardized blueberry extract containing 50% anthocyanins (Antho 50) had the ability to induce apoptosis in CLL B cells via the Bcl-2/Bad pathway. They evaluated the pro-apoptotic effect of Antho 50 on CLL B cells from 30 patients and on peripheral blood mononuclear cells (PBMCs) from healthy subjects. The main phenolic compounds in cranberry extract responsible for the pro-apoptotic effect in CLL B cells were delphinidin-3-O-glucoside and delphinidin-3-O-rutinoside. Antho 50-induced apoptosis has been associated with caspase-3 activation, down-regulation of UHRF1, dephosphorylation of Akt and Bad, and down-regulation of Bcl-2 [144]. 

Luteolin significantly induced apoptosis in chronic lymphocytic leukemia (CLL) cell lines by increasing caspase activity and triggering the intrinsic apoptotic pathway [145]. 

The main pharmacological effects exerted by natural compounds against chronic lymphocytic leukemia (CLL) are summarized in Table 5. 

The natural compounds with anti-tumoral activity against chronic lymphocytic leukemia (CLL) by in vitro and in vivo experiments or antagonizing activity against cytotoxicity of antineoplastic drugs, are summarized in Figure 4.
section_name: Natural Compounds in Chronic Lymphocytic Leukemia (CLL)

section_content: Several clinical studies are published in database ClinicalTrials. Gov regarding the anti-tumor action of biactive compounds and synergies with anti-neoplastic therapy of leukemias. 

The effect of genistein was tested in a phase I/II clinical study in combination with decitabine in pediatric relapsed refractory malignancies. Genistein was administered orally twice daily from day 2 to day 21, followed by a 7-day break (clinical trial number: NCT02499861). The aim of the research includes assessment of a tolerated dose of the combination of intravenous decitabine with oral genistein for children with refractory or recurrent solid malignancies and leukemia. The adverse events of the combination therapy and clinical benefit in phase IIa of the study measured by either volumetric MRI for solid tumor or by bone marrow aspiration or biopsy for leukemia at the end of cycles 2, 4, 6, 9, and 12 were assessed. To date, the results are not yet published in the database ClinicalTrials. Gov. 

The efficacy of concomitant administration of curcumin and colecalciferol was investigated in a phase II trial in the treatment of patients with chronic lymphocytic leukemia in stage 0-II, previously untreated and small lymphocytic lymphoma (clinical trial number: NCT02100423). 

Given that green tea extract contains ingredients that can slow the growth of certain cancers, its effect was tested in a phase I/II trial in the treatment of patients with chronic lymphocytic leukemia in stage 0, I, or II (clinical trial number: NCT00262743). In the phase I trial, patients were given orally 400 to 2000 mg of green tea extract (Polyphenon E) twice a day for 6 months [ 158]. In the phase II trial, oral administration of 2000 mg of Polyphenon E twice daily for 6 months was well tolerated [ 159]. Most patients experienced a decrease in absolute lymphocyte count (LAC) and lymphadenopathy following treatment with Polyphenon E [ 158, 159].
section_name: Clinical Trials and Synergic Activity with Conventional Anti-Leukemic Drugs

section_content: In this review, we presented the natural compounds that have shown an antileukemic activity in experimental studies on different cell lines or primary cultures, preclinical and clinical studies, results that could propose them in subsequent therapeutic
section_name: Conclusions

section_content: Several clinical studies are published in database ClinicalTrials. Gov regarding the anti-tumor action of biactive compounds and synergies with anti-neoplastic therapy of leukemias. 

The effect of genistein was tested in a phase I/II clinical study in combination with decitabine in pediatric relapsed refractory malignancies. Genistein was administered orally twice daily from day 2 to day 21, followed by a 7-day break (clinical trial number: NCT02499861). The aim of the research includes assessment of a tolerated dose of the combination of intravenous decitabine with oral genistein for children with refractory or recurrent solid malignancies and leukemia. The adverse events of the combination therapy and clinical benefit in phase IIa of the study measured by either volumetric MRI for solid tumor or by bone marrow aspiration or biopsy for leukemia at the end of cycles 2, 4, 6, 9, and 12 were assessed. To date, the results are not yet published in the database ClinicalTrials. Gov. 

The efficacy of concomitant administration of curcumin and colecalciferol was investigated in a phase II trial in the treatment of patients with chronic lymphocytic leukemia in stage 0-II, previously untreated and small lymphocytic lymphoma (clinical trial number: NCT02100423). 

Given that green tea extract contains ingredients that can slow the growth of certain cancers, its effect was tested in a phase I/II trial in the treatment of patients with chronic lymphocytic leukemia in stage 0, I, or II (clinical trial number: NCT00262743). In the phase I trial, patients were given orally 400 to 2000 mg of green tea extract (Polyphenon E) twice a day for 6 months [158]. In the phase II trial, oral administration of 2000 mg of Polyphenon E twice daily for 6 months was well tolerated [159]. Most patients experienced a decrease in absolute lymphocyte count (LAC) and lymphadenopathy following treatment with Polyphenon E [158, 159].
section_name: Clinical Trials and Synergic Activity with Conventional Anti-Leukemic Drugs

section_content: In this review, we presented the natural compounds that have shown an anti-leukemic activity in experimental studies on different cell lines or primary cultures, preclinical and clinical studies, results that could propose them in subsequent therapeutic protocols of different types of leukemia: acute myeloid leukemia (AML), chronic myeloid leukemia (CML), acute lymphocytic leukemia (ALL), and chronic lymphocytic leukemia (CLL). Mechanistically, they demonstrated the ability to induce cell cycle blockage and apoptosis or autophagy in cancer cells, as well as inhibition of proliferation/migration and tumor progression, antagonizing activity of cytotoxicity exerted by antineoplastic drugs, or exerted synergy with conventional therapy. Although in vitro results are promising, most bioactive compounds have not yet been tested in preclinical or clinical studies. Moreover, some of the compounds are not soluble and therefore have a reduced bioavailability when administered orally (e. g., flavonoids), which reduces their potential. Therefore, special formulations or chemical modification are needed to increase the bioactive potential. Overall, nature provides a wide range of bioactive compounds with anti-leukemic potential, and extensive research is still needed for them to be considered viable therapeutic options for the treatment of various types of leukemia.
section_name: Conclusions

section_name: Institutional Review Board Statement: Not applicable.

section_content: Funding: This research received no external funding.

section_content: Informed Consent Statement: Not applicable.
section_name: Institutional Review Board Statement: Not applicable.

section_name: Conflicts of Interest:

section_content: The authors declare no conflict of interest.
section_name: Conflicts of Interest: