Anti-CML activity of alkaloids.
Abstract
Chronic myeloid leukemia (CML) is a hematological malignancy that arises due to reciprocal translocation of 3′ sequences from c-Abelson (abl) protooncogene on chromosome 9 with 5′ sequence of truncated break point cluster region (bcr) to chromosome 22. The fusion gene product BCR-ABL, a functional oncoprotein p210, is a constitutively activated tyrosine kinase that activates several cell proliferative signaling pathways. BCR-ABL-specific tyrosine kinase inhibitors (TKIs) such as imatinib, nilotinib and ponatinib potently inhibit CML progression. However, drug resistance owing to BCR-ABL mutations and overexpression is still an issue. Natural products are chemical compounds or substances produced by living organisms. They are becoming an important research area for cancer drug discovery due to their low toxicity and cost-effectiveness. Several lines of evidence show that many NPs such as alkaloids, flavonoids, terpenoids, polyketides, lignans and saponins inhibit CML cell proliferation and induce apoptosis. NPs not only differentiate CML cells into monocyte/erythroid lineage but also can reverse the multi-drug resistance (MDR) in CML cells. In this chapter, we review the anti-CML activity of various NPs.
Keywords
- chronic myeloid leukemia (CML)
- BCR-ABL
- TKIs
- natural products (NPs)
- multi-drug resistance (MDR)
1. Chronic myeloid leukemia
Chronic myeloid leukemia (CML) is a hematoproliferative neoplasm that is marked by uncontrolled myeloid cell divisions in the bone marrow [1]. CML arises due to a reciprocal translocation between chromosome 9 and chromosome 22 [(9;22) (q34;q11)], eventually culminating in the genesis of the
The
Targeting Abl kinase is clearly a proven successful strategy to combat CML. First generation tyrosine kinase inhibitor (TKI), imatinib, also known as Gleevac or STI571 inhibited BCR-ABL and suppressed CML progression [4]. Second generation TKIs such as nilotinib, dasatinib & bosutinib and third generation TKIs (Ponatinib) that are more potent to inhibit BCR-ABL kinase are currently used to treat CML [5, 6]. All these TKIs were approved by the US Food and Drug Administration (FDA). TKIs have changed the clinical course of CML. However, mutations in
2. Natural products
Natural products (NPs) represent a large family of diverse secondary metabolites with profound biological activities. NPs are produced in several organisms like bacteria, fungi, plants and marine animals. NPs are inexpensive and have less (or) no side effects; hence, NPs are currently being explored as an invaluable source for treatment of cancerous and infectious diseases. As of 2013, 1453 new chemical entities (NCEs) have been approved by the US FDA, of which 40% are NPs or NP-inspired (semi-synthetic NP derivatives, synthetic compounds based on NP pharmacophores, or NP mimics) [8, 9]. A number of NPs Such as alkaloids, flavonoids, terpenoids, polyketides, lignans, saponins, peptides and plant extracts exhibited potent anti-CML activity.
2.1. Alkaloids
Alkaloids are naturally occurring organic compounds containing heterocyclic ring with nitrogen atom. Alkaloids, widely distributed in plant kingdom, are bitter secondary metabolites synthesized by plants, microbes and animals. They possess several physiological activities like anti-malarial, anti-asthmatic, anti-cancer, anti-bacterial, antiviral, anti-hyperglycemic and vasodilatory activities [10–13]. Their anti-CML activity is described below.
Berbamine (BBM) is a natural bisbenzylisoquinoline product, isolated from traditional Chinese herbal medicine
Camptothecin, isolated from
Capsaicin, an active component of capsicum genus, is a homovanillic acid derivative experimentally is shown to exhibit anti-mutagenic activity [28]. Capsaicin treatment of K562 cells decreased microRNA (miRNA) expression such as miR-520a-5p, a putative target of STAT3. Hence, capsaicin induced apoptosis
Homoharringtonine (HHT), isolated from
Sanguinarine, a benzophenanthridine alkaloid, isolated from blood root plant
Staurosporine, an alkaloid isolated from the bacterium
Tetrandrine is a bis-benzylisoquinoline alkaloid that is isolated from Chinese herb
Alkaloids from plant and microbial source inhibited CML cell proliferation in micromole (μM)/microgram (μg) concentration (Table 1) (Figure 2) [43–66]. Alkaloids are well documented to potently reduce tumor growth in
Alkaloid | Source of isolation | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|---|
Berbamine (bisbenzylisoquinoline alkaloid) | 8 μg/ml | ↓Bcl-2, Bcl-xL, NFκB(nuclear), IKK-α, IKB-α, BCR-ABL, p-BCR-ABL, Hsp90 | [14–17] | |
Camptothecin (quinoline alkaloid) | 57 nM | ↑Bax, cleavage of PARP-1, DNA—PK adducts | [24] | |
Homoharringtonine | 43.89 ng/ml | ↓Bcl-2, NF-κB, p-JAK2, p-STAT5, p-Akt, p-BCR-ABL and ⊥G0/G1 phase | [31, 32] | |
Sanguinarine (benzophenanthridine alkaloid) | – | At 1.5 μg/ml induced apoptosis | [33] | |
Tetrandrine (bis-benzylisoquinoline alkaloid) | – | ↑Caspase 3 mRNA, protein and ↓Bcl-2 mRNA, protein | [39, 40] | |
Ancistrotectorine E (napthylisoqunoline alkaloid) | 70% EtOH extract of | 4.18 μM | – | [43] |
1,2,3-Trimethoxy-5-oxonoraporphine and ouregidion (aporphine alkaloids) | Crude HEX, EtOAc and AQE extracts of | *63 and 64% | – | [44] |
Cathachunine | 9.3 ± 1.8 μM | – | [45] | |
Cepharanthine | – | ↓p-gp | [46] | |
Crebanine | 13 μg/ml | ↓Cyclin A, D & ↑Caspases 3,9,8 & PARP and ⊥G0/G1 phase | [48] | |
Curine | 17.8 ± 5.2 μM | – | [49] | |
Cyanogramide | – | At 5 μM, reversed MDR in K562/ADR | [50] | |
9-Deacetoxyfumigaclavine C | 3.1 μM | – | [51] | |
Evodiamine (quinazolinocarboline alkaloid) | 34.43 μM | – | [53] | |
Naamidine J (imidazole containing alkaloid) | 11.3 μM | – | [54] | |
Salvicine (diterpenoid alkaloid) | 7.82 ± 2.81 μM | ⊥G1 phase | [56] | |
Solamargine (glycoalkaloid) | 5.2 μM | ↑Caspases and ↓Bcl-2 | [57, 58] | |
α-Tomatine (glycoalkaloid) | 1.51 μM | Loss of MMP. ↑Bak, Mcl-1s, AIF and ↓survivin | [59] | |
Tylophora alkaloids (tylophorine, tylophorinine, tylophorindine) | – | Nuclear condensation, ↑Caspases activation, release of cyt.C | [60] | |
5-Chlorosclerotiamide and 10-episclerotiamide (prenylated indole alkaloids) | 44 and 53 μM | – | [61] | |
Eupolauramine and sampangine (azaphenanthrene alkaloids) | 18.97 and 10.95 μg/ml | – | [62] | |
Arthpyrones A, B and C (4-hydroxy-2-pyridone alkaloids) | 0.24—45 μM | [63] | ||
Auranomides A, B and C | *20.48, 76.36 and 5.78% | – | [64] | |
Malonganenones 1–3 (tetraprenylated alkaloids) | 0.35—10.82 μM | – | [65] | |
Virosecurinine | 32.984 μM | ↑PTEN & ↓mTOR, SHIP-2 BCR-ABL, and ⊥G1/S phase | [66] |
Name of NP | Type of NP | Mice strain | Type of CML cells used to induce tumors | Dosage | Mode of administration | Mechanism of action | References |
---|---|---|---|---|---|---|---|
BBM | Alkaloid | Balb/c | K562-r | 60 mg/kg BW | Intravenously | ↓ | [14] |
BBD9 | Analogue of BBM | nu−/− | K562/IR | 15 and 30 mg/kg BW | – | ↓p-BCR-ABL, IKKa, NF-κBp65 | [22] |
Tetrandrine citrate | Alkaloid | nu−/− | K562/IR | 100 mg/kg BW | Orally | ↓BCR-ABL, β-catenin | [41] |
d-Dicentrine | Alkaloid | SCID | K562 | 100 mg/kg BW | Intraperitoneal | ↓tumor size | [52] |
Oroxylin A | Flavonoid | SCID | K562 | 80 mg/kg BW | Intravenously | ↓STAT3 pathway | [76] |
Nobiletin | Flavonoid | Nude mice | K562 | 12.5, 25, 50 mg/kg BW | – | ↓VEGF | [99] |
dEpoF | Polyketide | Nude mice | K562 | 6 mg/kg | Intravenously | Complete tumor regression | [147] |
HSS | Protein extract from | – | K562/ADM | – | – | ↓mdr1, BCR-ABL and sorcin | [177] |
Gambogic acid | Balb/c | KBM5-T315I | 3 mg/kg/2 days | Intraperitoneal | ↓Bcr-Abl, Akt, Erk1/2, and STAT5 | [229] | |
TAF273 | Fraction of | Balb/c | K562 | 50 mg/kg | Intraperitoneal | ↑apoptosis and ↓blood vessel formation | [258] |
NPB001–05 | Piper betle extract | – | T315I | 500 mg/kg | Orally | ↓PI3K/AKT, MAPK pathways | [275] |
Name of NP | NP class | Differentiation of CML cells into | Mechanism of action | References |
---|---|---|---|---|
Capsaicin | Alkaloid | Erythroid cells | ↟GATA-1 promoter | [28–30] |
Staurosporine | Alkaloid | Megakaryocytes | ↟CD61, CD42b and ↓c-myc | [34–36] |
Crambescidin 800 | Alkaloid | Erythroblasts, induction of hemoglobin production | ⊥S-phase | [47] |
Piperine | Alkaloid | Macrophages/monocytes (20/40 μM) | – | [55] |
Apigenin | Flavonoid | Erythroid lineage | ↟ α and ϒ hemoglobin mRNA expression | [87] |
Galangin | Flavonoid | Monocytes | ↟CD61 | [90] |
Genistein | Flavonoid | Erythroid lineage | – | [92] |
EtOH extract of | Plant extract | Monocyte lineage | ↟CD14 | [243] |
EtOH extract of | Plant extract | Granulocytes | ↟CD11b | [250] |
Huangqi (Astragalus membranaceus) | Traditional Chinese medicine | Erythroid lineage | ↟β-globin gene expression | [272] |
2.2. Flavonoids
Flavonoids belong to polyphenolic compounds which are prevalent in plants. They contain two phenyl rings A, B and a heterocyclic ring C (commonly referred as C6-C3-C6 skeleton) and are classified into many major classes like flavones, flavonols, flavanones, flavanonols and isoflavonoids (Figure 3). They exhibit antioxidant, anti-inflammatory, anti-bacterial, antiviral and anti-cancer activities and play a significant role in human health [67–74].
Oroxylin A, an O-methylated flavone, found in the medicinal plant
Quercetin (Q), a major flavonol, found in the kingdom Plantae, exhibits many biological effects including Antioxidant, anti-inflammatory, anti-cancer and anti-diabetic activities [77]. While evaluating the anti-proliferative effect of pytoestrogens, it was found that Q specifically inhibits K562 and MDR K562/A cell growth [78]. When K562 cells were treated with Q at a concentration of 9.2 mg/ml for 72 h, it induced apoptosis and reduced the BCR-ABL levels in CML cells [79]. Combination of Q and ADR was tested on MDR K562/ADR cells. Combined treatment enhanced activation of caspases 3,8 and loss of mitochondrial membrane potential (MMP). Furthermore, it lowered Bcl-2, Bcl-xl and enhanced the p-c-Jun-N terminal kinase and p-p38 mitogen-activated protein kinase (p-p38-MAPK). Q also significantly decreased the p-gp levels [80] and sensitized MDR K562/ADM to DNR and reversed MDR in CML cells [81]. Q inhibited K562 and MDR K562/A in the range of 5–160 μM. Q treatment of K562/ADR cells (5 μM) enhanced accumulation of ADR and, in addition, decreased the expression of MDR-causing proteins like ABC, solute carrier (SLC). Moreover, it reduced Bcl-2, TNF expression reversing MDR in CML cells [82]. Moreover, Q arrested CML cells at G2/M phase [83]. IC50 of Q on K562 and K562/ADR was found to be 11 ± 2 μM and 5 ± 0.4 μM [84]. It also inhibited the Hsp70 levels in CML cells [85]. Q induced apoptosis
In sum, flavonoids not only inhibit the growth of CML cells (Table 4) but also induce their differentiation into erythroid or monocyte lineage (Table 3). Flavonoid fractions of plant extracts also inhibit CML cell proliferation and induced apoptosis [87–109].
Flavonoids/flavonoid fraction | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|
Oroxylin A (o-methylated flavone) | – | ↓CXCR4, PI3K/Akt/NF-κB pathways | [75, 76] |
Quercetin (flavonol) | 11 ± 2 | Loss of MMP. ↑caspases 3,8 & ↓Bcl-2, Bcl-xl, Hsp70, telomerase and ⊥G2/M phase | [77–86] |
Apigenin (flavone) | – | ↓Mcl-1, Bcl-2 & ↑caspases activation and ⊥G2/M phase | [87, 91] |
Baicalein (flavone) | – | ↑ caspase 3, Fas gene and ⊥ S phase | [88] |
Fistein (flavonol) | – | Induced apoptosis and Altered JAK/STAT, KIT pathways and ⊥S & G2/M phases | [89, 97] |
Galangin (flavonol) | – | ↓pRb, cdk4, cdk1, cycline B & Bcl-2 levels and ⊥G0/G1 phase | [90] |
Kaempferol (flavonol) | – | ↟ Bax, SIRT3, caspases 3, 9 and ↓ Bcl-2 | [93] |
Myricetin (flavonol) | – | Myricetin pre-treatment enhanced Natural killer cells to kill K562 | [96, 97] |
Naringenin (flavanone) | – | ↟ p21/WAF1 and ⊥G0/G1 phase | [98] |
Tamarixetin (o-methylated flavonol) | – | ↟ cyclin B1, Bub1, p21, caspases and ↓tublin polymerization | [100] |
3,5-Dihydroxy-6,7,3′,4′-tetramethoxyflavone (DHTMF) (polymethoxyflavone) | 7.85 μg/ml | ↟caspases 3, 9 & PARP cleavage | [101] |
2″,3″-Diidroochnaflavone ( | 89 μM | – | [102] |
Isochamaejasmin (biflavonoid) ( | 24.51 ± 1.62 μM | ↟caspases 3, 9 and PARP cleavage | [103] |
Protoapigenone (total flavonoid fraction of | 0.9 μg/ml | – | [104] |
Total flavonoids from | – | ↓Bcl-2 and ↑Fas, TRAIL & DR5 | [105] |
Total flavonoids of | 98.63 mg/L | ↓ cyclin D1 mRNA levels and ⊥G0/G1 phase | [106] |
Total oligomer flavonoids of | 196 μg/ml | – | [107] |
Flavonoid-enriched | 165 and 210.73 μg/ml | – | [108] |
Epigallocatechin-3-gallate ( | 50 μM | ↓CyclinD1, CDC25A and ↑TGF-β2 | [109] |
2.3. Terpenoids
Terpenoids are naturally occurring products representing the largest secondary metabolites. Approximately 60% of NPs are terpenoids. They are basically made up of five carbon isoprene units (IU). Depending upon the number of isoprene units present, terpenoids has been classified into hemiterpenoids (1 IU), monoterpenoids (2 IU), sesquiterpenoids (3 IU), diterpenoids (4 IU), sesterterpenoids (5 IU), triterpenoids (6 IU), tetraterpenoids (8 IU) and polyterpenoid (n IU). They have been documented to possess antioxidant, anti-inflammatory, anti-helminitic and anti-cancer activities [110–115].
Sesquiterpenoids, diterpenoids, sesterterpenoids and triterpenoidshas been shown to potently inhibit CML cell proliferation and induce apoptosis (Figure 3) (Table 5) [116–144]. Other diterpenoids such as scapaundulin C (from
Terpenoid class | Name of terpenoid | Source of isolation | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|---|---|
Sesquiterpenoids | EM23 | 10.8 μM | ↟ caspases, PARP cleavage and ↓ NFκB. Loss of MMP | [116] | |
Diterpenoids | Caesalminaxin D and H | 9.9 ± 1.7 and 9.2 ± 0.9 μM | – | [117] | |
Gukulenin A and diterpenoid pseudodimers (2–5) | *0.26 ± 0.03, 0.12 ± 0.01, 0.44 ± 0.01, 0.32 ± 0.05 and 0.04 ± 0.09 μM | – | [118] | ||
Diterpene compounds 11, 12, 13, 14 and 15 | petroleum ether soluble fraction of the aerial parts of | 86.4, 66.3, 91, 45.1 and 58.6 μM | – | [119] | |
7β,11β,14β-Trihydroxy-ent-kaur-20-al-6,15-dioxo-16-ene | 0.04 μM | – | [122] | ||
Hebeiabinin A, D and E | 53.21, 5.05 and 0.91 μM | – | [123] | ||
Parvifolines C | 13.8 μM | – | [125] | ||
3-Hydrogenwadaphnin | 15 nM con. caused 45% apoptosis | – | [126] | ||
Enanderianins K—P, Rabdocoetsin B and D | 0.13–0.87 μg/ml | – | [127] | ||
Ludongnin J | 0.18 μg/ml | – | [128] | ||
Tanshinone I | 38 ± 5.2 μM | ↟ Bax, caspase 3 and ↓Survivin | [129] | ||
ent-Kaurane diterpenoids 11, 16, 17 and 20 | 2.39, 4.11, 1.05 and 1.55 μM | [130] | |||
5-Episinuleptolideacetate | 4.09 μg/ml | ↓c-ABL, Akt, NFκB | [144] | ||
Sesterterpenoids | Felixins F and G | 1.27 and 19.9 μM | – | [131] | |
Compounds 8, 9 | *0.11 and 0.97μ/ml | – | [132] | ||
Two linear furanosesterterpenes | 3 and 31.6 μg/ml | – | [134] | ||
Triterpenoids | 3β,21β,24-Trihydroxyserrat-14-en-24-(4′-hydroxybenzoate) | 56.1 μg/ml | – | [137] | |
L-Arabinopyranosyloleanolic acid | 4.15 μM | – | [138] | ||
Nortriterpenoids | >100 μM | – | [139] | ||
Kadlongilactone D | 1.92 μM | – | [140] | ||
Six triterpenes | fractions of | 12.2—28.7 μM | – | [141] | |
Argetatin B | Cytotoxic at 5—25 μM con. | – | [142] | ||
Celastrol (quinone methide triterpene) | – | ↓pSTAT5, p-CRKL, pERK1/2, p-Akt, p-BCR-ABL, Bcl-xL, Mcl-1, survivin, Hsp90 | [143] |
2.4. Polyketides
Polyketides represent a large group of natural products that are produced by microorganisms and plants. These are secondary metabolites, derived by the repetitive condensation of acetate units or other short carboxylic acids catalyzed by multi-functional enzymes called polyketide synthases (PKSs) which is similar to fatty acid synthases [145]. Many polyketides suppress CML cell proliferation and induce apoptosis (Figure 3) (Table 6) [146–155].
Type of NP | Name of compound | Source of isolation | IC50 value on K562 | Mechanism of action | References |
---|---|---|---|---|---|
Epiaspinonediol | 44.3 μg/mL | – | [146] | ||
Geldanamycin | – | ↓c-Raf, Akt, BCR-ABL | [148] | ||
Heveadride | 82.7 ± 11.3 μM | ↟ TNFα | [149] | ||
Gilvocarin HE | Streptomyces sp. QD01–2 | 45 μM | – | [150] | |
Radicicol | – | ↓p-Raf1, p-BCR-ABL | [151] | ||
Rhizoxin | 5×10−7 μg/ml | – | [152] | ||
Salarin C | 0.1 μM | ↟ caspase 3 and 9 cleavage | [153] | ||
Tausalarin C | 1 μM | – | [154] | ||
Trineurone E | 26 μM | – | [155] | ||
Arctigenin | Asteraceae family | – | ↑Bax and ↓ Bcl-2 | [157] | |
Cleistanthin A | 0.4 μM | – | [158] | ||
5,5′-Dimethoxylariciresinol-4′-O-β-D-glucoside (DMAG) | Mahonia | – | ↓IC50 of DOX from 34.93 to 12.51 μM | [159] | |
Honokiol | 28.4 μM | – | [160] | ||
6-Hydroxyjusticidin C | 43.9 ± 2.9 μM | ↟ROS levels, casapase 3 | [161] | ||
(+)-Lariciresinol 9′-p-coumarate | 2.9 μg/ml | – | [162] | ||
4-Methoxy magndialdehyde | 3.9 μg/ml | – | [163] | ||
Astrgorgiosides A, B, C (19-norand aromatized B ring bearing steroid aglycone) | 26.8—45.6 μM | – | [168] | ||
Wattoside G, H, and I (steroidal saponins) | 35.67, 76.16 and 76.96 μM | – | [169] | ||
Tenacissoside C (steroidal saponins) | 31.4 μM | ↓ cyclin D, Bcl-2, Bcl-xL and ↑caspases 3, 9, Bax and Bak | [170] | ||
Compounds 14 and 15 (C21-steroidal pregnane sapogenins) | 6.72 μM | – | [171] | ||
Total saponin content | – | Loss of MMP. ↑ Bax and ↓ Bcl-2 | [172] | ||
Saponin rich fraction (GSE) | 18 ± 1.6 μg/ml | ↑ Bax and ↓ Bcl-2, PCNA | [173] | ||
23-Hydroxybetulinic acid | Total saponin content of | – | ↟ Bax, caspase 3 cleavage and ↓ Bcl-2, survivin | [174] | |
Chujamides A and B | *37 and 55.6 μM | – | [175] | ||
Gombamide A | *6.9 μM | – | [176] |
2.5. Lignans
Lignans, natural compounds that are exclusively found in plants, are derived from amino acid phenyl alanine. They possess anti-oxidant and anti-cancer activities [156]. Various lignans effectively inhibit CML cell proliferation and induced apoptosis (Figure 3) (Table 6) [157–163].
2.6. Saponins
Saponins are a diverse group of secondary metabolites widely distributed in the plant kingdom. They produce soap-like foam when shaken in aqueous solutions. Their structure comprise of triterpene or steroid aglycone and one or more sugar chains. They exhibit anti-cancer and anti-cholesterol activities [164, 165]. Various saponins inhibited CML cell proliferation (Table 6) [166–174].
2.7. Peptides
Two peptides, chujamides A (1) and B (2), isolated from the marine sponge
2.8. Others natural products
Other natural products such as acetylenic metabolites, betanin, bufadienolide, mamea a/ba, cryptotanshinone, bavachalcone, polyanthumin, cubebin, denbinobin, digallic acid, perforanoid A, β- and α-mangostin, parthenolide, perezone, polyphyllin D, squamocin, toxicarioside H, tripolide, woodfordin I and rhodexin A inhibited CML cell proliferation (Table 7) [180–230]. Moreover, many plant crude extracts enriched with NPs inhibited the CML cell proliferation and induced apoptosis (Table 8) [231–280].
Name of NP | Source of isolation | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|---|
Acetylenic metabolites | 43.5, 51.3 and 62.5 μg/ml | – | [180] | |
Betanin (betacyanin pigment) | 40 μM | ↟ PARP cleavage, release of Cyt C and ↓ BCl-2. Loss of MMP | [182] | |
Bufalin 3β-acrylic ester (Bufadienolide) | “Ch’an Su” | 6.83 nM | – | [183] |
3-Formylcarbazole, methylcarbazole-3-carboxylate and 2-methoxy-1-(3-methyl-buten-1-yl)-9H-carbazole-3-carbaldehyde | 20.48 ± 1.78, 26.5 ± 2.12 and 23.49 ± 1.85 μg/ml | – | [184] | |
Toxicarioside F and G | – | – | [185] | |
Pangelin and oxypeucedanin hydrate acetonide | 8.6–14.6 μg/ml | – | [186] | |
Mamea A/BA | 0.04–0.59 μM | – | [187, 188] | |
Cryptotanshinone (lipid soluble active compound) | – | induced apoptosis ↑ PARP cleavage and ↓BCR-ABL, STAT3, mTOR & eIF4E | [189, 190] | |
Bavachalcone (Chalcones) | – | 2.7 μM | – | [191] |
Polyanthumin (novel chalcone trimmer) and sulfuretin | 45.4 and 30.5 μg/ml | – | [192] | |
(−)-Cubebin | 8.66 ± 0.43 μM | – | [193] | |
Denbinobin | 5-Hydroxy-3,7-dimethoxy-1,4-phenanthraquinone | 1.84 μM | ↓ BCR-ABL, CrkL and⊥G2/M phase | [194] |
Digallic acid | – | Induced DNA fragmentation and pro-apoptotic effect in CML cells | [195] | |
1,4,5-Trihydroxy-7-methoxy-9H-fluoren-9-one, dendroflorin and denchrysan (fluorenones) | 32.18, 26.65 and 52.28 μg/ml | – | [196] | |
C27-Steroidal glycoside | 18.6 μg/ml | – | [198] | |
9α-Acetoxyartecanin, apressin, inducumenone and centaureidin | 9.84 ± 2.52, 4.44 ± 0.76, 52.53 ± 8.43 and 5.37 ± 0.8 μM | – | [199] | |
Perforanoid A (limonoid) | 4.24 μM | – | [200] | |
Linoleic acid | Methanol extracts of proso and Japanese millet | 68 μM | – | [201] |
β- and α-Mangostin | 0.40 μM and 0.48 μM | – | [202, 203] | |
Nudifloside and linearoside (iridoid) | EtOH extract of the aerial parts of | 20.7 and 36 μg/ml | – | [204] |
Parthenolide | – | 17.1, 8.67 and 9.42 for 24, 48 and 72 h | Induced apoptosis | [205] |
Perezone | – | Cytotoxic to CML cells at 25, 50 and 100 μM and induced apoptosis | [206] | |
Compound 6a (phenalenone metabolite) | 8.5 μM | – | [207] | |
Polyphyllin D | – | ↟ p21, Bax, caspase 3 & Cyt. C release and | [208] | |
Polysaccharide (PSP001) | 52.8 ± 0.9 μg/ml | – | [209] | |
Riccardin F and Pakyonol (macrocyclic bisbenzyls) | 0–6 μg/ml | – | [210] | |
Highly methoxylated bibenzyls | 11.3–49.6 μM | – | [211] | |
Sarcovagine and β-sitosterol 5- 8 | 2.5–5 μM | – | [212] | |
Squamocin (annonaceous acetogenins) | – | ↟ cdk inhibitors, p21, p27 & ↓ cdk1, cdk25c and ⊥G2/M phase | [213] | |
Klyflaccisteroid J | 12.7 μM | – | [214] | |
Suvanine (N,N-dimethyl-1,3-dimethylherbipoline salt) and suvanine-lactam derivatives (4–8) | * 2.2, 1.9, 3.9, 4.6, 3.9 and 3.6 μM | – | [215] | |
ar-Turmerone | 20–50 μg/ml | Induced DNA fragmentation and apoptosis | [216] | |
Terpene metabolites (1–3) | *4.7, 3.9 and 2.1 μM | – | [217] | |
Toxicarioside H (nor-cardenolide) | 0.037 μg/ml | – | [218] | |
Tripolide | Chinese herbal extract | – | ↓ Nrf2 and HIF-1α mRNA and protein expression | [219] |
10-(Chrysophanol-7′-yl)-10-hydroxychrysophanol-9-anthrone and ramosin | Fractions of EtOH extract of | 0.15 ± 0.02 and 0.65 ± 0.01 μM | – | [220] |
Withametelins I, J, K, L and N | MeOH extract of | 0.05, 2.5, 0.12, 0.55 and 0.46 μM | – | [221] |
Woodfordin I (macrocyclic ellagitannin dimer) | – | – | ↓ Bcl-2, Bcl-xL, Bax, c-Abl & BCR-ABL | [222] |
Gaudichaudic acid, isogambogenic acid and deoxygaudichaudione A (xanthones) | 0.41 ± 0.03, 2.1 ± 0.14 and 1.74 ± 0.22 μg/ml | – | [223] | |
Xindongnins C–D, A, B, melissoidesin G, dawoensin A and glabcensin V | 0.3–7.3 μg/ml | – | [224] | |
Hyperbeanols B and D | MeOH extract of | 16.9 and 20.7 μM | – | [225] |
Rhodexin A | 19 nM | ⊥G2/M phase induced apoptosis | [226] | |
Curcumin | 20 μg/ml | ↓BCR-ABL, Hsp90, WT1 | [227, 228] | |
Gambogic acid | 0.62 μM | ↓p-BCR-ABL, pSTAT5, p-CRKL, pERK1/2, p-Akt | [229, 230] |
Plant extract | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|
Acetone extract of | 14–10.27 μg/ml | – | [231] |
AQE extract of | 100 μg/ml | – | [232] |
AQE extracts of the husk fiber of the typical A and common varieties of | At 500 μg/ml the cell viability of CML cells was found to be 60.1 ± 8.5 and 47.5 ± 11.9% | – | [233] |
AQE extract of | – | ↓CML cell proliferation at 100 and 200 μg/ml for 72 hrs. induced ROS & apoptosis and ⊥G2/M phase | [234] |
Abnobaviscum F® (standardized AQE extract of European mistletoe from the host tree | – | ↟ caspase 9, JNK-1,2, p38 MAPK and ↓ Bcl-1, Erk-1/2 & PKB phosphorylation | [235] |
Chloroform extract of | 40–60μ/ml | – | [236] |
Chloroform extract of | 30 μg/ml | ↟ FAS, FADD, & caspase 8, 3/7. Induced DNA fragmentation & apoptosis | [237] |
DCM) extract of | 32 μg/ml | – | [238] |
DCM extract | 69 μg/ml | ↟ caspases, PARP cleavage. Induced DNA damage and apoptosis | [239] |
HEX and DCM extract of | *20 ± 1.5 and 43.75 ± 0.78 μg/ml | – | [240] |
HEX and DCM extract of | *17.5 ± 1.02 and 22.91 ± 1.25 μg/ml | – | [240] |
HEX extract of | 40.63 ± 1.45 μg/ml | – | [240] |
DCM fraction of | At 50 μg/ml concentration, it induced 65.04 ± 0.93% apoptotic rate | ↟ Fas, Bax mRNA levels and Bax/Bcl-2 ratio | [241] |
DCM fraction of the crude EtOH extract of | 30 μg/ml | – | [242] |
EtOH extract of | 130 ± 0.03 μg/ml | ↟ caspases, cyt. C release, p21 & p53 and ↓Akt and Bcl-2 | [244] |
EtOH extract of propolis (NP produced by stingless bee | At 250 and 500 μg/ml promoted cell death of CML cells by 15 ± 1 and 63 ± 2% | – | [245] |
EtOH extract of | 2.7 μg/ml | – | [246] |
EtOH root extract of | At 800 μg/ml showed cytotoxicity | – | [247] |
EtOH stem and leaf extract of | 0.02 and 0.03 g/ml | – | [248] |
Alcoholic extract of | 28 μl and 5 × 10−9M | – | [249] |
EtOH extract of | 1/400 dilution | – | [251] |
EtOH extract of | 0.5 μg/ml | ↟ CML cells in G2/M phase | [252] |
Fraction from EtoAc of | 44.5 ± 4.05 μg/ml | induced chromatin condensation. Loss of MMP & ↑ caspase 3 | [253] |
EtoAc extract of | 25.9 μg/ml | – | [254] |
MeOH extract of | 0.1 μg/ml | – | [255] |
MeOH extracts of | Less than 20 μg/ml | – | [256] |
MeOH extract of | 39.8 μg/ml | – | [256] |
MeOH extract | 175 ± 1.2 μg/ml | Induced DNA damage | [257] |
TAF273, F3 and F4 fractions of MeOH extract of | 19, 55 and 62 μg/ml | – | [258] |
MeOH extract of | – | Enhanced Natural killer cells to kill K562, ↟IFN-ϒ, TNF-α | [259] |
MeOH extract of | *235 μg/ml | – | [260] |
MeOH extract of | – | Induced apoptosis | [261] |
HEX, DCM, EtoAc, butanol and MeOH extracts of | 11.78 ± 0.94, 23.82 ± 6.54, 27.52 ± 4.96, 50.37 ± 3.28 and 74.88 ± 7.57 μg/ml (for 72 h) | – | [262] |
Acetate: MeOH (95:5), acetate, chloroform and HEX fractions of | 13.1 ± 0.63, 9.86 ± 0.56, 11.21 ± 0.46, 33.58 ± 1.33 μg/ml | – | [263] |
DCM extract of | ^17 μg/ml | – | [264] |
– | Reverse of MDR | [265] | |
Polyphenolic extract of | – | At 5, 10, 20 μg/ml con. ↓K562 cell proliferation | [266] |
EtOH extract of | 33.9 ± 4.3 μg/ml | – | [267] |
29 and74 μg/ml | – | [268] | |
Sangre de Drago is red viscous latex extract of | 2.5 ± 0.3 μg/ml | – | [269] |
20 μg/ml | – | [270] | |
*50 μg/ml | – | [271] | |
Crude MeOH extracts of | #8.1–5.4 μg/ml | – | [273] |
– | ↓p-gp | [274] | |
Ponicidin ( | – | ↓ Bcl-2 and ↑ Bax, caspase 3 & PARP cleavage | [276] |
– | ↟ caspase 3,8, PARP cleavage, Bax/Bcl-2 ratio | [278] | |
– | ↟ caspases 3,9, Cyt. C release and ⊥G2-M phase | [279] | |
Viscin, (lipophilic extract from | 252 ± 37 μg/ml | – | [280] |
2.9. Natural products in clinical trials
Of the several natural products, Homoharringtonine (alkaloid) (NCT00114959) is currently under phase II study sponsored by Chem Genex pharmaceuticals to reverse the Gleevac resistance in CML patients [281]. 17-AAG (analogue of glendamycin–polyketide) (NCT00100997) is currently under phase I clinical trial sponsored by Jonsson Comprehensive Cancer Center collaborated with National Cancer Institute (NCI). Efforts are underway to determine the side effects and optimal dose of 17-AAG for treating patients with CML in chronic phase who did not respond to imatinib-mesylate [282]. Paclitaxel (diterpenoid) (NCT00003230) is currently under Phase I/II trials to study the effectiveness in treating patients with refractory or recurrent acute leukemia or CML. This work is sponsored by Swiss Group for Clinical Cancer Research [283].
3. Conclusion
CML is a hematological malignancy that arises due to chromosomal translocation resulting in the presence of Ph chromosome. Initially, TKIs were designed to compete with the ATP binding site of BCR-ABL. TKIs effectively inhibited wild-type BCR-ABL; however, mutations in BCR-ABL and overexpression of drug efflux proteins following treatment decreased their potency.
Since, there is a need for alternative strategy to develop new BCR-ABL inhibitors; NPs (obtaining from living organisms) offers an alternate, effective and inexpensive design for CML therapy. Moreover, they have less (or) no side effects. Studies conducted so far have revealed that many NPs inhibit CML cell proliferation and, in addition, induce cell death through apoptosis. NPs alone or in combination with other TKIs are able to reverse the MDR, thereby increasing the sensitivity of TKIs towards CML. Moreover, many NPs are able to differentiate CML cells into erythroid, monocyte or macrophage lineage.
The authors declare that they do not have any competing interests.
CML | chronic myeloid leukemia |
Ph | Philadelphia chromosome |
MAPK | mitogen activated protein kinase |
STAT | signal transducers and activator of transcription |
PI3K | phosphoinositide 3-kinase |
TKIs | tyrosine kinase inhibitor |
FDA | Food and Drug Administration |
MDR | multi drug resistance |
p-gp | p-glycoprotein |
NPs | natural products |
NCEs | new chemical entities |
BBM | berbamine |
K562/IR | imatinib resistant K562 cell line |
cyt. C | cytochrome C |
BW | body weight |
ADR | adriamycin |
Hsp90 | heat shock protein 90 |
BBD9 | 4-chlorobenzoyl berbamine |
PARP | Poly(ADP-Ribose) polymerase |
LC3 II | LC3-phosphatidylethanolamine conjugate |
DOX | doxorubicin |
hCPT | homocampthothecin |
DNA-PK | DNA-dependent protein kinase |
miRNA | microRNA |
HHT | homoharringtonine |
UCN-01 | 7-hydroxy staurosporine |
μM | micromole |
μg | microgram |
Q | quercetin |
DNR | daunorubicin |
MMP | mitochondrial membrane potential |
p-p38-MAPK | p-p38 mitogen-activated protein kinase |
SLC | solute carrier |
hTERT | human telomerase reverse transcriptase |
IU | isoprene units |
PKSs | polyketide synthases |
DMAG | 5,5′-dimethoxylariciresinol-4′-O-β-D-glucoside |
HJC | 6-hydroxyjusticidin C |
HSS | Haishengsu |
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