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Natural Products for Treatment of Chronic Myeloid Leukemia
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Open access peer-reviewed chapter
By Kalubai Vari Khajapeer and Rajasekaran Baskaran
Submitted: May 2nd Reviewed: October 5th Published: December 7th
DOI: /
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 The fusion gene product BCR-ABL, a functional oncoprotein p, 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)
chapter and author info
Authors
Kalubai Vari Khajapeer
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, India
Rajasekaran Baskaran*
- Department of Biochemistry and Molecular Biology, School of Life Sciences, Pondicherry University, Pondicherry, India
*Address all correspondence to: rushbrookrathbone.co.ukkaran@rushbrookrathbone.co.uk
DOI: /
From the Edited Volume
Anti-cancer Drugs - Nature, Synthesis and Cell
Edited by Jasna Bankovic
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 bcr-abl oncogene. Approximately 90% of CML patients have shortened chromosome called “Philadelphia chromosome” (Ph) [2].
The bcr-abl oncogene encodes a constitutively activated tyrosine kinase, BCR-ABL. The catalytically activated kinase, in turn, activates multiple cell proliferatory signaling pathways such as RAS, a small GTPase, mitogen activated protein kinase (MAPK), signal transducers and activator of transcription (STAT), and phosphoinositidekinase (PI3K) pathways [3].
Targeting Abl kinase is clearly a proven successful strategy to combat CML. First generation tyrosine kinase inhibitor (TKI), imatinib, also known as Gleevac or STI 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 bcr-abl and multi-drug resistance (MDR) due to efflux of the drug as a result of overexpression of p-glycoprotein (p-gp) make TKIs less effective. Primary or secondary resistance to TKIs therapy still exists; however, there is a constant need for alternative therapeutic strategy (Figure 1) [7].
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 , 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.
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 Berberis amurensis, was tested on imatinib resistant K cell line (K/IR) both in vitro and in vivo. The IC50 value was found to be and μM at 24 and 48 h. BBM downregulated Bcl-2, Bcl-xL, mdr-1 mRNA, p-gp levels and enhanced Bax & cytochrome C (cyt.C) release. BALB/c or nu/nu mice were injected with Kr subcutaneously and the tumor-bearing mice, when treated with BBM [60 mg/kg body weight (BW)] intravenously effectively suppressed the xenotransplated tumors in these mice [14]. BBM also induced apoptosis in CML cells via downregulating survivin protein levels [15]. At 8 μg/ml dose of BBM, NFκB nuclear, IKK-α, IKB-α [16], BCR-ABL, p-BCR-ABL level were decreased [17]. Furthermore, BBM-induced differentiation of CML cells into RBC, granulocyte and megakaryocytes [18]. Interestingly, BBM is a heat shock protein 90 (Hsp90) inhibitor [19]. BBM inhibited MDR K/adriamycin (ADR) [20] and K/A02 cell lines consequently inducing apoptosis by reducing mdr-1 gene expression and reversing MDR effect [21]. 4-chlorobenzoyl berbamine (BBD9), an analogue of BBM was also tested against K/IR. BBD9 with IC50 μg/ml was found to be more effective than BBM (IC50 8 μg/ml), BBD9-lowered BCR-ABL, IKK a, nuclear NF-κB. Furthermore, it increased the cleaved caspases 3,9, Poly(ADP-Ribose) polymerase (PARP) and LC3-phosphatidylethanolamine conjugate (LC3 II) expression levels. In nude mice model bearing K tumors, BBD9 was effective in reducing the tumor weight, promoting tumor regression [22]. E6, a derivative of BBM, was tested against MDR K/doxorubicin (DOX) with 1, 3, 10 and 30 μM concentrations, and it significantly reduced the IC50 of DOX from μM to , , and μM. Co-treatment of E6 with DOX arrested K cells at G2/M phase [23].
Camptothecin, isolated from Camptotheca acuminate, is documented to display anti-CML activity. Homocampthothecin (hCPT), a synthetic analogue of camptothecin, showed potent activity at IC50 value of 11 nM suggesting its potential use compared to parent compound camptothecin (IC50 57 nM) [24]. BN, an analogue of camptothecin, effectively inhibited K cell proliferation with IC50 of nM [25]. NSC, an analogue of camptothecin, inhibited CML cell growth in a dose-dependent manner. The IC50 was found to be nM [26]. Combination of imatinib and camptothecin increased Bax, cleavage of PARP-1, DNA-dependent protein kinase (DNA–PK) in CML cells [27].
Capsaicin, an active component of capsicum genus, is a homovanillic acid derivative experimentally is shown to exhibit anti-mutagenic activity [28]. Capsaicin treatment of K cells decreased microRNA (miRNA) expression such as miRa-5p, a putative target of STAT3. Hence, capsaicin induced apoptosis via reducing mRNA involved in JNK/STAT pathway [29]. Capsaicin also stimulated GATA-1 promoter in CML cells which is an essential transcriptional factor for the development of erythroid cells [30].
Homoharringtonine (HHT), isolated from Cephalotaxus harringtona, has been documented to inhibit CML cell proliferation in a dose-dependent manner. The IC50 was found to be ng/ml. HHT arrested K cells at G0/G1 phase and, in addition, downregulated Bcl-2, NF-κB, p-JAK2, p-STAT5, p-Akt, p-BCR-ABL levels [31, 32].
Sanguinarine, a benzophenanthridine alkaloid, isolated from blood root plant Sanguinaria canadensis, belonging to the Papaveraceae family inhibited CML cell growth in a dose-dependent manner. At μg/ml, sanguinarine induced apoptosis in CML cells. At higher concentration ( μg/ml), sanguinarine caused blister formation in CML cells [33].
Staurosporine, an alkaloid isolated from the bacterium Streptomyces staurosporeus, not only inhibited CML cell growth but also induced differentiation of myeloid cell lineage to megakaryocytic lineage resulting in polypoidy formation. Staurosporine treatment resulted in upregulation and activation of JAK/STAT3, p-STAT3 nuclear translocation and downregulation of c-myc [34, 35]. Staurosporine also induced differentiation of CML cells into erythroid cells via increased CD61 and CD42b levels [36]. 7-Hydroxy staurosporine (UCN), a potent PKC inhibitor is effective in inhibiting CML cell proliferation at a concentration of 3 μM for 24 h [37, 38].
Tetrandrine is a bis-benzylisoquinoline alkaloid that is isolated from Chinese herb Stephania tetrandra. Combination of tetrandine and imatinib showed syngerisitic effect significantly inhibited CML cell growth. The combination treatment arrested CML cells at G1/S phase, enhanced caspase 3 mRNA, protein levels and decreased Bcl-2 mRNA, protein levels [39]. Combination of nilotinib and tetrandrine also effectively decreased the IC50 of daunorubicin (DNR) on K/A02 to ± μg/ml. This combinational effect not only increased Bax mRNA and protein levels but also decreased the survivin mRNA and protein levels [40]. Tetrandrine citrate, a novel tetrandrine salt which is highly soluble in water, Inhibited the growth of K/IR, primary leukemic cells and primitive CD34 (+) leukemic cells with IC50 ranging from to μg/ml. Tetrandrine citrate lowered BCR-ABL mRNA and β-catenin protein levels. Nude mice bearing CML tumors when orally administered with tetrandrine citrate ( mg/kg BW), reduced the tumor growth [41]. Combination of 5-bromotetrandrine (analogue of tetrandrine) and DNR decreased p-JNK 11,2 and MDR/p-gp levels in ADR resistant K cells [42].
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 in vivo models (Table 2). Besides, some alkaloids such as capasaicin, staurosporine induces differentiation of CML cells (Table 3).
| Alkaloid | Source of isolation | IC50 value on K cells | Mechanism of action | References |
|---|---|---|---|---|
| Berbamine (bisbenzylisoquinoline alkaloid) | Berberis amurensis | 8 μg/ml | ↓Bcl-2, Bcl-xL, NFκB(nuclear), IKK-α, IKB-α, BCR-ABL, p-BCR-ABL, Hsp90 | [14–17] |
| Camptothecin (quinoline alkaloid) | Camptotheca acuminate | 57 nM | ↑Bax, cleavage of PARP-1, DNA—PK adducts | [24] |
| Homoharringtonine | Cephalotaxus harringtona | ng/ml | ↓Bcl-2, NF-κB, p-JAK2, p-STAT5, p-Akt, p-BCR-ABL and ⊥G0/G1 phase | [31, 32] |
| Sanguinarine (benzophenanthridine alkaloid) | Sanguinaria canadensis | – | At μg/ml induced apoptosis | [33] |
| Tetrandrine (bis-benzylisoquinoline alkaloid) | Stephania tetrandra | – | ↑Caspase 3 mRNA, protein and ↓Bcl-2 mRNA, protein | [39, 40] |
| Ancistrotectorine E (napthylisoqunoline alkaloid) | 70% EtOH extract of Ancistrocladus tectorius | μM | – | [43] |
| 1,2,3-Trimethoxyoxonoraporphine and ouregidion (aporphine alkaloids) | Crude HEX, EtOAc and AQE extracts of Pseuduvaria rugosa (Blume) Merr | *63 and 64% | – | [44] |
| Cathachunine | Catharanthus roseus (L.) G. Don | ± μM | – | [45] |
| Cepharanthine | Stephania sp. | – | ↓p-gp | [46] |
| Crebanine | Stephania venosa | 13 μg/ml | ↓Cyclin A, D & ↑Caspases 3,9,8 & PARP and ⊥G0/G1 phase | [48] |
| Curine | Chondrodendron platyphyllum | ± μM | – | [49] |
| Cyanogramide | Actinoalloteichus cyanogriseus WHI | – | At 5 μM, reversed MDR in K/ADR | [50] |
| 9-Deacetoxyfumigaclavine C | Aspergillus fumigatus | μM | – | [51] |
| Evodiamine (quinazolinocarboline alkaloid) | Evodia rutaecarpa | μM | – | [53] |
| Naamidine J (imidazole containing alkaloid) | Pericharax heteroraphis | μM | – | [54] |
| Salvicine (diterpenoid alkaloid) | Salvia prioniti | ± μM | ⊥G1 phase | [56] |
| Solamargine (glycoalkaloid) | Solanum species | μM | ↑Caspases and ↓Bcl-2 | [57, 58] |
| α-Tomatine (glycoalkaloid) | Solanum lycopersicum | μM | Loss of MMP. ↑Bak, Mcl-1s, AIF and ↓survivin | [59] |
| Tylophora alkaloids (tylophorine, tylophorinine, tylophorindine) | Tylophora indica | – | Nuclear condensation, ↑Caspases activation, release of cyt.C | [60] |
| 5-Chlorosclerotiamide and episclerotiamide (prenylated indole alkaloids) | Aspergillus westerdijkiae DFFSCS | 44 and 53 μM | – | [61] |
| Eupolauramine and sampangine (azaphenanthrene alkaloids) | Anaxagorea dolichocarpa Sprague and sandwith | and μg/ml | – | [62] |
| Arthpyrones A, B and C (4-hydroxypyridone alkaloids) | Arthrinium arundinis ZSDS1-F3 | —45 μM | – | [63] |
| Auranomides A, B and C | Penicillium aurantiogriseum | *, and % | – | [64] |
| Malonganenones 1–3 (tetraprenylated alkaloids) | Euplexauria robusta | — μM | – | [65] |
| Virosecurinine | Securinega suffruticosa | μM | ↑PTEN & ↓mTOR, SHIP-2 BCR-ABL, and ⊥G1/S phase | [66] |
Table 1.
Anti-CML activity of alkaloids.
↑ ? upregulation, ↓ ? downregulation, ⊥ ? cell cycle arrest & * ? Inhibition rate (IR) at ?g/ml.
| 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 | Kr | 60 mg/kg BW | Intravenously | ↓mdr-1 mRNA, p-gp protein | [14] |
| BBD9 | Analogue of BBM | nu−/− | K/IR | 15 and 30 mg/kg BW | – | ↓p-BCR-ABL, IKKa, NF-κBp65 | [22] |
| Tetrandrine citrate | Alkaloid | nu−/− | K/IR | mg/kg BW | Orally | ↓BCR-ABL, β-catenin | [41] |
| d-Dicentrine | Alkaloid | SCID | K | mg/kg BW | Intraperitoneal | ↓tumor size | [52] |
| Oroxylin A | Flavonoid | SCID | K | 80 mg/kg BW | Intravenously | ↓STAT3 pathway | [76] |
| Nobiletin | Flavonoid | Nude mice | K | , 25, 50 mg/kg BW | – | ↓VEGF | [99] |
| dEpoF | Polyketide | Nude mice | K | 6 mg/kg | Intravenously | Complete tumor regression | [] |
| HSS | Protein extract from Tegillarca granosa | – | K/ADM | – | – | ↓mdr1, BCR-ABL and sorcin | [] |
| Gambogic acid | Garcinia hanburyi | Balb/c | KBM5-TI | 3 mg/kg/2 days | Intraperitoneal | ↓Bcr-Abl, Akt, Erk1/2, and STAT5 | [] |
| TAF | Fraction of Eurycoma longifolia MeOH extract | Balb/c | K | 50 mg/kg | Intraperitoneal | ↑apoptosis and ↓blood vessel formation | [] |
| NPB–05 | Piper betle extract | – | TI | mg/kg | Orally | ↓PI3K/AKT, MAPK pathways | [] |
Table 2.
In vivo results of anti-CML NPs.
| 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 | 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 Olea europaea | Plant extract | Monocyte lineage | &#;CD14 | [] |
| EtOH extract of Stellera chamaejasme | Plant extract | Granulocytes | &#;CD11b | [] |
| Huangqi (Astragalus membranaceus) | Traditional Chinese medicine | Erythroid lineage | &#;β-globin gene expression | [] |
Table 3.
List of some NPs and its differentiation capacity.
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 Scutellaria baicalensis, was tested against MDR K/ADR cells. Oroxylin A specifically enhanced the sensitivity of K/ADR to ADR by selectively inducing apoptosis. The treatment downregulated CXCR4 expression and inhibited PI3K/Akt/NF-κB pathways [75]. NOD/SCID mice-bearing K xenograft, treated with oroxylin A (30 mg/kg BW) alone or in combination with imatinib enhanced the sensitivity of imatinib to K cells through suppression of STAT3 pathway, decreasing p-gp levels thus reversing MDR in CML cells [76].
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 K and MDR K/A cell growth [78]. When K cells were treated with Q at a concentration of 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 K/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-pMAPK). Q also significantly decreased the p-gp levels [80] and sensitized MDR K/ADM to DNR and reversed MDR in CML cells [81]. Q inhibited K and MDR K/A in the range of 5– μM. Q treatment of K/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 K and K/ADR was found to be 11 ± 2 μM and 5 ± μM [84]. It also inhibited the Hsp70 levels in CML cells [85]. Q induced apoptosis via inhibiting the telomerase enzyme by enhancing human telomerase reverse transcriptase (hTERT) enzymes in CML cells [86].
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–].
| Flavonoids/flavonoid fraction | IC50 value on K 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 K | [96, 97] |
| Naringenin (flavanone) | – | &#; p21/WAF1 and ⊥G0/G1 phase | [98] |
| Tamarixetin (o-methylated flavonol) | – | &#; cyclin B1, Bub1, p21, caspases and ↓tublin polymerization | [] |
| 3,5-Dihydroxy-6,7,3′,4′-tetramethoxyflavone (DHTMF) (polymethoxyflavone) | μg/ml | &#;caspases 3, 9 & PARP cleavage | [] |
| 2″,3″-Diidroochnaflavone (Luxemburgia nobilis) | 89 μM | – | [] |
| Isochamaejasmin (biflavonoid) (Stellera chamaejasme L) | ± μM | &#;caspases 3, 9 and PARP cleavage | [] |
| Protoapigenone (total flavonoid fraction of Macrothelypteris torresiana) | μg/ml | – | [] |
| Total flavonoids from Lysimachia clethroides Duby (ZE4) | – | ↓Bcl-2 and ↑Fas, TRAIL & DR5 | [] |
| Total flavonoids of Astragali Radix | mg/L | ↓ cyclin D1 mRNA levels and ⊥G0/G1 phase | [] |
| Total oligomer flavonoids of Rhamnus alaternus | μg/ml | – | [] |
| Flavonoid-enriched Rhamnus alaternus root and leaf extracts | and μg/ml | – | [] |
| Epigallocatechingallate (Camellia sinensis) | 50 μM | ↓CyclinD1, CDC25A and ↑TGF-β2 | [] |
Table 4.
Anti-CML activity of flavonoids.
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 [–].
Sesquiterpenoids, diterpenoids, sesterterpenoids and triterpenoidshas been shown to potently inhibit CML cell proliferation and induce apoptosis (Figure 3) (Table 5) [–]. Other diterpenoids such as scapaundulin C (from Scapania undulate (L.) Dum.,) [], parvifoline Z, parvifoline AA (from Isodon parvifolius) [], labdane-type diterpenes (from Chloranthus henryi Hemsl.) [] and sesterterpenoid compounds 3, 11 and 12 (from Sarcotragus sp.) [] and triterpenoid compounds 1, 2, 5, 7 and 9 (from Ganoderma hainanense) [], (24R/S)hydroxy-3α 10α-epoxyeip-cucurbitaene (1a, b) (from Fructus Viticis Negundo) [] are also shown to efficiently inhibit CML cell proliferation.
| Terpenoid class | Name of terpenoid | Source of isolation | IC50 value on K cells | Mechanism of action | References |
|---|---|---|---|---|---|
| Sesquiterpenoids | EM23 | Elephantopus mollis | μM | &#; caspases, PARP cleavage and ↓ NFκB. Loss of MMP | [] |
| Diterpenoids | Caesalminaxin D and H | Caesalpinia minax | ± and ± μM | – | [] |
| Gukulenin A and diterpenoid pseudodimers (2–5) | Phorbas gukhulensis | * ± , ± , ± , ± and ± μM | – | [] | |
| Diterpene compounds 11, 12, 13, 14 and 15 | petroleum ether soluble fraction of the aerial parts of Tirpitzia ovoidea ethanol extract | , , 91, and μM | – | [] | |
| 7β,11β,14β-Trihydroxy-ent-kaural-6,dioxoene | Isodon xerophilus | μM | – | [] | |
| Hebeiabinin A, D and E | Isodon rubescens var. rubescens | , and μM | – | [] | |
| Parvifolines C | Isodon parvifolius | μM | – | [] | |
| 3-Hydrogenwadaphnin | Dendrostellera lessertii | 15 nM con. caused 45% apoptosis | – | [] | |
| Enanderianins K—P, Rabdocoetsin B and D | Isodon enanderianus | – μg/ml | – | [] | |
| Ludongnin J | Isodon rubescens var. lushiensis | μg/ml | – | [] | |
| Tanshinone I | Salvia miltiorrhiza Bunge. | 38 ± μM | &#; Bax, caspase 3 and ↓Survivin | [] | |
| ent-Kaurane diterpenoids 11, 16, 17 and 20 | Isodon nervosus | , , and μM | [] | ||
| 5-Episinuleptolideacetate | Sinularia species | μg/ml | ↓c-ABL, Akt, NFκB | [] | |
| Sesterterpenoids | Felixins F and G | Ircinia felix | and μM | – | [] |
| Compounds 8, 9 | Smenospongia sp. | * and μ/ml | – | [] | |
| Two linear furanosesterterpenes | Smenospongia sp. | 3 and μg/ml | – | [] | |
| Triterpenoids | 3β,21β,Trihydroxyserraten(4′-hydroxybenzoate) | Palhinhaea cernua | μg/ml | – | [] |
| L-Arabinopyranosyloleanolic acid | Garcinia hanburyi resin | μM | – | [] | |
| Nortriterpenoids | Schisandra propinqua var. propinqua | > μM | – | [] | |
| Kadlongilactone D | Kadsura longipedunculata | μM | – | [] | |
| Six triterpenes | fractions of Aceriphyllum rossii methanolic extract | — μM | – | [] | |
| Argetatin B | Parthenium argentatum | Cytotoxic at 5—25 μM con. | – | [] | |
| Celastrol (quinone methide triterpene) | Tripterygium wilfordiiHook F | – | ↓pSTAT5, p-CRKL, pERK1/2, p-Akt, p-BCR-ABL, Bcl-xL, Mcl-1, survivin, Hsp90 | [] |
Table 5.
Anti-CML activity of terpenoids.
*LC50, lethal concentation.
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 []. Many polyketides suppress CML cell proliferation and induce apoptosis (Figure 3) (Table 6) [–].
| Type of NP | Name of compound | Source of isolation | IC50 value on K | Mechanism of action | References |
|---|---|---|---|---|---|
| Polyketides | Epiaspinonediol | Aspergillus sp. 16–02–1 | μg/mL | – | [] |
| Geldanamycin | StreptomycesHygroscopicus | – | ↓c-Raf, Akt, BCR-ABL | [] | |
| Heveadride | Ascomycota Dichotomyces cejpii | ± μM | &#; TNFα | [] | |
| Gilvocarin HE | Streptomyces sp. QD01–2 | 45 μM | – | [] | |
| Radicicol | Diheterospora chlamydosporia and Monosporium bonorden | – | ↓p-Raf1, p-BCR-ABL | [] | |
| Rhizoxin | Burkholderia rhizoxina | 5×10−7 μg/ml | – | [] | |
| Salarin C | Fascaplysinopis sp. | μM | &#; caspase 3 and 9 cleavage | [] | |
| Tausalarin C | Fascaplysinopis sp. | 1 μM | – | [] | |
| Trineurone E | Peperomia trineura | 26 μM | – | [] | |
| Lignans | Arctigenin | Asteraceae family | – | ↑Bax and ↓ Bcl-2 | [] |
| Cleistanthin A | Cleistanthus collinus (Rox B) | μM | – | [] | |
| 5,5′-Dimethoxylariciresinol-4′-O-β-D-glucoside (DMAG) | Mahonia | – | ↓IC50 of DOX from to μM | [] | |
| Honokiol | Magnolia officinalis Rend. Et wils. | μM | – | [] | |
| 6-Hydroxyjusticidin C | Justica procumbens | ± μM | &#;ROS levels, casapase 3 | [] | |
| (+)-Lariciresinol 9′-p-coumarate | Larix olgensis rushbrookrathbone.co.uka. | μg/ml | – | [] | |
| 4-Methoxy magndialdehyde | Magnolia officinalis | μg/ml | – | [] | |
| Saponins | Astrgorgiosides A, B, C (norand aromatized B ring bearing steroid aglycone) | Astrogor dumbea | — μM | – | [] |
| Wattoside G, H, and I (steroidal saponins) | Tupistra wattii Hook.F. | , and μM | – | [] | |
| Tenacissoside C (steroidal saponins) | Marsdenia tenacissima | μM | ↓ cyclin D, Bcl-2, Bcl-xL and ↑caspases 3, 9, Bax and Bak | [] | |
| Compounds 14 and 15 (Csteroidal pregnane sapogenins) | Cynanchum wilfordii roots | μM | – | [] | |
| Total saponin content | Aralia Taibaiensis | – | Loss of MMP. ↑ Bax and ↓ Bcl-2 | [] | |
| Saponin rich fraction (GSE) | Gleditsia sinensis Lam. fruit extract | 18 ± μg/ml | ↑ Bax and ↓ Bcl-2, PCNA | [] | |
| Hydroxybetulinic acid | Total saponin content of Pulsatilla chinensis (Bunge) Regel | – | &#; Bax, caspase 3 cleavage and ↓ Bcl-2, survivin | [] | |
| Peptides | Chujamides A and B | Suberites waedoensis | *37 and μM | – | [] |
| Gombamide A | Clathria gombawuiensis | * μM | – | [] |
Table 6.
Anti-CML activities of polyketides, lignans, saponins and peptides.
*LC50—lethal concentation.
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 []. Various lignans effectively inhibit CML cell proliferation and induced apoptosis (Figure 3) (Table 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 [, ]. Various saponins inhibited CML cell proliferation (Table 6) [–].
Peptides
Two peptides, chujamides A (1) and B (2), isolated from the marine sponge Suberites waedoensis inhibited K cell growth with LC50 values of 37 and μM []. Another peptide, gombamide A (1), isolated from the marine sponge Clathria gombawuiensis inhibited CML cell proliferation with LC50 of μM []. Haishengsu (HSS), a protein extract from Tegillarca granosa, when administered in mice-bearing MDR K/ADM cell tumors inhibited tumor growth and downregulated mdr1 gene, BCR-ABL and sorcin []. HSS was also tested against MDR K/ADR cells, and it induced apoptosis at 20 mg/l []. HSS also inhibited K cells at G0/G1 and S phase and lowered Bcl-2 and enhanced Bax levels (Figure 2) (Table 6) [].
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) [–]. Moreover, many plant crude extracts enriched with NPs inhibited the CML cell proliferation and induced apoptosis (Table 8) [–].
| Name of NP | Source of isolation | IC50 value on K cells | Mechanism of action | References |
|---|---|---|---|---|
| Acetylenic metabolites | Stelletta sp. | , and μg/ml | – | [] |
| Betanin (betacyanin pigment) | Opuntia ficus-indica | 40 μM | &#; PARP cleavage, release of Cyt C and ↓ BCl Loss of MMP | [] |
| Bufalin 3β-acrylic ester (Bufadienolide) | “Ch’an Su” | nM | – | [] |
| 3-Formylcarbazole, methylcarbazolecarboxylate and 2-methoxy(3-methyl-butenyl)-9H-carbazolecarbaldehyde | Clausena lansium (Lour.) Skeels | ± , ± and ± μg/ml | – | [] |
| Toxicarioside F and G | Latex of Antaris toxicaria (Pers.) Lasch | – | – | [] |
| Pangelin and oxypeucedanin hydrate acetonide | Angelica dahurica | – μg/ml | – | [] |
| Mamea A/BA | Calophyllum brasiliense | – μM | – | [, ] |
| Cryptotanshinone (lipid soluble active compound) | Salvia miltiorrhiza | – | induced apoptosis ↑ PARP cleavage and ↓BCR-ABL, STAT3, mTOR & eIF4E | [, ] |
| Bavachalcone (Chalcones) | – | μM | – | [] |
| Polyanthumin (novel chalcone trimmer) and sulfuretin | Memecylon polyanthum H.L. Li. | and μg/ml | – | [] |
| (−)-Cubebin | Piper cubeba | ± μM | – | [] |
| Denbinobin | 5-Hydroxy-3,7-dimethoxy-1,4-phenanthraquinone | μM | ↓ BCR-ABL, CrkL and⊥G2/M phase | [] |
| Digallic acid | Pistascia lentiscus | – | Induced DNA fragmentation and pro-apoptotic effect in CML cells | [] |
| 1,4,5-Trihydroxymethoxy-9H-fluorenone, dendroflorin and denchrysan (fluorenones) | Dendrobium chrysotoxum | , and μg/ml | – | [] |
| CSteroidal glycoside | Liriope graminifolia (Linn.) Baker | μg/ml | – | [] |
| 9α-Acetoxyartecanin, apressin, inducumenone and centaureidin | Achillea clavennae | ± , ± , ± and ± μM | – | [] |
| Perforanoid A (limonoid) | – | μM | – | [] |
| Linoleic acid | Methanol extracts of proso and Japanese millet | 68 μM | – | [] |
| β- and α-Mangostin | Garcinia malaccensis | μM and μM | – | [, ] |
| Nudifloside and linearoside (iridoid) | EtOH extract of the aerial parts of Callicarpa nudiflora Hook | and 36 μg/ml | – | [] |
| Parthenolide | – | , and for 24, 48 and 72 h | Induced apoptosis | [] |
| Perezone | Perezia spp. | – | Cytotoxic to CML cells at 25, 50 and μM and induced apoptosis | [] |
| Compound 6a (phenalenone metabolite) | Coniothyriumcereal | μM | – | [] |
| Polyphyllin D | Paris polyphyllin | – | &#; p21, Bax, caspase 3 & Cyt. C release and ↓ cyclin B1, cdk1, Bcl Loss of MMP and ⊥ G2/M phase | [] |
| Polysaccharide (PSP) | Punica granatum | ± μg/ml | – | [] |
| Riccardin F and Pakyonol (macrocyclic bisbenzyls) | Plagiochasm intermedium | 0–6 μg/ml | – | [] |
| Highly methoxylated bibenzyls | Frullania inouei | – μM | – | [] |
| Sarcovagine and β-sitosterol 5- 8 | Sarcococca saligna | –5 μM | – | [] |
| Squamocin (annonaceous acetogenins) | – | – | &#; cdk inhibitors, p21, p27 & ↓ cdk1, cdk25c and ⊥G2/M phase | [] |
| Klyflaccisteroid J | Klyxum flaccidum | μM | – | [] |
| Suvanine (N,N-dimethyl-1,3-dimethylherbipoline salt) and suvanine-lactam derivatives (4–8) | Coscinoderma sp. sponge | * , , , , and μM | – | [] |
| ar-Turmerone | Curcuma longa L | 20–50 μg/ml | Induced DNA fragmentation and apoptosis | [] |
| Terpene metabolites (1–3) | Clathria gombawuiensis | *, and μM | – | [] |
| Toxicarioside H (nor-cardenolide) | Antiaris toxicaria (Pers.) Lesch | μg/ml | – | [] |
| Tripolide | Chinese herbal extract | – | ↓ Nrf2 and HIF-1α mRNA and protein expression | [] |
| (Chrysophanol-7′-yl)hydroxychrysophanolanthrone and ramosin | Fractions of EtOH extract of Asphodelus microcarpus rushbrookrathbone.co.uk Vivi | ± and ± μM | – | [] |
| Withametelins I, J, K, L and N | MeOH extract of Datura metel flowers | , , , and μM | – | [] |
| Woodfordin I (macrocyclic ellagitannin dimer) | – | – | ↓ Bcl-2, Bcl-xL, Bax, c-Abl & BCR-ABL and Loss of MMP | [] |
| Gaudichaudic acid, isogambogenic acid and deoxygaudichaudione A (xanthones) | Garcinia hanburyi resin | ± , ± and ± μg/ml | – | [] |
| Xindongnins C–D, A, B, melissoidesin G, dawoensin A and glabcensin V | Isodon rubescens var. rubescens | – μg/ml | – | [] |
| Hyperbeanols B and D | MeOH extract of Hypericum beanie | and μM | – | [] |
| Rhodexin A | Rhodea japonica | 19 nM | ⊥G2/M phase induced apoptosis | [] |
| Curcumin | Curcumina longa | 20 μg/ml | ↓BCR-ABL, Hsp90, WT1 | [, ] |
| Gambogic acid | Garcinia hanburyi | μM | ↓p-BCR-ABL, pSTAT5, p-CRKL, pERK1/2, p-Akt | [, ] |
Table 7.
Anti-CML activity of other natural products.
*LC50–lethal concentation.
| Plant extract | IC50 value on K cells | Mechanism of action | References |
|---|---|---|---|
| Acetone extract of Peucedanum nebrodense (Guss.) Strohl., | 14– μg/ml | – | [] |
| AQE extract of Cornus officinalis Sieb. et Zuce | μg/ml | – | [] |
| AQE extracts of the husk fiber of the typical A and common varieties of Cocos nucifera (Palmae) | At μg/ml the cell viability of CML cells was found to be ± and ± % | – | [] |
| AQE extract of Rhodiola imbricate | – | ↓CML cell proliferation at and μg/ml for 72 hrs. induced ROS & apoptosis and ⊥G2/M phase | [] |
| Abnobaviscum F® (standardized AQE extract of European mistletoe from the host tree Fraxinus) | – | &#; caspase 9, JNK-1,2, p38 MAPK and ↓ Bcl-1, Erk-1/2 & PKB phosphorylation | [] |
| Chloroform extract of Polyalthia rumphii stem | 40–60μ/ml | – | [] |
| Chloroform extract of Tecomella undulata bark | 30 μg/ml | &#; FAS, FADD, & caspase 8, 3/7. Induced DNA fragmentation & apoptosis | [] |
| DCM) extract of Psidium guajava L. | 32 μg/ml | – | [] |
| DCM extract Artemisia turanica Krasch | 69 μg/ml | &#; caspases, PARP cleavage. Induced DNA damage and apoptosis | [] |
| HEX and DCM extract of Mesua beccariana | *20 ± and ± μg/ml | – | [] |
| HEX and DCM extract of Mesua ferrea | * ± and ± μg/ml | – | [] |
| HEX extract of Mesua congestiflora | ± μg/ml | – | [] |
| DCM fraction of Melissa officinalis | At 50 μg/ml concentration, it induced ± % apoptotic rate | &#; Fas, Bax mRNA levels and Bax/Bcl-2 ratio | [] |
| DCM fraction of the crude EtOH extract of Echinops grijissi Hance roots | 30 μg/ml | – | [] |
| EtOH extract of Pereskia sacharosa | ± μg/ml | &#; caspases, cyt. C release, p21 & p53 and ↓Akt and Bcl-2 | [] |
| EtOH extract of propolis (NP produced by stingless bee Melipona orbignyi) | At and μg/ml promoted cell death of CML cells by 15 ± 1 and 63 ± 2% | – | [] |
| EtOH extract of Isodon japonicas | μg/ml | – | [] |
| EtOH root extract of Allamanda schottii | At μg/ml showed cytotoxicity | – | [] |
| EtOH stem and leaf extract of Physalis peruviana | and g/ml | – | [] |
| Alcoholic extract of Dendrostellera lessertii | 28 μl and 5 × 10−9M | – | [] |
| EtOH extract of Rosmarinus officinalis L | 1/ dilution | – | [] |
| EtOH extract of Goldfussia psilostachys | μg/ml | &#; CML cells in G2/M phase | [] |
| Fraction from EtoAc of Caesalpinia spinosa | ± μg/ml | induced chromatin condensation. Loss of MMP & ↑ caspase 3 | [] |
| EtoAc extract of Helichrysum plicatum flowers | μg/ml | – | [] |
| MeOH extract of Linum persicum | μg/ml | – | [] |
| MeOH extracts of Echinophora cinerea and Cirsium bracteosum | Less than 20 μg/ml | – | [] |
| MeOH extract of Galium mite | μg/ml | – | [] |
| MeOH extract of Cyperus rotundus | ± μg/ml | Induced DNA damage | [] |
| TAF, F3 and F4 fractions of MeOH extract of Eurycoma longifolia Jack | 19, 55 and 62 μg/ml | – | [] |
| MeOH extract of Rhaphidophora korthalsii | – | Enhanced Natural killer cells to kill K, &#;IFN-ϒ, TNF-α | [] |
| MeOH extract of Rhinella jimi Stevaux (Anura: Bufonidae) skin | * μg/ml | – | [] |
| MeOH extract of Hypericum perforatum L.flower extract | – | Induced apoptosis | [] |
| HEX, DCM, EtoAc, butanol and MeOH extracts of Helichrysum zivojinii &#;ernjavski and Soška | ± , ± , ± , ± and ± μg/ml (for 72 h) | – | [] |
| Acetate: MeOH (), acetate, chloroform and HEX fractions of |
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