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Pharmacology, Toxicology and Pharmaceutical Science » Drug Discovery » "Anti-cancer Drugs - Nature, Synthesis and Cell", book edited by Jasna Bankovic, ISBN 978-953-51-2814-4, Print ISBN 978-953-51-2813-7, Published: December 7, 2016 under CC BY 3.0 license. © The Author(s).

Chapter 1

Natural Products for Treatment of Chronic Myeloid Leukemia

By Kalubai Vari Khajapeer and Rajasekaran Baskaran
DOI: 10.5772/66175

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Schematic representation of NPs and TKIs on BCR-ABL inhibition and downregulation of downstream signaling pathways (NP—natural products, TKI—tyrosine kinase inhibitor, CML—chronic myeloid leukemia, MDR—multi-drug resistance).
Figure 1. Schematic representation of NPs and TKIs on BCR-ABL inhibition and downregulation of downstream signaling pathways (NP—natural products, TKI—tyrosine kinase inhibitor, CML—chronic myeloid leukemia, MDR—multi-drug resistance).
List of anti-CML alkaloids as 1—Ancistrotectorine E, 2—Berbamine, 3—BBD9, 4—Camptothecin, 5—BN80927, 6—NSC606985, 7—Homocamptothecin, 8—Capsaicin, 9—Cathachunine, 10—Cephranathine, 11—Crambescidin 800, 12—Crebanine, 13—Curine, 14—Cyanogramide, 15—9-deacetoxyfumigaclavine C, 16—d-Dicentrine, 17—Evodiamine, 18—Homoharringtonine, 19—Naamidine J, 20—Piperine, 21—Salvicine, 22—Staurosporine, 23—UCN-01, 24—Tetrandrine, 25—5-bromotetrandrine, 26—α-tomatine, 27—tylophorine, 28—tylophorinine, 29—5-chlorosclerotiamide, 30—10-episclerotiamide, 31—Eupolauramine, 32—Sampangine, 33, 34, 35—Arthpyrones A, B and C, 36–38—Auranomides A, B and C and 39—Virosecurinine.
Figure 2. List of anti-CML alkaloids as 1—Ancistrotectorine E, 2—Berbamine, 3—BBD9, 4—Camptothecin, 5—BN80927, 6—NSC606985, 7—Homocamptothecin, 8—Capsaicin, 9—Cathachunine, 10—Cephranathine, 11—Crambescidin 800, 12—Crebanine, 13—Curine, 14—Cyanogramide, 15—9-deacetoxyfumigaclavine C, 16—d-Dicentrine, 17—Evodiamine, 18—Homoharringtonine, 19—Naamidine J, 20—Piperine, 21—Salvicine, 22—Staurosporine, 23—UCN-01, 24—Tetrandrine, 25—5-bromotetrandrine, 26—α-tomatine, 27—tylophorine, 28—tylophorinine, 29—5-chlorosclerotiamide, 30—10-episclerotiamide, 31—Eupolauramine, 32—Sampangine, 33, 34, 35—Arthpyrones A, B and C, 36–38—Auranomides A, B and C and 39—Virosecurinine.
Anti-CML activity of some NPs which include ? flavonoids: 1—Apigenin, 2—Baicalein, 3—Fistein, 4—Galangin, 5—Genistein, 6—Kaempferol, 7—Myricetin, 8—Naringenin, 9—Nobiletin, 10—Oroxylin A and 11—Tamarixetin. Terpenoids: 1—Gukulenin A, 2–4—Hebeiabinin A, D & E, 5—Parvifolines C, 6—3-hydrogenwadaphnin, 7—Tanshinone I, 8—EM23, 9, 10—Felixins F & G, 11—Kadlongilactone D. Polyketides: 1—Epiaspinonediol, 2—aza-EpoB, 3—dEpoF, 4—Heveadride, 5—Gilvocarin HE, 6—Rhizoxin, 7—Salarin C, 8—Tausalarin C, 9—Trineurone E. Lignans: 1—Arctigenin, 2—Cleistanthin A, 3—Honokiol, 4—6-hydroxyjusticidin C, 5—(+) –lariciresinol 9’-p-coumarate, 6—4-methoxy magndialdehyde. Peptides: 1, 2—chujamide A, B, 3—gombamide A.
Figure 3. Anti-CML activity of some NPs which include ? flavonoids: 1—Apigenin, 2—Baicalein, 3—Fistein, 4—Galangin, 5—Genistein, 6—Kaempferol, 7—Myricetin, 8—Naringenin, 9—Nobiletin, 10—Oroxylin A and 11—Tamarixetin. Terpenoids: 1—Gukulenin A, 2–4—Hebeiabinin A, D & E, 5—Parvifolines C, 6—3-hydrogenwadaphnin, 7—Tanshinone I, 8—EM23, 9, 10—Felixins F & G, 11—Kadlongilactone D. Polyketides: 1—Epiaspinonediol, 2—aza-EpoB, 3—dEpoF, 4—Heveadride, 5—Gilvocarin HE, 6—Rhizoxin, 7—Salarin C, 8—Tausalarin C, 9—Trineurone E. Lignans: 1—Arctigenin, 2—Cleistanthin A, 3—Honokiol, 4—6-hydroxyjusticidin C, 5—(+) –lariciresinol 9’-p-coumarate, 6—4-methoxy magndialdehyde. Peptides: 1, 2—chujamide A, B, 3—gombamide A.

Natural Products for Treatment of Chronic Myeloid Leukemia

Kalubai Vari Khajapeer and Rajasekaran Baskaran
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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 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 phosphoinositide-3-kinase (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 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 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].


Figure 1.

Schematic representation of NPs and TKIs on BCR-ABL inhibition and downregulation of downstream signaling pathways (NP—natural products, TKI—tyrosine kinase inhibitor, CML—chronic myeloid leukemia, MDR—multi-drug resistance).

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 [1013]. 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 K562 cell line (K562/IR) both in vitro and in vivo. The IC50 value was found to be 17.1 and 11.1 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 K562-r 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 K562/adriamycin (ADR) [20] and K562/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 K562/IR. BBD9 with IC50 0.5 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 K562 tumors, BBD9 was effective in reducing the tumor weight, promoting tumor regression [22]. E6, a derivative of BBM, was tested against MDR K562/doxorubicin (DOX) with 1, 3, 10 and 30 μM concentrations, and it significantly reduced the IC50 of DOX from 79.19 μM to 35.18, 21.86, 6.31 and 1.97 μM. Co-treatment of E6 with DOX arrested K562 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]. BN80927, an analogue of camptothecin, effectively inhibited K562 cell proliferation with IC50 of 8.4 nM [25]. NSC606985, an analogue of camptothecin, inhibited CML cell growth in a dose-dependent manner. The IC50 was found to be 6.25 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 K562 cells decreased microRNA (miRNA) expression such as miR-520a-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 43.89 ng/ml. HHT arrested K562 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 1.5 μg/ml, sanguinarine induced apoptosis in CML cells. At higher concentration (12.5 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-01), 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 K562/A02 to 3.12 ± 0.13 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 K562/IR, primary leukemic cells and primitive CD34 (+) leukemic cells with IC50 ranging from 1.2 to 2.97 μg/ml. Tetrandrine citrate lowered BCR-ABL mRNA and β-catenin protein levels. Nude mice bearing CML tumors when orally administered with tetrandrine citrate (100 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 K562 cells [42].

Alkaloids from plant and microbial source inhibited CML cell proliferation in micromole (μM)/microgram (μg) concentration (Table 1) (Figure 2) [4366]. 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).


Figure 2.

List of anti-CML alkaloids as 1—Ancistrotectorine E, 2—Berbamine, 3—BBD9, 4—Camptothecin, 5—BN80927, 6—NSC606985, 7—Homocamptothecin, 8—Capsaicin, 9—Cathachunine, 10—Cephranathine, 11—Crambescidin 800, 12—Crebanine, 13—Curine, 14—Cyanogramide, 15—9-deacetoxyfumigaclavine C, 16—d-Dicentrine, 17—Evodiamine, 18—Homoharringtonine, 19—Naamidine J, 20—Piperine, 21—Salvicine, 22—Staurosporine, 23—UCN-01, 24—Tetrandrine, 25—5-bromotetrandrine, 26—α-tomatine, 27—tylophorine, 28—tylophorinine, 29—5-chlorosclerotiamide, 30—10-episclerotiamide, 31—Eupolauramine, 32—Sampangine, 33, 34, 35—Arthpyrones A, B and C, 36–38—Auranomides A, B and C and 39—Virosecurinine.

AlkaloidSource of isolationIC50 value on K562 cellsMechanism of actionReferences
Berbamine (bisbenzylisoquinoline alkaloid)Berberis amurensis8 μg/ml↓Bcl-2, Bcl-xL, NFκB(nuclear), IKK-α, IKB-α, BCR-ABL, p-BCR-ABL, Hsp90[1417]
Camptothecin (quinoline alkaloid)Camptotheca acuminate57 nM↑Bax, cleavage of PARP-1, DNA—PK adducts[24]
HomoharringtonineCephalotaxus harringtona43.89 ng/ml↓Bcl-2, NF-κB, p-JAK2, p-STAT5, p-Akt, p-BCR-ABL and ⊥G0/G1 phase[31, 32]
Sanguinarine (benzophenanthridine alkaloid)Sanguinaria canadensisAt 1.5 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 tectorius4.18 μM[43]
1,2,3-Trimethoxy-5-oxonoraporphine and ouregidion (aporphine alkaloids)Crude HEX, EtOAc and AQE extracts of Pseuduvaria rugosa (Blume) Merr*63 and 64%[44]
CathachunineCatharanthus roseus (L.) G. Don9.3 ± 1.8 μM[45]
CepharanthineStephania sp.↓p-gp[46]
CrebanineStephania venosa13 μg/ml↓Cyclin A, D & ↑Caspases 3,9,8 & PARP and ⊥G0/G1 phase[48]
CurineChondrodendron platyphyllum17.8 ± 5.2 μM[49]
CyanogramideActinoalloteichus cyanogriseus WHI-2216-6At 5 μM, reversed MDR in K562/ADR[50]
9-Deacetoxyfumigaclavine CAspergillus fumigatus3.1 μM[51]
Evodiamine (quinazolinocarboline alkaloid)Evodia rutaecarpa34.43 μM[53]
Naamidine J (imidazole containing alkaloid)Pericharax heteroraphis11.3 μM[54]
Salvicine (diterpenoid alkaloid)Salvia prioniti7.82 ± 2.81 μM⊥G1 phase[56]
Solamargine (glycoalkaloid)Solanum species5.2 μM↑Caspases and ↓Bcl-2[57, 58]
α-Tomatine (glycoalkaloid)Solanum lycopersicum1.51 μMLoss of MMP. ↑Bak, Mcl-1s, AIF and ↓survivin[59]
Tylophora alkaloids (tylophorine, tylophorinine, tylophorindine)Tylophora indicaNuclear condensation, ↑Caspases activation, release of cyt.C[60]
5-Chlorosclerotiamide and 10-episclerotiamide (prenylated indole alkaloids)Aspergillus westerdijkiae DFFSCS01344 and 53 μM[61]
Eupolauramine and sampangine (azaphenanthrene alkaloids)Anaxagorea dolichocarpa Sprague and sandwith18.97 and 10.95 μg/ml[62]
Arthpyrones A, B and C (4-hydroxy-2-pyridone alkaloids)Arthrinium arundinis ZSDS1-F30.24—45 μM[63]
Auranomides A, B and CPenicillium aurantiogriseum*20.48, 76.36 and 5.78%[64]
Malonganenones 1–3 (tetraprenylated alkaloids)Euplexauria robusta0.35—10.82 μM[65]
VirosecurinineSecurinega suffruticosa32.984 μM↑PTEN & ↓mTOR, SHIP-2 BCR-ABL, and ⊥G1/S phase[66]

Table 1.

Anti-CML activity of alkaloids.

[i] - ↑ ? upregulation, ↓ ? downregulation, ⊥ ? cell cycle arrest & * ? Inhibition rate (IR) at 100 ?g/ml.

Name of NPType of NPMice strainType of CML cells used to induce tumorsDosageMode of administrationMechanism of actionReferences
BBMAlkaloidBalb/cK562-r60 mg/kg BWIntravenouslymdr-1 mRNA, p-gp protein[14]
BBD9Analogue of BBMnu−/−K562/IR15 and 30 mg/kg BW↓p-BCR-ABL, IKKa, NF-κBp65[22]
Tetrandrine citrateAlkaloidnu−/−K562/IR100 mg/kg BWOrally↓BCR-ABL, β-catenin[41]
d-DicentrineAlkaloidSCIDK562100 mg/kg BWIntraperitoneal↓tumor size[52]
Oroxylin AFlavonoidSCIDK56280 mg/kg BWIntravenously↓STAT3 pathway[76]
NobiletinFlavonoidNude miceK56212.5, 25, 50 mg/kg BW↓VEGF[99]
dEpoFPolyketideNude miceK5626 mg/kgIntravenouslyComplete tumor regression[147]
HSSProtein extract from Tegillarca granosaK562/ADM↓mdr1, BCR-ABL and sorcin[177]
Gambogic acidGarcinia hanburyiBalb/cKBM5-T315I3 mg/kg/2 daysIntraperitoneal↓Bcr-Abl, Akt, Erk1/2, and STAT5[229]
TAF273Fraction of Eurycoma longifolia MeOH extractBalb/cK56250 mg/kgIntraperitoneal↑apoptosis and ↓blood vessel formation[258]
NPB001–05Piper betle extractT315I500 mg/kgOrally↓PI3K/AKT, MAPK pathways[275]

Table 2.

In vivo results of anti-CML NPs.

Name of NPNP classDifferentiation of CML cells intoMechanism of actionReferences
CapsaicinAlkaloidErythroid cells↟GATA-1 promoter[2830]
StaurosporineAlkaloidMegakaryocytes↟CD61, CD42b and ↓c-myc[3436]
Crambescidin 800AlkaloidErythroblasts, induction of hemoglobin production⊥S-phase[47]
PiperineAlkaloidMacrophages/monocytes (20/40 μM)[55]
ApigeninFlavonoidErythroid lineage↟ α and ϒ hemoglobin mRNA expression[87]
GenisteinFlavonoidErythroid lineage[92]
EtOH extract of Olea europaeaPlant extractMonocyte lineage↟CD14[243]
EtOH extract of Stellera chamaejasmePlant extractGranulocytes↟CD11b[250]
Huangqi (Astragalus membranaceus)Traditional Chinese medicineErythroid lineage↟β-globin gene expression[272]

Table 3.

List of some NPs and its differentiation capacity.

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 [6774].


Figure 3.

Anti-CML activity of some NPs which include ? flavonoids: 1—Apigenin, 2—Baicalein, 3—Fistein, 4—Galangin, 5—Genistein, 6—Kaempferol, 7—Myricetin, 8—Naringenin, 9—Nobiletin, 10—Oroxylin A and 11—Tamarixetin. Terpenoids: 1—Gukulenin A, 2–4—Hebeiabinin A, D & E, 5—Parvifolines C, 6—3-hydrogenwadaphnin, 7—Tanshinone I, 8—EM23, 9, 10—Felixins F & G, 11—Kadlongilactone D. Polyketides: 1—Epiaspinonediol, 2—aza-EpoB, 3—dEpoF, 4—Heveadride, 5—Gilvocarin HE, 6—Rhizoxin, 7—Salarin C, 8—Tausalarin C, 9—Trineurone E. Lignans: 1—Arctigenin, 2—Cleistanthin A, 3—Honokiol, 4—6-hydroxyjusticidin C, 5—(+) –lariciresinol 9’-p-coumarate, 6—4-methoxy magndialdehyde. Peptides: 1, 2—chujamide A, B, 3—gombamide A.

Oroxylin A, an O-methylated flavone, found in the medicinal plant Scutellaria baicalensis, was tested against MDR K562/ADR cells. Oroxylin A specifically enhanced the sensitivity of K562/ADR to ADR by selectively inducing apoptosis. The treatment downregulated CXCR4 expression and inhibited PI3K/Akt/NF-κB pathways [75]. NOD/SCID mice-bearing K562 xenograft, treated with oroxylin A (30 mg/kg BW) alone or in combination with imatinib enhanced the sensitivity of imatinib to K562 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 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 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 [87109].

Flavonoids/flavonoid fractionIC50 value on K562 cellsMechanism of actionReferences
Oroxylin A (o-methylated flavone)↓CXCR4, PI3K/Akt/NF-κB pathways[75, 76]
Quercetin (flavonol)11 ± 2Loss of MMP. ↑caspases 3,8 & ↓Bcl-2, Bcl-xl, Hsp70, telomerase and ⊥G2/M phase[7786]
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 (Luxemburgia nobilis)89 μM[102]
Isochamaejasmin (biflavonoid) (Stellera chamaejasme L)24.51 ± 1.62 μM↟caspases 3, 9 and PARP cleavage[103]
Protoapigenone (total flavonoid fraction of Macrothelypteris torresiana)0.9 μg/ml[104]
Total flavonoids from Lysimachia clethroides Duby (ZE4)↓Bcl-2 and ↑Fas, TRAIL & DR5[105]
Total flavonoids of Astragali Radix98.63 mg/L↓ cyclin D1 mRNA levels and ⊥G0/G1 phase[106]
Total oligomer flavonoids of Rhamnus alaternus196 μg/ml[107]
Flavonoid-enriched Rhamnus alaternus root and leaf extracts165 and 210.73 μg/ml[108]
Epigallocatechin-3-gallate (Camellia sinensis)50 μM↓CyclinD1, CDC25A and ↑TGF-β2[109]

Table 4.

Anti-CML activity of flavonoids.

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 [110115].

Sesquiterpenoids, diterpenoids, sesterterpenoids and triterpenoidshas been shown to potently inhibit CML cell proliferation and induce apoptosis (Figure 3) (Table 5) [116144]. Other diterpenoids such as scapaundulin C (from Scapania undulate (L.) Dum.,) [120], parvifoline Z, parvifoline AA (from Isodon parvifolius) [121], labdane-type diterpenes (from Chloranthus henryi Hemsl.) [124] and sesterterpenoid compounds 3, 11 and 12 (from Sarcotragus sp.) [133] and triterpenoid compounds 1, 2, 5, 7 and 9 (from Ganoderma hainanense) [135], (24R/S)-24-hydroxy-3α 10α-epoxy-9-eip-cucurbita-25-ene (1a, b) (from Fructus Viticis Negundo) [136] are also shown to efficiently inhibit CML cell proliferation.

Terpenoid className of terpenoidSource of isolationIC50 value on K562 cellsMechanism of actionReferences
SesquiterpenoidsEM23Elephantopus mollis10.8 μM↟ caspases, PARP cleavage and ↓ NFκB. Loss of MMP[116]
DiterpenoidsCaesalminaxin D and HCaesalpinia minax9.9 ± 1.7 and 9.2 ± 0.9 μM[117]
Gukulenin A and diterpenoid pseudodimers (2–5)Phorbas gukhulensis*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 15petroleum ether soluble fraction of the aerial parts of Tirpitzia ovoidea ethanol extract86.4, 66.3, 91, 45.1 and 58.6 μM[119]
7β,11β,14β-Trihydroxy-ent-kaur-20-al-6,15-dioxo-16-eneIsodon xerophilus0.04 μM[122]
Hebeiabinin A, D and EIsodon rubescens var. rubescens53.21, 5.05 and 0.91 μM[123]
Parvifolines CIsodon parvifolius13.8 μM[125]
3-HydrogenwadaphninDendrostellera lessertii15 nM con. caused 45% apoptosis[126]
Enanderianins K—P, Rabdocoetsin B and DIsodon enanderianus0.13–0.87 μg/ml[127]
Ludongnin JIsodon rubescens var. lushiensis0.18 μg/ml[128]
Tanshinone ISalvia miltiorrhiza Bunge.38 ± 5.2 μM↟ Bax, caspase 3 and ↓Survivin[129]
ent-Kaurane diterpenoids 11, 16, 17 and 20Isodon nervosus2.39, 4.11, 1.05 and 1.55 μM[130]
5-EpisinuleptolideacetateSinularia species4.09 μg/ml↓c-ABL, Akt, NFκB[144]
SesterterpenoidsFelixins F and GIrcinia felix1.27 and 19.9 μM[131]
Compounds 8, 9Smenospongia sp.*0.11 and 0.97μ/ml[132]
Two linear furanosesterterpenesSmenospongia sp.3 and 31.6 μg/ml[134]
Triterpenoids3β,21β,24-Trihydroxyserrat-14-en-24-(4′-hydroxybenzoate)Palhinhaea cernua56.1 μg/ml[137]
L-Arabinopyranosyloleanolic acidGarcinia hanburyi resin4.15 μM[138]
NortriterpenoidsSchisandra propinqua var. propinqua>100 μM[139]
Kadlongilactone DKadsura longipedunculata1.92 μM[140]
Six triterpenesfractions of Aceriphyllum rossii methanolic extract12.2—28.7 μM[141]
Argetatin BParthenium argentatumCytotoxic at 5—25 μM con.[142]
Celastrol (quinone methide triterpene)Tripterygium wilfordii Hook F↓pSTAT5, p-CRKL, pERK1/2, p-Akt, p-BCR-ABL, Bcl-xL, Mcl-1, survivin, Hsp90[143]

Table 5.

Anti-CML activity of terpenoids.

[i] - *LC50, lethal concentation.

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) [146155].

Type of NPName of compoundSource of isolationIC50 value on K562Mechanism of actionReferences
PolyketidesEpiaspinonediolAspergillus sp. 16–02–144.3 μg/mL[146]
GeldanamycinStreptomyces Hygroscopicus↓c-Raf, Akt, BCR-ABL[148]
HeveadrideAscomycota Dichotomyces cejpii82.7 ± 11.3 μM↟ TNFα[149]
Gilvocarin HEStreptomyces sp. QD01–245 μM[150]
RadicicolDiheterospora chlamydosporia and Monosporium bonorden↓p-Raf1, p-BCR-ABL[151]
RhizoxinBurkholderia rhizoxina5×10−7 μg/ml[152]
Salarin CFascaplysinopis sp.0.1 μM↟ caspase 3 and 9 cleavage[153]
Tausalarin CFascaplysinopis sp.1 μM[154]
Trineurone EPeperomia trineura26 μM[155]
LignansArctigeninAsteraceae family↑Bax and ↓ Bcl-2[157]
Cleistanthin ACleistanthus collinus (Rox B)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]
HonokiolMagnolia officinalis Rend. Et wils.28.4 μM[160]
6-Hydroxyjusticidin CJustica procumbens43.9 ± 2.9 μM↟ROS levels, casapase 3[161]
(+)-Lariciresinol 9′-p-coumarateLarix olgensis var.koreana.2.9 μg/ml[162]
4-Methoxy magndialdehydeMagnolia officinalis3.9 μg/ml[163]
SaponinsAstrgorgiosides A, B, C (19-norand aromatized B ring bearing steroid aglycone)Astrogor dumbea26.8—45.6 μM[168]
Wattoside G, H, and I (steroidal saponins)Tupistra wattii Hook.F.35.67, 76.16 and 76.96 μM[169]
Tenacissoside C (steroidal saponins)Marsdenia tenacissima31.4 μM↓ cyclin D, Bcl-2, Bcl-xL and ↑caspases 3, 9, Bax and Bak[170]
Compounds 14 and 15 (C21-steroidal pregnane sapogenins)Cynanchum wilfordii roots6.72 μM[171]
Total saponin contentAralia TaibaiensisLoss of MMP. ↑ Bax and ↓ Bcl-2[172]
Saponin rich fraction (GSE)Gleditsia sinensis Lam. fruit extract18 ± 1.6 μg/ml↑ Bax and ↓ Bcl-2, PCNA[173]
23-Hydroxybetulinic acidTotal saponin content of Pulsatilla chinensis (Bunge) Regel↟ Bax, caspase 3 cleavage and ↓ Bcl-2, survivin[174]
PeptidesChujamides A and BSuberites waedoensis*37 and 55.6 μM[175]
Gombamide AClathria gombawuiensis*6.9 μM[176]

Table 6.

Anti-CML activities of polyketides, lignans, saponins and peptides.

[i] - *LC50—lethal concentation.

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) [157163].

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) [166174].

2.7. Peptides

Two peptides, chujamides A (1) and B (2), isolated from the marine sponge Suberites waedoensis inhibited K562 cell growth with LC50 values of 37 and 55.6 μM [175]. Another peptide, gombamide A (1), isolated from the marine sponge Clathria gombawuiensis inhibited CML cell proliferation with LC50 of 6.9 μM [176]. Haishengsu (HSS), a protein extract from Tegillarca granosa, when administered in mice-bearing MDR K562/ADM cell tumors inhibited tumor growth and downregulated mdr1 gene, BCR-ABL and sorcin [177]. HSS was also tested against MDR K562/ADR cells, and it induced apoptosis at 20 mg/l [178]. HSS also inhibited K562 cells at G0/G1 and S phase and lowered Bcl-2 and enhanced Bax levels (Figure 2) (Table 6) [179].

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) [180230]. Moreover, many plant crude extracts enriched with NPs inhibited the CML cell proliferation and induced apoptosis (Table 8) [231280].

Name of NPSource of isolationIC50 value on K562 cellsMechanism of actionReferences
Acetylenic metabolitesStelletta sp.43.5, 51.3 and 62.5 μg/ml[180]
Betanin (betacyanin pigment)Opuntia ficus-indica40 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-carbaldehydeClausena lansium (Lour.) Skeels20.48 ± 1.78, 26.5 ± 2.12 and 23.49 ± 1.85 μg/ml[184]
Toxicarioside F and GLatex of Antaris toxicaria (Pers.) Lasch[185]
Pangelin and oxypeucedanin hydrate acetonideAngelica dahurica8.6–14.6 μg/ml[186]
Mamea A/BACalophyllum brasiliense0.04–0.59 μM[187, 188]
Cryptotanshinone (lipid soluble active compound)Salvia miltiorrhizainduced apoptosis ↑ PARP cleavage and ↓BCR-ABL, STAT3, mTOR & eIF4E[189, 190]
Bavachalcone (Chalcones)2.7 μM[191]
Polyanthumin (novel chalcone trimmer) and sulfuretinMemecylon polyanthum H.L. Li.45.4 and 30.5 μg/ml[192]
(−)-CubebinPiper cubeba8.66 ± 0.43 μM[193]
Denbinobin5-Hydroxy-3,7-dimethoxy-1,4-phenanthraquinone1.84 μM↓ BCR-ABL, CrkL and⊥G2/M phase[194]
Digallic acidPistascia lentiscusInduced DNA fragmentation and pro-apoptotic effect in CML cells[195]
1,4,5-Trihydroxy-7-methoxy-9H-fluoren-9-one, dendroflorin and denchrysan (fluorenones)Dendrobium chrysotoxum32.18, 26.65 and 52.28 μg/ml[196]
C27-Steroidal glycosideLiriope graminifolia (Linn.) Baker18.6 μg/ml[198]
9α-Acetoxyartecanin, apressin, inducumenone and centaureidinAchillea clavennae9.84 ± 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 acidMethanol extracts of proso and Japanese millet68 μM[201]
β- and α-MangostinGarcinia malaccensis0.40 μM and 0.48 μM[202, 203]
Nudifloside and linearoside (iridoid)EtOH extract of the aerial parts of Callicarpa nudiflora Hook20.7 and 36 μg/ml[204]
Parthenolide17.1, 8.67 and 9.42 for 24, 48 and 72 hInduced apoptosis[205]
PerezonePerezia spp.Cytotoxic to CML cells at 25, 50 and 100 μM and induced apoptosis[206]
Compound 6a (phenalenone metabolite)Coniothyrium cereal8.5 μM[207]
Polyphyllin DParis polyphyllin↟ p21, Bax, caspase 3 & Cyt. C release and ↓ cyclin B1, cdk1, Bcl-2. Loss of MMP and ⊥ G2/M phase[208]
Polysaccharide (PSP001)Punica granatum52.8 ± 0.9 μg/ml[209]
Riccardin F and Pakyonol (macrocyclic bisbenzyls)Plagiochasm intermedium0–6 μg/ml[210]
Highly methoxylated bibenzylsFrullania inouei11.3–49.6 μM[211]
Sarcovagine and β-sitosterol 5- 8Sarcococca saligna2.5–5 μM[212]
Squamocin (annonaceous acetogenins)↟ cdk inhibitors, p21, p27 & ↓ cdk1, cdk25c and ⊥G2/M phase[213]
Klyflaccisteroid JKlyxum flaccidum12.7 μM[214]
Suvanine (N,N-dimethyl-1,3-dimethylherbipoline salt) and suvanine-lactam derivatives (4–8)Coscinoderma sp. sponge* 2.2, 1.9, 3.9, 4.6, 3.9 and 3.6 μM[215]
ar-TurmeroneCurcuma longa L20–50 μg/mlInduced DNA fragmentation and apoptosis[216]
Terpene metabolites (1–3)Clathria gombawuiensis*4.7, 3.9 and 2.1 μM[217]
Toxicarioside H (nor-cardenolide)Antiaris toxicaria (Pers.) Lesch0.037 μg/ml[218]
TripolideChinese herbal extract↓ Nrf2 and HIF-1α mRNA and protein expression[219]
10-(Chrysophanol-7′-yl)-10-hydroxychrysophanol-9-anthrone and ramosinFractions of EtOH extract of Asphodelus microcarpus Vivi0.15 ± 0.02 and 0.65 ± 0.01 μM[220]
Withametelins I, J, K, L and NMeOH extract of Datura metel flowers0.05, 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 and Loss of MMP[222]
Gaudichaudic acid, isogambogenic acid and deoxygaudichaudione A (xanthones)Garcinia hanburyi resin0.41 ± 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 VIsodon rubescens var. rubescens0.3–7.3 μg/ml[224]
Hyperbeanols B and DMeOH extract of Hypericum beanie16.9 and 20.7 μM[225]
Rhodexin ARhodea japonica19 nM⊥G2/M phase induced apoptosis[226]
CurcuminCurcumina longa20 μg/ml↓BCR-ABL, Hsp90, WT1[227, 228]
Gambogic acidGarcinia hanburyi0.62 μM↓p-BCR-ABL, pSTAT5, p-CRKL, pERK1/2, p-Akt[229, 230]

Table 7.

Anti-CML activity of other natural products.

[i] - *LC50–lethal concentation.

Plant extractIC50 value on K562 cellsMechanism of actionReferences
Acetone extract of Peucedanum nebrodense (Guss.) Strohl.,14–10.27 μg/ml[231]
AQE extract of Cornus officinalis Sieb. et Zuce100 μg/ml[232]
AQE extracts of the husk fiber of the typical A and common varieties of Cocos nucifera (Palmae)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 Rhodiola imbricate↓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 Fraxinus)↟ caspase 9, JNK-1,2, p38 MAPK and ↓ Bcl-1, Erk-1/2 & PKB phosphorylation[235]
Chloroform extract of Polyalthia rumphii stem40–60μ/ml[236]
Chloroform extract of Tecomella undulata bark30 μg/ml↟ FAS, FADD, & caspase 8, 3/7. Induced DNA fragmentation & apoptosis[237]
DCM) extract of Psidium guajava L.32 μg/ml[238]
DCM extract Artemisia turanica Krasch69 μg/ml↟ caspases, PARP cleavage. Induced DNA damage and apoptosis[239]
HEX and DCM extract of Mesua beccariana*20 ± 1.5 and 43.75 ± 0.78 μg/ml[240]
HEX and DCM extract of Mesua ferrea*17.5 ± 1.02 and 22.91 ± 1.25 μg/ml[240]
HEX extract of Mesua congestiflora40.63 ± 1.45 μg/ml[240]
DCM fraction of Melissa officinalisAt 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 Echinops grijissi Hance roots30 μg/ml[242]
EtOH extract of Pereskia sacharosa130 ± 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 Melipona orbignyi)At 250 and 500 μg/ml promoted cell death of CML cells by 15 ± 1 and 63 ± 2%[245]
EtOH extract of Isodon japonicas2.7 μg/ml[246]
EtOH root extract of Allamanda schottiiAt 800 μg/ml showed cytotoxicity[247]
EtOH stem and leaf extract of Physalis peruviana0.02 and 0.03 g/ml[248]
Alcoholic extract of Dendrostellera lessertii28 μl and 5 × 10−9M[249]
EtOH extract of Rosmarinus officinalis L1/400 dilution[251]
EtOH extract of Goldfussia psilostachys0.5 μg/ml↟ CML cells in G2/M phase[252]
Fraction from EtoAc of Caesalpinia spinosa44.5 ± 4.05 μg/mlinduced chromatin condensation. Loss of MMP & ↑ caspase 3[253]
EtoAc extract of Helichrysum plicatum flowers25.9 μg/ml[254]
MeOH extract of Linum persicum0.1 μg/ml[255]
MeOH extracts of Echinophora cinerea and Cirsium bracteosumLess than 20 μg/ml[256]
MeOH extract of Galium mite39.8 μg/ml[256]
MeOH extract of Cyperus rotundus175 ± 1.2 μg/mlInduced DNA damage[257]
TAF273, F3 and F4 fractions of MeOH extract of Eurycoma longifolia Jack19, 55 and 62 μg/ml[258]
MeOH extract of Rhaphidophora korthalsiiEnhanced Natural killer cells to kill K562, ↟IFN-ϒ, TNF-α[259]
MeOH extract of Rhinella jimi Stevaux (Anura: Bufonidae) skin*235 μg/ml[260]
MeOH extract of Hypericum perforatum L.flower extractInduced apoptosis[261]
HEX, DCM, EtoAc, butanol and MeOH extracts of Helichrysum zivojinii Černjavski and Soška11.78 ± 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 Erythroxylum caatingae plowman13.1 ± 0.63, 9.86 ± 0.56, 11.21 ± 0.46, 33.58 ± 1.33 μg/ml[263]
DCM extract of Arctium lappa root^17 μg/ml[264]
Alisma orientalis (Sam) Juzep extractReverse of MDR[265]
Polyphenolic extract of Ichnocarpus fructescens leavesAt 5, 10, 20 μg/ml con. ↓K562 cell proliferation[266]
EtOH extract of Orbignya speciosa33.9 ± 4.3 μg/ml[267]
Coptis chinensis and Epimedium sagittatum extracts29 and74 μg/ml[268]
Sangre de Drago is red viscous latex extract of Croton lechleri2.5 ± 0.3 μg/ml[269]
Dionysia termeana extract20 μg/ml[270]
Ganoderma lucidum extract*50 μg/ml[271]
Crude MeOH extracts of Luehea candicans Mart. et Zucc. branches and leaves#8.1–5.4 μg/ml[273]
Nerium oleander extract↓p-gp[274]
Ponicidin (Rabdosia rubescens extract)↓ Bcl-2 and ↑ Bax, caspase 3 & PARP cleavage[276]
Scutellaria litwinowii Bornm. and Sint. ex Bornm.↟ caspase 3,8, PARP cleavage, Bax/Bcl-2 ratio[278]
Swietenia mahagoni leaf extract↟ caspases 3,9, Cyt. C release and ⊥G2-M phase[279]
Viscin, (lipophilic extract from Viscum album L)252 ± 37 μg/ml[280]

Table 8.

Anti-CML activity of plant extracts.

[i] - AQE, aqueous, DCM, dichloromethane, HEX, hexane, EtOH, ethanol, EtoAc, ethyl acetate, MeOH, methanol, ^TGI, tumor growth inhibition,*ED50, –effective concentration; # GI50, growth inhibition.

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. In vivo results have clearly shown that NPs potently suppress tumor growth. In sum, NPs serve as an inexhaustible source which renders an attractive alternate strategy to combat CML.

Conflict of interests

The authors declare that they do not have any competing interests.


CMLchronic myeloid leukemia
PhPhiladelphia chromosome
MAPKmitogen activated protein kinase
STATsignal transducers and activator of transcription
PI3Kphosphoinositide 3-kinase
TKIstyrosine kinase inhibitor
FDAFood and Drug Administration
MDRmulti drug resistance
NPsnatural products
NCEsnew chemical entities
K562/IRimatinib resistant K562 cell line
cyt. Ccytochrome C
BWbody weight
Hsp90heat shock protein 90
BBD94-chlorobenzoyl berbamine
PARPPoly(ADP-Ribose) polymerase
LC3 IILC3-phosphatidylethanolamine conjugate
DNA-PKDNA-dependent protein kinase
UCN-017-hydroxy staurosporine
MMPmitochondrial membrane potential
p-p38-MAPKp-p38 mitogen-activated protein kinase
SLCsolute carrier
hTERThuman telomerase reverse transcriptase
IUisoprene units
PKSspolyketide synthases
HJC6-hydroxyjusticidin C


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