Anticancer Effects and Mechanisms of Artemisinin and Its

Derivatives on Hematological Malignancies

Xinlei An

†

, Qiao Huang

†

and Yuheng Wu

†

College of Grassland Science, Xinjiang Agricultural University, Xinjiang, 830052, China

Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, 999077, China

College of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan, 430074, China

†

These authors contributted equally

Keywords:

Artemisinin, Dihydroartemisinin, Hematological Maglignancies.

Abstract:

Traditional Chinese medicine believes that artemisinin (ART) could treat malaria which are extracted from

artemisia. Modern medicine found that except the use of curing malaria, artemisinin and its derivatives also

show anticancer activities in vitro and in vivo by reducing the proliferation, migration, invasion,

tumorigenesis and metastasis of cancer cells. As the components of natural plants, artemisinin and its

derivatives demonstrated multi-specific manner in the treatment of hematological malignancies. The major

mechanisms of effects of artemisinin and its derivatives on anticancer activities include induction of apoptosis,

inhibition of angiogenesis, inhibition of proliferation, etc., through regulating multiple pathways, such as JNK,

KDR / Flk-1, MAPK, STAT3 and Wnt/β-catenin signalling pathways. This review discusses the anticancer

activity of artemisinin, artesunate and dihydroartemisinin (DHA) in the treatment of hematological

malignancies, and from which it is demonstrated that ART and its derivatives are effective in vitro and in vivo.

Future research is required in this promising field of cancer drug discovery.

1 INTRODUCTION

Hematological malignancies is the general name of a

large class of malignant tumors originated from

hematopoietic system, mainly including leukemia,

lymphoma and myeloma. It has become a severe

challenge to public health and public hygiene.

According to the statistics of common malignant

tumors in China, the acute leukemia and lymphoma

in hematological malignancies rank the top ten in the

"ten common malignant tumors", and the incidence

rate is increasing year by year. Multiple myeloma is

the second most common malignancy in the blood

system. The incidence rate has also increased in

recent years. Except the old way of treating cancer

such as chemotherapy, World Health Organization

publicated that artemisinin is one of the most efficient

drugs for the treatment of resistant malaria (World

Health Organization 1998). In recent years,

increasing amount of artemisinin's other functions

https://orcid.org/0000-0002-3172-9537

https://orcid.org/0000-0002-5043-8372

https://orcid.org/0000-0001-7415-043X

have been discovered and applied, such as treatment

potential on pulmonary hypertension, anti-diabetes

effects, anti-fungal, immune regulation, antiviral

effects (Kapepula 2020). Importantly, anti-cancer

effects of artemisinin within the scientific and

medical community are evidenced by the fact that the

Nobel Prize in Medicine and Physiology was

awarded in 2015 for the discovery of artemisinin in

China by the pharmaceutical chemist Tu Youyou (Su

2015). Hence, among these numerous effects,

anticancer effect of artemisinin and its derivatives

attracted attention of researchers with its properties of

well-tolerance by human body and no significant

side-effect.

As a derivant of artemisinin, artsunate also

presents potential anticancer activity. Several studies

showed varying degrees of inhibitory effect on liver

cancer cells, breast cancer cells as well as lung cancer

cells in vitro (Sun 2015, Dong 2014). This review

summarizes its potential anticancer mechanisms on

An, X., Huang, Q. and Wu, Y.

Anticancer Effects and Mechanisms of Artemisinin and Its Derivatives on Hematological Malignancies.

DOI: 10.5220/0011377300003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 1057-1064

ISBN: 978-989-758-595-1

1057

inducing tumor apoptosis and inhibiting

angiogenesis.

Dihydroartemisinin (DHA), which is another

derivative of artemisinin with better water solubility,

could be more easily absorbed by the human body

(Adam 2018). This review discusses the treatment

with hematological malignancies with DHA and the

potential mechanisms including its role of inhibiting

cancer cell proliferation (Zhang 2019), as well as

inducing cancer apoptosis (Yan 2018, Hu 2018).

Figure 1: The chemical structure of artemisinin, artesunate

and dihydroartemisinin.

2 CONSTRUCTION AND

ANTICANCER EFFECT OF

ARTEMISININ

2.1

Description of Specimens

Artemisinin, with the formula of C

, is a

sesquiterpene (Fig1) (Kumar 2017). High-resolution

mass spectrometry (HRMS) showed a molecular ion

at m/z 282.1470 which is corresponding to the

formula C15H20 (Zheng 1994). The reaction with

triphenylphosphine to give the phosphine oxide

proved that there's a peroxide group in artemisinin

(Kumar 2017). However, research showed that there

existed some shortcomings such as short half-life and

poor solubility when artemisinin was applied to

cancer cells (Zhang 2020). Hence, efforts have been

made to synthesis hybridization of artemisinin as well

as other anticancer physicochemical for triggering a

solution toward these problems (Meunier 2008).

2.1.1 The Cytotoxicity Activity of

Artemisinin

Nine sesquiterpene compounds were tested for their

cytotoxicity toward several cancer cell lines, though

only artemisinin exhibited potent cytotoxicity toward

A-549 (human lung carcinoma), P-388 (murine

lymphocytic leukemia) and HT-29 (human colon

adenocarcinoma) cells with ED

values of 0.0962,

4.16, and 4.41μg/ml, respectively (Zheng 1994).

Apart from these cell lines, another group tested the

cytotoxicity of artemisinin to Ehrlich ascites cancer

cells by microculture tetrazolium (MTT) assay and

found a dramatic inhibition of cell proliferation with

of 29.8μM (Woerdenbag 1993).

Hence, Artemisinin showed higher cytotoxicity

toward most of cancer cells, implying a potential

therapeutic way to treat cancers in clinical medicine.

However, importantly, artemisinin has stronger

cytotoxicity effects on normal cells than its

derivatives which may lead to the death of normal

tissues and consequently potential side effect, which

makes it urgent to find more derivatives with efficient

anticancer effects while less cytotoxicity on normal

cells.

2.1.2 Artemisinin Induces Apoptosis

It was found that B cell-specific Moloney murine

leukemia virus integration site 1 (BMI1) inhibitors

induced apoptosis with a fluorescence-activated cell

sorting (FACS) assay (Ohtaka 2017). Artemisinin, as

one of the BMI1 inhibitors, was found potential

therapeutic effects on six acute myeloid leukaemia

and two normal lymphoblastic cell lines (Hu 2018).

It’s showed in the Dose-response curves that ART

suppressed multiplication of Jurkat cells, which

provided another evidence that artemisinin inhibits

some certain cancer cells proliferation (Ohtaka

2017).

Besides the inhibition function, ART also didn’t

weaken the multiplication of normal cells within the

concentration range used (Ohtaka 2017). In this case,

a potential advantage of using artemisinin as a

treatment toward leukemia is that it may minimize

leukemia cell proliferation while seldom infect the

normal lymphocyte. Studies on patients with

artemisinin also showed well-tolerance and did not

show severe side effects based on a large number of

clinical trials of artemisinin (Efferth 2010).

Artemisinin decreased the expression of BMI1,

NOTCH1, and in Jurkat cells it nullified NOTCH1

and the downstream targets of NOTCH, indicating

that a potential mechanism of artemisinin inducing

apoptosis is to down-regulate the expression of BMI1

and NOTCH1 (Ohtaka 2017). BMI inhibitors might

be used as drugs targeting leukemia stem cells owing

to its ability to regulate cell stemness (Ohtaka 2017).

However, there should be more experiments to clarify

molecular pathways targeted by BMI inhibitors, as

well as test their effects for normal hematopoietic

stem cells.

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

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2.2 Artesunate

Artesunate is a water-soluble esterification derivative

of artemisinin. The anticancer mechanisms of

artesunate involve induction of reactive oxygen

species (ROS) production and ROS dependent DNA

damage, inhibition of angiogenesis, induction of

apoptosis and cell cycle stagnation (Zhang 2015).

2.2.1 Pro-apoptosis Effect

It was found that ART may induce cell proliferation

and programmed cell death in human leukemia cells,

which have been proven in in vitro tests on cell line

K562 (Sun 2015). The effects of different

concentrations of Artesunate on the viability of K562

cells decreased (98.9 ± 2.3 % to 37.9 ± 6.2 %) with

the increase of drug concentration (0 to 400 μmol/L)

as a dose-dependent manner (Sun 2015). Specifically,

Artesunate played an pro-apoptosis effect of K562

cells, as the study showed that after 24 hours of

treatment with 100μmol/L Artesunate, there were

increasing number of cells in early apoptosis (2.48 ±

0.9%), late apoptosis (9.96 ± 1.5)% and necrotic cells

(3.25 ± 0.5)% compared with the control group (1.46

± 0.7)%, (2.79 ± 0.6)%, and (1.68 ± 0.4)%,

respectively (Sun 2015). Hence, the Bcl-2 family

members play an important role in regulating

apoptosis in intrinsic pathway, which can be divided

into anti-apoptosis including Bcl-2 and Bcl XL, as

well as pro-apoptosis including Bid, Bax, Bad, and

Bim. Bcl-2 may suppress the apoptosis-inducing

signals while Bax may antagonize Bcl-2 by

promoting apoptosis. Furthermore, the ratio of these

two molecules determines the survival or apoptosis of

cells. Artesunate was displayed the dual role for the

anti-apoptotic Bcl-2 protein in mitochondria and

endoplasmic reticulum of cancer cells (Alk 2014).

Studies showed that after 24 hours with 100μmol/L

of Artesunate treatment, it exerted a positive effect on

the expression of Bcl-2 while did not change the

expression of Bcl-2 significantly (Alk 2014),

indicating that the pro-apoptosis effect of Artesunate

may be related to the regulation of Bcl-2 family and

potentially the intrinsic pathway.

The cell cycle of K562 cell lines was also affected

under Artesunate treatment, with a decreasing cell

population in the S phase while increasing the cell

population in the G2M phase in a dose-dependent

manner. After the treatment with a higher

concentration of Artesunate (200μmol/L), the

percentage of apoptosis was up to 39.65%, and the

cells in the S and G2M phase were reduced (Sun

2015). Moreover, with an increase of drug

concentration, cell proliferation was significantly

inhibited in a dose-dependent manner. Applying

12.5, 25, 50, 100, 200 and 400 μmol/L ART inhibits

rates of cell proliferation by (6.90 ± 3.3)%, (17.8 ±

5.5)%, (38.4 ± 5.8)%, (52.8 ± 6.1)%, (64.0 ± 5.8)%,

(69.9 ± 7.2)%, respectively, and the 50%

proliferation inhibition concentration (IC

) was

about 95.0 μmol/L (Sun 2015).

In summary, Artesunate could regulate cell cycle

change, inhibit cell proliferation, and induce

apoptosis through the intrinsic pathway, which may

be related to the down-regulating expression level of

Bcl-2 and the up-regulating expression level of Bax

(Solaini 2011). The in vitro methods that usually used

in related studies include cell culture, cell vitality

detection, apoptosis detection, cell proliferation

detection, cell cycle analysis, etc. (Sun 2015), while

further in vivo studies as well as potential clinical

research are required to further understanding the

influence of Artesunate on cell proliferation process.

2.2.2 Anti-angiogenesis Effects

Angiogenesis is one of the critical process to

migration, division, and differentiation of vascular

endothelial cells or stromal stem cells, followed by

the formation of lumen structure, and consequently

malignant growth and metastasis of tumors (Zhang

2007). Various research showed an inhibition effect

of Artesunate on angiogenesis. For instance, at the

concentration range of 0.5-50 μmol/L, Artesunate

significantly supressed angiogenesis in a

concentration-dependent manner (Li 2013).

However, the mechanisms of Artesunate induced

anti-angiogenesis effects have not been fully

recognized.

Tumor cells and endothelial cells may interact

with each other to regulate tumor angiogenesis.

During this process, the vascular endothelial growth

factor (VEGF) is one of the most important major

ligand for angiogenesis leading to malformation and

dysfunctional vascular system, activates two tyrosine

kinase receptors, VEGFR-1 (Flt-1) and VEGFR-2

(KDR / Flk-1). After the activation of these two

receptors, the sign for angiogenesis will be enabled

(Shibuya 2011). Studies have found that Artesunate

may play a role in mitigating the activation of KDR /

Flk-1 and consequently affects the process of

angiogenesis with limited production of pro-

angiogenic cytokines from tumor cells (Wei 2017). It

was found that Artesunate significantly inhibited the

proliferation, migration, and subsequent tube

formation of human umbilical vein endothelial cells

(HUVEC), with a significantly decreased expression

Anticancer Effects and Mechanisms of Artemisinin and Its Derivatives on Hematological Malignancies

1059

of Flt-1 and KDR / Flk-1 in endothelial cells.

Moreover, in embryonic samples derived from mouse

embryonic stem cells, Artesunate down-regulated

HUVEC Bcl-2 while up-regulated Bax levels, caused

changes in the proportion of Bcl-2 and Bax, and

significantly induced HUVEC apoptosis (Wu 2004).

Importantly, the mRNA expression of more than 6

angiogenic genes is related to the sensitivity and drug

resistance of tumor cells to eight artemisinin

derivatives (Anfosso 2006), which provided a clue as

to potential clinical precise therapy.

Taken together, the anti-angiogenesis

mechanisms of Artesunate may be related to

disarranging pathways including JNK, p38 MAPK,

KDR / Flk-1 and Akt, etc. (Table 1). Subsequently,

Artesunate could inhibit endothelial cell

proliferation, induce endothelial cell apoptosis, and

play an anti-tumor angiogenesis role by inhibiting

VEGF expression, downregulating Flt-1 and KDR /

Flk-1 expression levels, downregulating Bcl-2, as

well as upregulating Bax levels, and in turn

suppression the vessel formation.

Table 1. Mechanisms underlying the anti-angiogenesis effects of Artesunate (modified from Ref. (Wei 2017)).

Cell types Mechanisms Artesunate effect Ref(s)

HUVECs JNK activation ↓

p38 MAPK activation ↑

KDR / Flk-1 activation ↓

Proliferation ↓

Apoptosis ↑

Angiogenesis ↓

(Cheng 2013)

(Wu 2004)

RAFLS Akt phosphorylation ↓

Akt phosphorylation ↓

Production of VEGF

and IL-8↓ IL-8

production↓

(Uckun 2021)

(Xu 2007)

2.3

Dihydroartemisinin

Dihydroartemisinin (DHA) is semi-synthesized from

artemisinin which is modified to retain the

antimalarial active group. Thus, DHA contains the

hydroxyl group, which greatly improves its

antimalarial effect. As shown in Fig.1, its anticancer

effect mainly depends on its unique peroxide bridge

structure. The DHA is more water-soluble than

artemisinin and is easier to be absorbed by the human

body. Hence, it has been showing the great

advantages of a faster metabolism rate, more efficient

effect, and lower toxicity (Adam 2018).

The anticancer activity of DHA in the treatment

of hematologic malignancies was discussed from

three aspects: inhibition of cancer cell proliferation

and DHA induction of cancer cell death.

2.3.1 DHA Inhibits Cancer Cell

Proliferation

DHA can inhibit the proliferation of leukemia cell

K562 by inhibiting aerobic glycolysis mediated by

Pyruvate kinase M2 (PKM2) and glucose transporter

1 (GLUT1). Gao et al. illustrated the inhibitory effect

of DHA on the proliferation of human chronic

myeloid leukemia cells by presenting an example of

the inhibitory effect of DHA on human chronic

myeloid leukemia K562 cells (Gao 2020).

The rapid growth of cancer cells requires a

dramatic increase in glucose and glucose metabolites.

Normal cells obtain energy mainly through oxidative

phosphorylation of mitochondria, while most cancer

cells rely on aerobic glycolysis. Glycolysis produces

large amounts of lactic acid and induces metabolic

waste. Lactic acid, in turn, promotes the development

of cancers (Zhang 2019). Thus, the specific

dependence of cancer cells on glycolysis makes them

susceptible to specific glycolysis target inhibitors.

Figure 2: mechanisms of DHA induced proliferation

inhibition and apoptosis.

Overexpression of glucose transporters (GLUTs)

can be usually observed in cancer cells to regulate the

"Warburg effect" in cancer cells. It was found that

DHA can gradually inhibit the expression of GLUT1

at protein levels (Gao 2020). These results indicated

that DHA could inhibit lactate secretion, block

glucose uptake and inhibit GLUT1 expression in

K562 cells through inhibition. At the same time,

DHA may also inhibit PKM2, which is important for

phosphoenolpyruvate (PEP) to generate pyruvate.

Therefore, DHA may regulate the metabolism of

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

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cancer cells by inhibiting the expression of GLUT1

and PKM2, thus inhibiting the proliferation of cancer

cells as shown in Fig.2a (modified from Ref. (Gao

2020)).

2.3.2 DHA Induced Cancer Apoptosis

The increase of abnormal cell response is mainly

through increasing the transmembrane response of

GLUT1. Studies have shown that the low expression

level of cells GLUT1 is related to abnormal

conditions. GLUT1 is the most widely distributed

glucose transporter known, and is highly expressed in

brain, blood-brain barrier, myocardium, adipose

tissue and skeletal muscle, which are adapted to the

glucose needs of the body's microenvironment (Cai

2004, Takata 1990). It has been showing that GLUT1

played an important role in cancer progression and

abnormal expression of GLUT1 has been found in

many cancers. Studies have found that GLUT was

overexpressed in juvenile hemangioma, and an

abnormally elevated expression of GLUT1 was found

in multiple cancers such as pancreatic cancer, gastric

cancer, ovarian cancer, cervical cancer, lung cancer,

and nasopharyngeal cancer (Drut 2004). Thus,

GLUT1 could be regarded as a potential biomarker of

cancer early diagnosis, differentiation of benign and

malignant, as well as prognostic evaluation.

To better understand the anti-cancer effects of

DHA, it has been found that its mechanism of

inducing cancer cell apoptosis is related to multiple

signal pathways, such as PI3K/Akt, MAPK, STAT3,

Wnt/β-catenin, NF-κB and other signal pathways

(Table 2).

Table 2: DHA targets in cancer cell signaling.

Reported target Function/pathway of

tar

DHA

Effect

Ref(s)

PI3K/Akt Activates downstream

target of rapamycin,

mTOR

Inhibits proliferation;

Promotes apoptosis;

Abnormal invasion

(Li 2017)

(Tang 2014)

MAPK Decreases DNA repair

enzyme (PARP)

expression

Down-regulates mRNA

and protein expression

Induces caspase-

dependent apoptosis

Inhibits proliferation

Promotes apoptosis

(Dong 2015)

(Zhang

2017)

STAT3 Regulates of transcription

of target genes

Activates Bax and leads to

programmed cell death

Inhibits proliferation

Promotes apoptosis

(Hu 2018)

Wnt/β-catenin Reduces the adhesion

between cells

Promotes the interstitial

transformation of cells

Promotes apoptosis (Qiao 2016)

Notch Down-regulatesof mRNA

expression in cells

Promotes apoptosis (Liu 2014)

NF-κB Leads to the accumulation

of ROS

Promotes apoptosis (Hu 2014)

Anticancer Effects and Mechanisms of Artemisinin and Its Derivatives on Hematological Malignancies

1061

JAK-STAT signaling pathway is one of the

critical pathways during tumorigenesis by which

DHA induces apoptosis. JAK/STAT signaling

pathway is a widely expressed intracellular signal

transduction pathway stimulated by a variety of

cytokines, which is mainly involved in many

important biological processes such as cell

proliferation, differentiation, and apoptosis.

Lymphocyte adaptor protein (LNK) gene was found

to play an important role in regulating hematopoietic

stem regeneration and proliferation. The protein

encoded by the LNK gene is lymphocyte linker

(SH2B3), which belongs to the SH2B connexin

family and is a key factor in normal hematopoietic.

LNK was highly expressed in hematologic cancer

cells. It was found that LNK mutation could cause

mutations in corresponding domains such as SH2

or/and PH, which may weaken or lose the inhibitory

function of activated JAK receptor and its

downstream genes, and in turn leads to the high

expression of STAT3, as a consequence causing

abnormal proliferation of hematopoietic cells and

accelerating the occurrence and development of

hematologic cancer cells (Vainchenker 2011).

Importantly, studies have showing that expression

level of LNK protein increased after DHA

application, and LNK protein inhibited STAT3

protein expression, so DHA further inhibited STAT3

protein expression. Furthermore, the Bcl-2 protein

level was decreased while Bax protein level was

increased, which promoted the apoptosis of AML

cells (Fig2a) (Yan 2018, Hu 2018).

The effect of DHA on laryngeal cancer was

investigated and it was demonstrated that the

treatment of DHA can prolong the survival time of

mice and inhibit the activation of STAT3 in cancer

cells. These results indicated that DHA inhibits the

invasion and metastasis induced by cancer STEM

cells by inhibiting the activation of STAT3 in

laryngeal cancer (Wang 2020). It was found that

DHA inhibited melanoma proliferation in a time- and

dose-dependent manner by studying the effect of

DHA on melanoma (Yu 2020). Moreover, DHA

significantly promoted mitochondrial apoptosis in

melanoma by regulating the STAT3 pathway.

Researchers studied the antitumor activity of DHA in

head and neck squamous cell carcinoma and found

that DHA showed significant specific inhibitory

effect on STAT3 activation through selective

blocking of Jak2/STAT3 signaling pathway (Jia

2016). In addition, DHA could also inhibit the growth

of squamous cell carcinoma of the head and neck in

vitro and in vivo, possibly by inducing apoptosis and

inhibiting cell migration (Jia 2016).

In summary, DHA may be a STAT3 inhibitor and

may represent a new effective drug for the treatment

of cancer and for the treatment of sensitization in

cancer patients.

3 CONCLUSION

Artemisinin and its derivatives, including artemisinin,

DHA, and artesunate, have been showing remarkable

anticancer effects on hematological malignancies.

Artemisinin and its derivatives may regulate multiple

pathways, such as JNK, KDR / Flk-1, MAPK,

STAT3 and Wnt/β-catenin. A better understanding of

the common mechanisms under similar conditions in

different cell systems would greatly contribute to the

development of targeted artemisinin derivativesas

well as improving the cytotoxicity of artemisinin by

reducing IC

, emergence of drug resistance, drug-

related toxicity and enhancing drug interaction. At

present, there have been a large number of studies

applying artemisinin and its derivatives to the

treatment of various types of cancers. This article

reviews the latest advances in the research of

artemisinin and its derivatives in hematological

malignancies. Various studies have shown that it can

play a role through a variety of mechanisms, such as

inducing cell cycle arrest, inducing autophagy and

apoptosis. In addition, artemisinin and its derivatives

also show anti-cancer effects in many drug-resistant

hematological malignancies, and have a synergistic

effect with other drugs. Nevertheless, the potential

drug reaction, drug interaction, drug resistance, as

well as the side effects toward normal cells remains a

concern. An increasing number of studies have been

focusing on determining the biological activation

mechanism and molecular events behind the

artemisinin effect. However, how artemisinin exerts

its antitumor activity after activation remains unclear.

Besides, future investigation may be required to

futher understand the effects of artemisinin to reveal

potential of artemisinin as a clinical drug on not only

malaria, but also hematological malignancies.

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