Artemisinin Derivatives: Anti-cancer Effects and Mechanisms

Yuwei He

1,† a

, Chang Liu

2,† b

and Linkun Zhang

3,† c

Department of pharmacoanalysis, Heilongjiang University of Chinese Medicine, Harbin, China

Department of chemistry, University of Waterloo, Waterloo, Canada

Department of biotechnology, Henan Normal University, Zhengzhou, China

†

These authors contributted equally

Keywords: Artemisinin Derivatives, Apoptosis, Oncosis, Ferroptosis, SM1044.

Abstract: Abstract-Artemisinin derivatives have been studied as anti-malaria drugs in many aspects, while were found

anti-cancer affects recently. However, the mechanisms of their anti-cancer effect remain unclear. Research

has showed that Artemisinin derivatives may affect the cell cycle of cancer cells through blocking G1 to S

phase, and subsequently reduce cell proliferation. Artemisinin derivatives may also cause oncosis and cancer

cell apoptosis by promoting Ferroptosis. A new water-soluble derivative, SM1044, was found its anti-cancer

ability through inducing apoptosis and blocking cell cycle. Future research is required to better understand

the potential mechanisms as well as to expand their clinical applications.

1 INTRODUCTION

Cancer is a serious hazard to human health and is

listed as one of the most important public health

problems in the world, which needs to be solved

urgently (Yang, 2020). The cancer epidemiology data

released by Bray et al. indicated a great burden caused

on society (Bray, 2018). There were 1,806,590 new

cancer cases and 606,520 deaths in 2020 in the United

States. It was estimated that there would be 28.4

million cancer cases worldwide in 2040 (Liu, 2021).

Artemisinin has been known as an effective anti-

malaria drug. This active ingredient is isolated from

the Chinese herbal medicine Artemisinin annua.

Artemisinin and its derivatives can usually be

extracted from plant species at the same time as a

mixture. They are sesquiterpene lactones with peroxy

bridges, which have strong anti-malarial effects.

Through the structural modification of artemisinin

scientists designed and synthesized new derivatives

of artemisinin. Obtained dihydroartemisinin (DHA)

and new derivatives with different substituents

introduced at each point of dihydroartemisinin.

Through research in recent years, artemisinin and

its derivatives have been confirmed to have anti-

https://orcid.org/0000-0003-4439-0429

https://orcid.org/0000-0002-0763-9670

https://orcid.org/0000-0002-1643-5127

cancer effects, though the mechanisms of their anti-

cancer effects remain unclear. Current researchers

found that the possible mechanism may include the

following aspects: (1) blocking the growth of cancer

cells by inhibiting the cell cycle, such as ART

inducing apoptosis of human retinoblastoma cells

(Yang, 2019); (2) causing cell death through oncosis;

(3) reacting with a huge number of ferrous ions in

cells which are cancerous. Importantly, during the

oncosis and ferroptosis in cancer cells, the oxidative

stress was caused by artemisinin derivatives through

producing of reactive oxygen species, which leads to

the expansion of intracellular organelles, the disorder

of the antioxidant mechanism in cancer cells, as well

as other factors which caused cell death. Though the

mechanisms of oncosis and Ferroptos remain unclear.

The anti-cancer mechanism of the newly synthesized

artemisinin derivative SM1044 and its advantages

over the anti-cancer mechanism of traditional

artemisinin derivatives is a new direction to

preparation and innovation of anticancer drugs.

He, Y., Liu, C. and Zhang, L.

Artemisinin Derivatives: Anti-cancer Effects and Mechanisms.

DOI: 10.5220/0011211500003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 385-390

ISBN: 978-989-758-595-1

385

2 THE MECHANISM OF

ARTEMISININ DERIVATIVES

2.1 Properties of Artemisinin and Its

Derivatives

Artemisinin is a sesquiterpene lactone. There are

several names. Artemisinin, Arteannuin,

Artemisinine, Qinghaosu. It is chemically knows as

(1R,4S,5R,8S,9R,12S,13R)-1,5,9-trimethyl-

11,14,15,16-

tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-

one (Fig.1).

Figure 1: Chemical structure diagram.

Artemisinin is colorless needle crystal and tastes

bitter, soluble in organic solvent. Though by

modifying the structure of the Artemisin such as

doubling hydrogen of artemisinin, in order to improve

the double hydrogen artemisinin molecules

chemically unstable hemiacetal structure, obtained

derivatives showed better antimalarial activity.

Further structure modification could get the

artemether, artemisia ether, artesunate (Fig.1) and

other dissolved solution and better compound

(Mercer, 2007).

The common feature of artemisinin compounds is

that they all have a peroxide bridge structure in their

components. Studies have shown that the peroxide

bridge is an essential structure for artemisinin to exert

its pharmacological activity, and its pharmacological

activity is significantly reduced after the loss of the

peroxide bridge structure (Mercer, 2007).

2.2 Affecting the Cell Cycle by

Blocking G1 to Enter S

Blocking proliferation of uncontrolled cell growth is

one of the important ways to inhibit tumorigenesis. In

the normal cells, cyclin will express special proteins

at specific periods and activate CDK to drive cells to

complete the cell cycle and proliferation. There are

two important stages: G1 to S and G2 to M. This

review focuses on the G1 to S, which rely on the

CyclinD1 combine with the CDK4 (Li, 2018).

CyclinD1 regulates the cell proliferation cycle by

binding and activating to CDK4 protein, which

promotes cell proliferation. Then the complexes

promote the phosphorylation of Rb protein,

promoting the cell cycle from G1 phase to S phase,

and finally accelerating the cell cycle, which

improves the cell proliferation. Researchers found

that high expression of CyclinD1 protein would

accelerated the cell cycle and rapid abnormal

proliferation (Vermeulen, 2003). Eventually, when

cancer cells were inhibited, the expression of

CyclinD1 and CDK4 would be significantly reduced

(Li, 2018). As a result, cell cycle would be negatively

regulated, and cell proliferation would be inhibited.

P16 plays a key role in regulating cell cycle

through preventing the CyclinD1 combining with the

CDK4 (Ding, 2019). In normal cells, the balance of

P16 and cyclinD1 maintains a stable state, which

keeps the cells in a relatively stable cell cycle. One

possible mechanism of conversion from normal cells

to cancer cells is losing control of the cell cycle

(Lutful Kabir, 2013).

DHA, as another derivative apart from

Artesunate, showed an inhibition effect on the

proliferation of cancer cells by blocking the process

from G1 to S phase, which reduced the DNA

synthesis and replication of cells in vitro (Gao, 2020,

Caglar, 2020) (Tab.1). Through determination of

intracellular protein levels, it was found that cyclinD1

and P16 play an important role in the regulation of

cancer cell cycle. With the increase of DHA

concentration, cyclinD1 protein expression was

gradually down-regulated, while P16 protein up-

regulated (Caglar 2020). DHA reduced the combining

of cyclinD1 to CDK4 and up-regulated P16 protein,

thus achieving cell cycle arrested from G1 to S phase

and inducing apoptosis of cancer cells. Importantly,

normal cells also have a complete cell cycle which

may also be one of the targets of anti-cancer drugs

together with cancer cells. Researchers found that

compared with traditional anticancer drugs, DHA has

the advantage of specific selection for cancer cells

(Caglar, 2020). Future research may focus on

explanation of the specific expression of DHA in

cancer cells. If the cancer specificity of DHA can be

combined with molecular targeting technology to find

the specific antigen sites of cancer cells, it might be

able to achieve a breakthrough in the synthesis of

anticancer drugs.

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

386

Table 1: Effect to different cell models within Artemisinin derivatives.

Cell line Dru

Effect Ref.

BGC-823 DHA

Inhibit cell growth.

Induction of apoptosis.

Make cell c

cle sta

in G1.

(Gao 2020)

Panc-1 ART

Mitochondria with decreased matrix

density and swelling of

cristae, cells severely damaged.

(Du 2010)

BJeLR and DRD siGPX4 Cell death (Yang 2014)

BJeH and BJeHLT siGPX4 No cell death (Yang 2014)

HL60 SM1044

Inhibited the proliferation, promoted the

apoptosis of HL60 cells

(Yu 2013)

Kasumi-1 SM1044

Change cell cycle apoptosis-related

protein to inhibit the proliferation of

Kasumi-1 cells

(Liu 2011)

SU-DHL-4

(DLBCL)

SM1044

Induced he apoptosis of SU-DHL-4cells

in a dose-dependent manner up-regulated

the expression of caspase 3 nd PARP

fragments

(Yu 2014)

2.3 Oncosis

The effect of artemisinin derivatives on cancer cells

can lead to cell oncosis (Weerasinghe, 2012). Oncosis

originated in the Greek word “onkos” which means

swelling. Oncosis and apoptosis have obvious

morphological differences. Apoptosis is a process in

which cells actively die through gene regulation. The

main manifestations of apoptosis are cell atrophy and

nuclear fragmentation. Oncosis is passive cell death

caused by some factors such as the physical and

chemical properties of drugs or other chemical

reagents or the environment (Leppo, 2003). The main

manifestations of oncosis are the expansion of cells

and organelles, the increase of cell membrane

permeability and the dissolution of cell nuclei

(Majno,

1995).

It was exerted that artemisinin derivatives caused

mitochondrial dysfunction when acting on cancer

cells, leading to the expansion of the intracellular

mitochondrial plasma reticulum (Du, 2010). In

addition, the cells undergoing oncosis did not appear

to undergo apoptosis after the Hoechst dye entering

the cells.

The mechanisms of oncosis induced by

artemisinin derivatives remain unclear. Du et al.

found that on the death of pancreatic cancer cells

induced by artesunate, artemisinin derivatives

induced changes in mitochondrial membrane

potential (MMP, or Δψm) and reactive oxygen

species mediated cell death in pancreatic cancer cells

(Du, 2010) (Tab.1).

The change of mitochondrial membrane potential

is one of the most important signs of cell

physiological state (Guan, 2018). Through the

detection of mitochondrial membrane potential, it can

be roughly inferred whether cell homeostasis is

disrupted, etc. (Xiao, 2020). Thus, the change of

MMP may be a manifestation of cell oncosis. The

excessive production of ROS (reaction oxygen

species) leads to oxidative stress and damage to

intracellular molecules and organelles.

Overall, oncosis, as a different pathway of cell

death from apoptosis, could be induced by partial

derivatives of artemisinin, which might be a new and

effective anti-cancer approach for cancer cells with

defective apoptotic pathways. Futher research is

required to better understand the mechanisms of

oncosis induced by artemisinin derivatives and

potential of artemisin derivatives as anti-cancer

drugs.

2.4 Ferroptosis

Ferroptosis is an iron-dependent way of inducing

apoptosis by attacking the cell's antioxidant system,

which was named by Dr. Brent R. Stockwell (Dixon,

2012). Different from other types of apoptosis such as

necroptosis, autophagic cell death and apoptosis,

normal apoptosis inhibitors are ineffective against

ferroptosis, but iron chelator can inhibit the

production of ferroptosis (Dixon, 2012). These facts

indicated that ferroptosis refers to an iron-dependent,

non-apoptotic cell death (Imai, 2017). Here are some

of the mechanisms of ferroptosis.

Artemisinin Derivatives: Anti-cancer Effects and Mechanisms

387

Cancer cells are usually over proliferating with

high metabolization level and oxygen consumption,

which requires more haemoglobin. In turn, with

overcrowded haemoglobin, excessive Fe2+ can

produce ferroptosis in cells through Fenton reaction.

The Fenton reaction means that Fe2+ reacts with the

peroxy group (the -OOH) in DHA to produce OH•,

which belongs to Reactive oxygen species (ROS).

Normal doses of ROS are metabolized by cells

through a series of reactions (such as peroxide can be

degraded by CAT into water and oxygen) while

excess ROS can overwhelm the antioxidant system in

cells, leading to cell death.

GSH plays a crucial role in the antioxidant system

of the body through specifically combining with ROS

and eliminating the toxicity of ROS to cells. The

expression of GSH is regulated by SLC7A11/XcT,

GR and GPX4 (Yang, 2014) (Tab.1). SLC7A11/XcT

can transport Cystine into cells to provide raw

material for GSH synthesis. GR provides hydrogen

for converting GSSG to GSH. GPX4 not only

eliminates peroxide, but also converts excess GSH

into GSSG for storage. Although there are so many

mechanisms in the cell to promote GSH production,

the rate of any chemical reaction has an upper limit.

When the ROS production rate exceeds the GSH

clearance rate, the cell would be enriched in ROS and

ROS will attack the cell, leading to cell death.

It was found that intracellular ROS levels of

SMMC⁃7721 and Huh⁃7, of which the genomic

characteristics are very sensitive to the number of

passages and detecting gene expression is a

convenient and inexpensive way, increased 2.6 times

and 2.1 times respectively at DHA 35 μmol/L, and

lipid peroxides increased 2.3 times and 1.7 times(Li

2019). In the SMMC⁃7721 cells GSH decreased by

59% and GPX4 decreased by 81.3% at DHA 35

μmol/L (Li, 2019).

These findings suggested that the inhibitory effect

of DHA on the proliferation and anticancer

mechanism of Hepatocellular Carcinoma (HCC) cells

may not only be limited to cell apoptosis, but also iron

death plays an important role in the anti-HCC

mechanism of DHA. However, the interaction

between iron death and apoptosis in inhibiting

hepatocellular carcinoma cell activity and its

mechanisms require to be further studied.

Figure 2: Mechanisms of anti-cancer effect of DHA.

2.5 SM1044

In recent years, artemisinin and its derivatives have

been making great contributions to drug research.

Fat-soluble drugs have been proved to be very

inefficient in drug absorption in experiments, and

their efficacy is usually not fully utilized. Among the

many artemisin derivatives, SM1044 is a newly

developed water-soluble artemisinin derivative. It is

superior to fat-soluble drugs in blocking cell growth

cycle, inducing cell apoptosis and other therapeutic

regimens.

Another study of the effects of artemisinin

derivative SM1044 is on acute myeloid leukemia cell

line HL60 to analyse the anti-cancer effects of

SM1044 on AML and related mechanisms. It was

found that SM1044 inhibited the proliferation of

HL60 cells; promoted the apoptosis of HL60 cells

with an increase of the percentage of apoptosis

population with a dose-dependent manner. There are

two main pathways of apoptosis: external pathway

and internal pathway respectively. The external

pathway is the activation of death receptors by

extracellular signals, which causes the self-activation

of apoptosis promoter caspase -8. The internal

pathway is that when it is activated, mitochondrial

transmembrane potential is lost, then releasing

cytochrome C to stimulate the self-activation of the

apoptotic promoter cystein-9. However, after the

activated caspase 8 and caspase 9 react each other and

stimulate the production of caspase 3, which in turn

degrades important proteins including PARP leading

to apoptosis. Therefore, apoptosis may occur when

both cysteinase-8 and cysteinase-9 are activated and

mitochondrial transmembrane potential is lost after

the action of SM1044 (Yu, 2013). Hence, the effect

of SM1044 on the expression of apoptosis-related

proteins was similar as that of SM1044 on kasumi-1

cells and effect of SM1044 on mitochondrial

transmembrane potential of HL60 cells was the same

as that of SM1044 on transmembrane expression of

SU-DHL-4 cells. Therefore, the in vitro studies

showed an anti-AML effect of the SM1044, though

in vivo studies and potentially clinical studies are

required to better understanding the mechanisms and

its therapeutic effects (Yu, 2013) (Tab.1).

Kasumi-1 cells were used as the model to test the

effect of SM1044, and the results showed that

SM1044 could inhibit the proliferation of Kasumi-1

cells through alter in cell cycle and apoptosis-related

proteins. The main possible mechanism is that with

an increasing concentration of SM1044 (μ24=0.92,

μ48 =0.98, μ72 =0.97, p˂0.05) an increasing portion

of Kasumi-1 cells were blocked in the G0/G1 phase,

ICBEB 2022 - The International Conference on Biomedical Engineering and Bioinformatics

388

which in turn inhibited the proliferation of Kasumi-1

cells with a time- and dose-dependent manner,

stopped the cell growth, and thus induced cell

apoptosis. Second, L Caspase inhibitor was added in

the experiment of co-incubation with different

concentrations of SM1044 and cells for 24 hours, and

it was found that Caspase was the main mediating

mode leading to cell apoptosis. Finally, examination

the expression of apoptosis-related proteins showed

that SM1044 could induce apoptosis by activating

apoptosis-related proteins, including associated

protein Caspase 3, PARP and the fusion protein

AML1-ETO (Liu, 2011) (Tab.1).

NHL is a hematologic malignancy that causes

more than 60,000 new cases in the United States each

year, with Diffuse Large B-cell lymphoma (DLBCL)

being the most common, so the development of new

drugs to combat this disease has become a priority

(Cultrera, 2012). In 2006, artemisinin-based ACTs

were found to have a 95% cure rate against

plasmodium falciparum malaria (Njuguna, 2012). In

the study of DLBCL cell line SU-DHL-4 treated with

SM1044, it was found that SM1044 induced the

apoptosis of SU-DHL-4 cells in a dose-dependent

manner, with a possible mechanism through up-

regulated the expression of caspase 3 and PARP

fragments which were related to apoptosis. It was

known that artemisinin may directly act on membrane

structures such as the endoplasmic reticulum (ER)

which plays an important role in the endogenous

apoptosis pathway. Therefore, future studies may

focus on endoplasmic reticulum stress and the

mechanism of SM1044 inducing SU-DHL-4 cell

apoptosis. Thus, according to the recent study,

SM1044 can induce the expression of ER stress-

related genes and proteins in SU-DHL-4 cells.

Artemisinin exerted their anti-malaria effect by

targeting the calcium dependent ATPase PfATP6 in

plasmodium/sarcoplasmic reticulum, thus greatly

increasing the calcium ion level in parasites and

leading to the death of plasmodium parasites (Yu,

2014). The role of calcium ion SM1044 in inducing

endoplasmic reticulum stress and apoptosis of SU-

DHL-4 cells was determined. Hence, SM1044

induced apoptosis of SU-DHL-4 cells may be a

complex process involving multiple mechanisms.

Due to the greater safety of SM1044 and the strong

water solubility of other artemisinin derivatives,

SM1044 might be a promising new anti-cancer drug

(Yu, 2014) (Tab.1).

Until now, most studies have concluded that the

mechanism of artemisinin-induced apoptosis is

similar to its antimalarial mechanism, that is, the

reaction between the internal peroxide group and iron

ions produces free radicals or electron-philic

intermediates, which increases the intracellular

reactive oxygen species level and then activates the

upstream apoptotic signalling pathway (Mercer,

2007). Follow-up work may continue to investigate

the mechanisms of anti-cancer effects of SM1044 as

well as its potential clinical application.

3 CONCLUSIONS

In conclusion, the results of different studies and

experiments indicate that uncontrolled cell growth is

known to cause cancer and many complications in

vivo and inducing apoptosis is the primary treatment

for blocking the overgrowth of cancer cells. Firstly,

in terms of the stages of cell division, the G1 to S

stages play a key role in regulating proteins that block

cancer cell growth which SM1044 could induce

Kasumi-1 cell cycle and block Kasumi-1 cells at

G0/G1 phase, and at the same time, S phase cells

decreased significantly. Secondly, through

antimalarial mechanisms, the Fenton reaction

between the peroxide bridge and iron destroys cancer

cells and blocks cell growth. Finally, among

artemisinin derivatives, water-soluble derivatives are

more efficient in absorption and function than fat-

soluble derivatives.

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