Research of Inducing Apoptosis and Ferroptosis in Ovarian Cancer

and Its Synergistic Anticancer Significance

Qian Yang

School of Pharmaceutical Science & Technology, Tianjin University, Tianjin 300072, China

Keywords:

Ovarian Cancer, Apoptosis, Ferroptosis, Drug Resistance.

Abstract: Ovarian cancer (OC), as a highly malignant tumor of female reproductive system, has the highest mortality.

At present, in the clinical treatment of OC, although the action mechanism of some chemical drugs is clear

and the curative effect is remarkable, they are easy to result in drug resistance, which seriously hinders the

anticancer effect of chemotherapeutic drugs. In this brief article, we summarized the two cell death modes of

apoptosis and ferroptosis, discussed the correlation between apoptosis, ferroptosis and OC, and emphasized

the synergistic effect of combined application of drugs that can induce cell apoptosis and ferroptosis to deal

with the drug resistance of OC. The latest progress of this subject will help to deal with the drug resistance of

OC and expand more ideas for clinical treatment.

1 INTRODUCTION

Ovarian cancer (OC) is a malignant tumor of the

reproductive system, its mortality rate ranked the top

among North American women in cancer death.

(

Henley, 2020)

In the clinical treatment, surgery,

radiotherapy and adjuvant chemotherapy are

commonly used, and chemotherapy is widely

appeared in tumor treatment. However, drug

resistance is one of the severe problems face by

cancer patients in the process of chemotherapy

treatment. (

Emmings, 2019)

Apoptosis escape is considered one of the result

of cancer development, which promote the resistance

of tumor cells to radiotherapy and chemotherapy.

(

Skarkova, 2019)

One mechanism for drug

resistance is alterations in apoptotic molecules that

ultimately help the cell's ability to evade death.

Therefore, it is essential to restore apoptosis of OC

cells. Besides, ferroptosis, as a new form of regulated

cell death (RCD), can enhance the therapeutic effect

of chemotherapeutic drugs on tumors. (

Scott, 2012)

Therefore, ferroptosis associated with lipid reactive

oxygen species has received clinical attention and

considered as a underlying therapeutic strategy for

OC. (

Bebber, 2020)

This article focuses on two types of cell death

process known as apoptosis and ferroptosis. We

discuss recent cases of OC treatment by inducing

apoptosis and ferroptosis of OC cells and their

synergistic antitumor significance. Therefore, it is a

new strategy to cause tumor cells to cooperate with

ferroptosis and apoptosis to conquer OC. The main

pathways of apoptosis and ferroptosis together with

the relationship between ferroptosis, apoptosis and

OC are discussed to find a breakthrough for OC

therapy.

2 APOPTOSIS

Apoptosis is a biochemical process of cell

decomposition through the interaction of specific

proteins and the programmed transmission of death-

inducing signals. (

Simon, 2019)

It was reported that

some molecules contained similar B-cell lymphoma

2 (Bcl-2) homology domains (BH domains) in

protein structure, and these molecules are all

classified as Bcl-2 family molecules. (

Maji, 2018)

Bcl-2 family proteins as indicator of chemotherapy

response and prognosis in patients with advanced

OC, suggesting that Bcl-2 family proteins are closely

related to the mechanism of apoptosis escape in OC

cells. Therefore, Bcl-2 family proteins become

promising targets for OC because apoptosis of OC

cells could be regulated by Bcl-2 family, which

provided ideas for OC treatment. (

Ridder, 2021)

The

Bcl-2 family proteins were classified into three

Yang, Q.

Research of Inducing Apoptosis and Ferroptosis in Ovarian Cancer and Its Synergistic Anticancer Signiﬁcance.

DOI: 10.5220/0012018700003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 223-227

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

223

subcategories: anti-apoptotic Bcl-2 family proteins,

pro-apoptotic Bcl-2 family proteins and BH3-only

proteins. (

Basu, 2021)

(Fig.1) Many researchers

have targeted anti-apoptotic proteins to reverse the

apoptotic escape of OC cells and thus reverse drug

resistance. The anti-apoptotic family proteins include

Bcl-2, Bcl-extra long (Bcl-xL) and Myeloid leukemia

1 (Mcl-1).

Figure 1: Processes of apoptosis induced by Bcl-2 family proteins.

2.1 Regulation of BCL-2 and BCL-xL in

Ovarian Cancer

Combinations of two or more synthetic anticancer

drugs have been reported as possible alternatives for

improving efficacy and reducing the expected

toxicity and side effects of drugs. (

Xu, 2011)

Takuhei Yokoyama et al. evaluated the possible

synergistic cytotoxicity of combination therapy with

two drugs in high-grade serous OC cells. The results

showed that two drugs could induce more apoptosis

and produce synergistic cytotoxic effect on HGSOC

cells through inhibition of Bcl-2/Bcl-xL.

(

Yokoyama, 2017)

The inhibiton of Bcl-2/Bcl-xL

caused the release of Bcl-2 associated X protein

(Bax) and Bcl-2 homologous antagonist/killer

protein (Bak). Then the oligomerization of effectors

Bax and Bak caused the release of cytochrome c (cyto

c), which lead to the activation of caspases and the

induction of apoptosis. In addition, nano-targeting

systems for OC were being developed, and Farideh

Rezaie Amale et al. considered that gold

nanoparticles was a promising and appropriate

targeting system for enhancing anti-tumor activity

against OC cells. (

Amale, 2021)

2.2 Regulation of Mcl-1 in Ovarian

Cancer

At present, UMI-77 is considered to be an effective

inhibitor to reduce the activity of Mcl-1 protein, and

there are also many studies targeting Mcl-1 through

other small molecules. Qi et al. revealed the

intervention effect of apigenin on OC. (Qi, 2020)

They investigated the effect of apigenin and

determined its mechanism in the regulation of

chemotherapy resistance. The results showed that

apigenin increased the Bax/Bcl-2 ratio and by down-

regulating Mcl-1 on OC. Enhanced permeability lead

to the release of various apoptotic stimulators into the

cytoplasm, thus promoting caspases to trigger cell

apoptosis. Apigenin triggered cell death in OC cells

by enhancing mitochondria-regulated cell death and

eliminated cisplatin (DDP)-induced resistance.

3 FERROPTOSIS

Ferroptosis is a novel non-apoptotic programmed cell

death process. With the development of research, the

general pathogenesis of ferroptosis has been partially

elucidated. The general process of ferroptosis is the

direct or indirect activation of different signaling

pathways through the induction of small molecules,

thereby decreasing the activity of glutathione

peroxidase 4 (GPX4) and inhibiting the intracellular

antioxidant energy. This leads to excessive

accumulation of reactive oxygen species (ROS),

which ultimately leads to cell death. (Xie, 2016) The

occurrence of ferroptosis can be regulated by a

variety of pathways. (Fig. 2) (1) System xc- is a

cystine-glutamate reverse transporter system that

ICBB 2022 - International Conference on Biotechnology and Biomedicine

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binds to a twelve-channel transmembrane transporter

protein SLC7A11 (xCT). Cystine and glutamate enter

cells through system xc- on the cell membrane. The

following step is the synthesis of glutathione (GSH),

the substrate of GPX4. (

Imai, 2017)

(2) Iron is

closely related to ROS accumulation and ferroptosis.

Almost all lipid peroxides can be diminished by iron

chelators, which closely connects the process of iron

metabolism with the occurrence of ferroptosis.

(

Minotti, 1987)

During iron ion oxidation, it is

oxidized to lipid ROS by Fenton reaction. (3) The

survival of all cells requires the maintenance of

membrane fluidity, and polyunsaturated fatty acids

(PUFAs) on lipid membranes are one of the factors

that maintain this fluidity. Doll et al. reported that the

acyl-CoA synthase long chain family member 4

(ACSL4) that synthesized during PUFAs oxidation

drives ferroptosis through the accumulation of

membrane phospholipids. (

Doll, 2017)

(4)

Mevalonate pathway (MVA) is a metabolic pathway

that synthesizes the precursor of steroid and terpenoid

biomolecular synthesis using acetyl coenzyme A as

raw material. (

Shimada)

Coenzyme Q10 (CoQ10)

can be produced through this pathway. As an

endogenous antioxidant, it inhibits ferroptosis by

blocking lipid peroxidation process.

3.1 The Regulation of System

xc- / GPX4 / GSH

Hong Ting et al. suggested that the cell death and

tumor suppression induced by olaparib in OC is

ferroptosis, and suggested that olaparib partially

promotes ferroptosis by inhibiting SLC7A11-

mediated GSH biosynthesis. (Hong, 2021) In

addition, Cheng Qi et.al suggested that erastin in

combination with DDP synergistically inhibits OC

cell growth and maximizes the efficacy of OC

treatment. (Cheng, 2021) When erastin was used in

combination with DDP, cell survival and the activity

of GPX4 were significantly reduced, while ROS

levels were elevated and ferroptosis occurred. Direct

targeting of GPX4 may be more effective, and Li et

al. confirmed that inhibition of GPX4 inhibited the

growth of OC cells, induced ferroptosis, reduced

Fe3+ accumulation, and inhibited lipid peroxidation

reduction ability. (Li, 2021)

3.2 The Regulation of ACSL4

ACSL4 is upregulated in a variety of cancers,

including OC, which promotes resistance to

conventional therapy through lipid metabolism

disorder. (Cui, 2018) Targeting ACSL4 could be a

key therapeutic approach for OC treatment. Ma et al.

found that ACSL4 was over-expressed in OC and

ferroptosis could be regulated in OC through

targeting ACSL4. (Ma, 2020) They demonstrated

that knockdown or over-expression of Tumor

suppressor sensitized and inhibited erastin and RSL3

induced ferroptosis in OC cells, respectively.

Figure 2: Processes of ferroptosis.

Research of Inducing Apoptosis and Ferroptosis in Ovarian Cancer and Its Synergistic Anticancer Signiﬁcance

225

4 CONCLUSIONS

This article focuses on the treatment of OC by

inducing apoptosis and ferroptosis in recent years.

(Table 1) Unfortunately, there are few studies on the

synergistic treatment of OC by apoptosis and

ferroptosis. The significance of this article lies in that

it is of great significance to select the lowest effective

dose of multiple drugs for OC treatment, not only to

reduce the toxic and side effects of drugs, but also to

achieve the synergistic effect of ferroptosis and

apoptosis against cancer. Such treatment

combinations may lead to novel treatment strategies

that reduce the recurrence or drug resistance in order

to increase the sensitivity of OC to drugs.

Table 1: Summary of targets that promote cell death in ovarian cancer.

Mode of cell

death

Targets Cell lines Rf.

Apoptosis Bcl-2/Bcl-xL OVCAR3; OVCAR8; OV90 11

Apoptosis Bcl-2 A2780; HEK-293 12

Apoptosis Mcl-1 SKOV3; SKOV3/DPP 13

Ferroptosis SLC7A11 HEY; A2780 19

Ferroptosis GPX4

A2780; SKOV3; OVCA433;

OVCAR5; OVCAR8; HEY;

HOSE

Ferroptosis ACSL4 HO8910; SKOV3 23

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