Cisplatin and Its Intercellular Cytotoxicity: Mechanism Derived from

Different Pathway and Progression Targeting Toxicity Concern

Minhui Liu

1,†

, Yingxuan Yuan

2,*,†

and Xiuqi Zhang

3,†

Univeristy of Rochester, NY, U.S.A.

NORTHWEST A&F University, Shaanxi, China

World Foreign Language Academy, Shanghai, China

†

These authors contributed equally

Keywords: Cisplatin, Mechanism, Resistance, Toxicity, Applications.

Abstract:

Cisplatin is a metal platinum complex with anticancer activity. It is a cell cycle nonspecific antitumor drug

that can produce effective cytotoxicity. It mainly crosslinks with DNA, induces apoptosis, inhibits cell

viability and kills tumor cells, and also has a certain effect on RNA and protein of tumor cells. Cisplatin, as a

kind of classic anticancer drug, plays an important role in clinical chemotherapy. The emergence of cisplatin

resistance is the product of the interaction of multiple mechanisms. In this paper, by consulting the relevant

literature on cisplatin in recent years, the paper summarizes cisplatin's main mechanisms and recent research

progresses.

1 INTRODUCTION

Antineoplastic drugs, specifically against tumor cells,

exert their effects through multiple mechanisms, but

more or less have counter-effects present in each type

of drugs. 5-fluorouracil (5-Fu), a pyrimidine

antagonist, blocks the DNA synthesis by converting

to 5F-dUMP and subsequently prevents tumor cell

growth by inhibiting cell proliferation (Paul, 2021).

However, fluorouracil has a high toxicity in rapidly

growing cells, such as bone marrow and intestinal

epithelium, and it also causes mild leukopenia

(decreasing in white cell counts), thrombocytopenia

(decreasing in blood platelets counts), and central

nerve system (CNS) toxicity that's inversible (Papich,

2016).

Vinblastine, an anticancer drug often used in the

past years binds to microtubules protein tubulin,

which leads to the termination of microtubules

assembly in metaphase and the chromosome splitting

to stop the growth of the cell. Yet, in Zhou's research,

vinblastine causes the death of myocardial cells

through coronary spasm and cardiac arrest. As a

result, heart damage inevitably happened in both vitro

and vivo use of vinblastine (Zhou, 2021). In addition,

vinblastine leads to hyperpigmentation or bluish-

black discoloration over the nose and fingertips along

with darkening of the nail beds without any other

sources of influences (Chakraborti, 2020). Cisplatin

(CP) as a metallic-platinum-containing anticancer

drug targets multiple locations to exert its effects on

the sexual organs on both male and female,

respiration system, pancreas, and breast to block the

growth of the tumor in cells (Santos, 2020), and

platinum based concurrent chemoradiotherapy

becomes a necessary step in cure of locoregionally

advanced nasopharyngeal carcinoma or a head and

neck cancer with a specific geographic distribution

(Zhang, 2019). It generally binds to the mitochondrial

DNA and damages the DNA that triggers the immune

system to haveresponses to the damage (Papich,

2016). CP affects the level of expressed mtDNA

reactive oxygen species (ROS) which disrupts the

equilibrium of oxygen, ATP production, and ROS

which increases the expression of apoptosis caspases

and leads to cell death. Lastly, the release of

chemokines and cytokines from DNA damage

induced by ROS causes inflammation in cell (Papich,

2016; Zhang, 2019) (figure 1).

Despite the number of routes to control the growth

of cancer cells, cisplatin has limitations, so it does not

exhibit its full potential. One limitation is resistance

which the DNA repair system repeals the outsider

Liu, M., Yuan, Y. and Zhang, X.

Cisplatin and Its Intercellular Cytotoxicity: Mechanism Derived from Different Pathway and Progression Targeting Toxicity Concern.

DOI: 10.5220/0012002600003625

In Proceedings of the 1st International Conference on Food Science and Biotechnology (FSB 2022), pages 80-87

ISBN: 978-989-758-638-5

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

Figure 1: The overall picture of different pathways involved in cisplatin nephrotoxicity (Manohar, 2018).

Figure 2: The variety of toxicities produced after cisplatin is injected (Qi, 2019).

cisplatin and lowers the effectiveness of the drug;

another limitation is the inactivation of the drug by

binding to different proteins which lead to weakened

signaling to apoptosis and pro-survival mechanisms

(Ghosh, 2019); lastly, cisplatin is highly dosage

dependent, and when a higher dose is taken, it leads

the different type of toxicities in the body, and the

nephrotoxicity is the most common one (figure 2).

Those toxicities are not lethal, but they affect the life

quality of the patients through discomfort, and

subsequently reduce the treatment time and the effect

of cisplatin (Qi, 2019). The main focus of this paper

is to introduce different pathways hat are derived

from DNA damage and the production of ROS and

analyze how the resistance occurs.

2 MECHANISM

2.1 DNA Damage and ROS

Cisplatin (CP) contains a platinum atom that can

covalently bind to DNA, but only a small percentage

of CP is directly bound to DNA, and most of the

Cisplatin and Its Intercellular Cytotoxicity: Mechanism Derived from Different Pathway and Progression Targeting Toxicity Concern

binding is through histone H1. H1, platinum (pt), and

DNA form a ternary complex. This complex makes

the binding between cisplatin to DNA stronger than

just them alone, and H1 also strengthens the effect of

cisplatin by inhibiting the DNA repair mechanisms

(Cheng, 2019). Recently, another paper has proposed

another mechanism for the binding of CP to DNA

based on dissociative electron transfer (DET), in

which cisplatin accepts electrons from DNA to form

two reactive radicals and DNA adducts (Li, 2019).

Due to the binding, cells activate the repair pathway

to fix the DNA adducts (Kleih, 2019), and two types

of repair are activated, global repair (GR) and

transcription-coupled repair (TCR). Acting on

transcribed strands of active genes to repair the

modified DNA, TCR is initiated by the translocating

RNA polymerases and Escherichia coli RNA

polymerase (RNAP). GR, on the other hand, acts on

the non-transcribed strands of transcribed genes and

is initiated by NER factor UvrA and it removes DNA

damage from the entire genome (Yimit, 2019). If the

DNA adduct is not being fixed by the repairment,

ROS will be produced. ROS is produced during

mitochondrial respiration (Kleih, 2019; Yimit, 2019).

In most situations, the energy is produced in the form

of ATP by mitochondria, and oxygen produced from

the ETC will form water molecules. However, some

oxygen can escape from this process, and ROS are

produced. The overproduction of ROS can cause

oxidative stress which disrupts the equilibrium of

organelles and lowers the ATP synthesis from the

ETC which increases apoptotic factors and decreases

in anti-apoptotic factors which lead to cell death and

other serious issues.

2.2 Mitochondrial Pathway

It is known that mitochondria confer bioenergetic

plasticity to tumor cells, enabling cells to escape

death pathways under stress conditions such as

chemotherapy. To date, we recognize the central role

of mitochondria, and we recognize that mitochondria

are promising pharmacological targets for

overcoming cisplatin resistance. Cisplatin-induced

cytotoxicity is not caused by the heavy metals

themselves, but rather by active metabolites

transformed by high concentrations of cisplatin into

the intracellular environment. Under cisplatin,

mitochondria regulate death receptors by affecting

the expression of tumor suppressor proteins (TNF-)

and then lead to cell mitochondrial dysfunction which

activates AIF, caspases, and other pro-apoptotic

factors to induce tumor cell apoptosis (Volarevic,

2019).

The first pathway is the pro-apoptotic factor

cytochrome activates caspase-9. This is an apoptotic

pattern dependent on proapoptotic factors. This

process is after cisplatin stimulated cells, BH3-

Interacting Domain Death Agonist (Bid), a member

of the Bcl-2 protein family that regulates the

permeability of exterior mitochondrial membranes,

and apoptosis-promoting gene BCL2-Associated X

protein (Bax), a water-soluble-associated protein that

belongs to the rabbit anti-human monoclonal

antibody. Activation of isoproteins induces increased

mitochondrial outer membrane permeability,

interferes with mitochondrial function, and induces

the automatic release of cytochrome c-mitochondria,

which all lead to the activation of Caspase-9 (Bernal-

Barquero, 2019). Meanwhile, the reduction in ATP

synthesis forces the stressed cells to function in a

starvation mode and activate the caspase-induced

apoptosis through the release of caspase-9 mediators

which is an irreversible cell apoptosis process.

Figure 3: Caspase-dependent mechanism in cisplatin-

induced apoptosis.

Although caspase is an important pro-apoptotic

factor in apoptosis, there is increasing evidence for a

caspase-independent mechanism in cisplatin-induced

apoptosis, which is the AIF-induced apoptosis. This

is an apoptotic pathway independent of the caspase

pro-apoptotic factor (Pabla, 2008).

AIF, the universal apoptosis inducer factor, was

the first factor to induce caspase-independent cell

apoptosis in 1999. It is present in the inner

mitochondrial membrane. It differs from the typical

apoptotic process, where AIF transfers from the

mitochondria to the cytoplasm and then enters the

FSB 2022 - The International Conference on Food Science and Biotechnology

nucleus leading to nuclear DNA agglutination,

forming 50kb size fragments (Feldman, 2008).

Typically, AIF has oxidoreductase activity and is

involved in mitochondrial ATP generation and redox

reactions. When mitochondrial dysfunction occurs,

mitochondrial membrane permeability increases,

prompting the release of AIF molecules from the

mitochondrial cytoplasm, which then translocated to

the nucleus according to their nuclear localization

sequence and binds to chromosomal DNA. This leads

to DNA condensation and degradation, thereby

generating caspase-independent forms of apoptosis

induction. During cisplatin-induced apoptosis, AIF is

cleaved and activated and mediates caspase-

independent apoptosis signals, working together with

caspase-dependent apoptosis to induce more efficient

apoptosis in a complementary manner (Zheng, 2016).

2.3 Inflammatory Pathway

The ROS produced from the DNA damage causes the

release of chemokines and other cytokines like TNF-

α (Padgett, 2013). Resident kidney cells, such as

mesangial cells, glomerular cells, endothelial cells,

and renal tubular cells, produce TNF-α locally

(Zhang, 2007). Of all these cells, mainly renal tubular

cells contribute to the production (Ramesh, 2006).

TNF-α is essential to the generation of pro-

inflammatory factors and activation of inflammatory

cells. There are two types of TNF-α receptors in a

kidney cell: TNFR1 and TNFR2. Different signaling

cascades are activated when TNF-α binds to these

two receptors. The binding of TNF-α toTNFR2 leads

to the inflammatory response (Figure 4). When

membrane-bound TNF-α activates TNFR2, it recruits

TNFR-associated factor 2 (TRAF2), which then

activates NF-κB-inducing kinase (NIK) and

subsequently activates IKK complex (Xiao, 2001).

Originally, an inhibitory protein IκBα associates with

the NF-kappaB dimer, preventing Nf-kappaB from

entering the nucleus. Upon activation of IKK

complex, IKK phosphorylates IκBα at two N-

terminal serines, which triggers ubiquitin-dependent

IκBα degradation in the proteasome, resulting in the

nuclear translocation of NF-κB dimers (Beinke,

2004; Hayden, 2008). NF-κB dimers then drive the

expression of pro-inflammatory genes in innate

immune cells, while also controlling the activation of

inflammatory T cells (Lawrence T, 2009).

Figure 4: TNF-α production and involvement in cisplatin-

induced acute kidney injury (Dong, 2007).

2.4 Autophagy in Kidney

Autophagy is a process in which some damaged

proteins or organelles are wrapped by autophagic

vesicles with double membrane structure and then

sent to lysosomes (animals) or vacuoles (yeast and

plants) for degradation and recycling. Because it

occurs in both physiological and pathological

processes of the body, so far the relevant research has

not fully elucidated the role of autophagy in the

human body. In the past 20 years, autophagy has

always occurred in the research related to cisplatin.

Therefore, autophagy is generally considered to be

the key to promote cell survival and prevent acute

cisplatin nephrotoxicity.

Autophagy protects the kidney from damage

during cisplatin exposure, thereby limiting or

inhibiting tumor growth, but it may also reduce the

efficacy of chemotherapy because of the protection

of cancer cells. Autophagy plays an intrinsic

protective role in renal tubular cells. Under normal

physiological conditions, autophagy in the kidney

usually plays a protective cell model of promoting

growth to maintain the homeostasis of kidney cells.

When the kidney is damaged or in the period of

cisplatin exposure, cell stress will rapidly activate

induced autophagy to protect the kidney. This

autophagy is a form of cytotoxicity that promotes

tumor cell death. In addition, there is an unprotected

form that does not seem to directly affect cell

proliferation or apoptosis (Xu, 2022). When it is

proposed that autophagy may inhibit the sensitivity

of cisplatin or lead to drug resistance, it is necessary

Cisplatin and Its Intercellular Cytotoxicity: Mechanism Derived from Different Pathway and Progression Targeting Toxicity Concern

to distinguish the function of autophagy. In addition,

autophagy also plays a role in regulating kidney

repair, renal fibrosis, acute renal injury and other

renal diseases in the kidney.

3 CISPLATIN RESISTANCE

The main disadvantage of cisplatin therapy is its

resistance to cancerous cells. Resistance to cisplatin

varies with the kind of cancer. For example, small

cell lung, testicular, ovarian, head and neck cancers

are highly susceptible to cisplatin, while non-small

cell lung cancers and colorectal cancers are highly

resistant to cisplatin (Ghosh S, 2019). For to solve

this thorny problem, current treatments are taken

from the following perspectives: reducing cellular

drug uptake, reducing drug influx or increasing

efflux, cell thiol detoxification, changing drug

targets, and repairing DNA (Ghosh S, 2019; Zhang,

2018). There are four primary positions for resistance

to cisplatin in the human body as followed.

3.1 Resistance to Drugs When

Circulating Through the Blood

Stream

As cisplatin is injected intravenously, it flows into the

blood before entering cancerous cells. Proteins in the

blood may bind to cisplatin, particularly proteins that

contain groups of thiols, such as human serum

albumin (the carrier of fatty acids in the blood). When

the body needs energy, fat cells will release fatty

acids into the blood, which will be collected by serum

proteins and transported to the place where they are

needed. And cysteine (a common amino acid in an

organism.). Binding of this protein results in the

inactivation of cisplatin.

3.2 Resistance to Drug Influx or

Outflow Through Cell Membranes

A decrease in inflow and an increase in cisplatin

efflux leads to a decrease in drug accumulation in

cancer cells. Fulnos et al. mentioned that the decrease

in cisplatin build-up was due to a decrease in drug

uptake rather than an increase in drug efflux (Wang,

2016). In the human body, extracellular cisplatin

lowers the concentration of Ctr1, so that the dose of

its intracellular cisplatin is significantly reduced,

resulting in drug resistance. In addition, the two

copper carriers, ATP7A and ATP7B, contribute to

the flow of cisplatin from the cells, exacerbating drug

resistance.

3.3 Resistance To Cisplatin Is Present

in The Cytoplasm

By binding to glutathione and metallosulfur proteins

(low-molecular-weight proteins with metal-binding

capacity and high induction properties), the GSH and

cisplatin complex is then excreted using an outlet

pump with gs-coupling. There have been reports

suggesting that GST either aids in this response or

occurs spontaneously (Holzer, 2006).

3.4 Resistance After Cisplatin-DNA

Binding

NER is the most effective way to eliminate DNA

damage to produce resistance to cisplatin. To restore

expression of gene integrity, the NER system

removes damaged nucleotides from the two strands

to resynthesize DNA. Cells overexpressed with the

NER would be far less cisplatin conscious. The MMR

(miss match repair protein) protein is a very essential

protein that is commonly used to repair DNA-

cisplatin injuries. If it can be fixed, those cells can

still survive. In place of this, apoptosis is caused

(Ghosh S, 2019). As a result, drug resistance takes

place.

3.5 Toxicity

Cisplatin induces different levels of nephrotoxicity,

ototoxicity, and neurotoxicity depending on the dose

and the individual difference. The nephrotoxicity is

the most severe one. Cisplatin-induced Acute kidney

injury (AKI) involves proximal tubular injury,

apoptosis, oxidative stress, inflammation, and

vascular injury in the kidneys, which followed by

acute renal failure, chronic kidney disease if the

toxicity remain untreated and the medicines are keep

in using. From Fang's studies, it shows that natural

products have the ability to against oxidants,

inflammatory, and apoptosis, which regulate the

damage caused by cisplatin. As example, ginseng and

pomegranate reduce ROS that's produced from

cisplatin by restoring the antioxidant enzymes, which

decreases the inflammation and subsequently the

level of nephrotoxicity in the body (Fang, 2021).

Cisplatin causes hearing damage that is

irreversible, high frequency hearing loss. Cisplatin

mainly damages the outer sensory hair cells, and it

also could have impacts on the spiral ganglion

neurons (SGNs) in the cochlea. To prevent the harm,

FSB 2022 - The International Conference on Food Science and Biotechnology

the main goal is to prevent inflammation, oxidation,

and apoptosis occurring in the cells. Alpha-Lipoic

acid according to research can lower the ROS levels,

and strengthen the hearing ability. In addition,

neurotrophins have also been proposed in the

treatmentof ototoxicity, because hair cells maintain a

healthy SGNs by releasing neurotrophic factors, and

ototoxic damages conduct degeneration of SGNs.

Moreover, because neurotrophins’ receptors are

present in neurons but not in cancer cells, it

maximizes the effect of chemotherapy without

interrupting other treatment on cancer cells (Santos,

2020).

Neurotoxicity in some situations is pherpieral

toxicity which is the loss of proprioception or feeling

of one's position and body parts (Santos, 2020).

Agomelatine, an antioxidant, has been proven on its

ability to prevent cisplatin-induced neurotoxicity in

the mouse hippocampal neuronal cell line by areduce

oxidative stress and inflammation (Cankara, 2021).

Additionally, Cisplatin has been discovered toreduce

serotonin-regulated pharyngeal pumping activity

independent of neurons such as dopamine and

glutamates (Wellenberg, 2021). However, two of

serotonin derivatives, -feruloylserotonin and

coumaroyl serotonin has ability to significantly

reduce the level of ROS by increase the level of

glutathione peroxidase in the kidney, which reduce

the neurotoxicity caused by cisplatin (Park, 2019).

4 RESEARCH AND

APPLICATION OF RELATED

TECHNOLOGIES

At present, there are still a lot of scientific problems

to be solved in this field. In view of the above four

processes, cisplatin resistance in human body has

been treated in recent years. In view of that drug

resistance of cisplatin in the process of blood

circulation, Nanoparticles coupled with platinum

drugs is also one of the effective ways to solve drug

resistance, The combination of nanoparticles and

platinum has the following advantages: they can

carry more platinum compounds and the targeting

drugs to locate cancer cells more accurately, and we

can add some hydrophilic molecules to increase drug

solubility. Thus, this combination to spread in tumor

sites widely. That is not only soars efficiency, but

also declines the toxic and adverse effects of drugs

(Zhu, 2016). When cisplatin develops drug resistance

through the inflow or outflow of cell membrane, we

usually use cisplatin sensitizers, which can improve

the sensitivity to drugs at normal doses, among which

thiazides are typical representatives. It can reduce

cisplatin outflow by inhibiting P-glycoprotein (P-gP)

in drug-resistant KBV20C cells, and increase the

concentration of cisplatin in cells, thus enhancing the

cytotoxicity of cisplatin (Choi, 2014). As a new drug

delivery system, nano-micelles have great potential

advantages in reducing the toxic and side effects of

cisplatin and exerting the best therapeutic effect. For

the inactivation of platinum drugs, for example, PEG-

b-PBEMA micelles loaded with tetravalent platinum

were prepared by combining platinum complexes

with glutathione consumer-quinone methylate by

pharmaceutical means. By improving the efficiency

of platinum uptake, reducing intracellular glutathione

level and reducing platinum inactivation, the cisplatin

resistance of tumor cells can be reversed (Han, 2018).

Cisplatin binds to DNA to produce drug resistance.

At present, it is mainly by inhibiting the expression

of DNA damage repair related proteins to inhibit

DNA damage repair and improve platinum drug

resistance. PolyADPribose polymerase (PARP) is a

kind of DNA damage repair enzyme, and its inhibitor

can play a synergistic role in combination with

platinum drugs by inhibiting DNA damage repair (Li,

2021), which can enhance the anti-tumor activity of

drugs and effectively overcome tumour resistance to

cisplatin.A membrane glycoprotein PD-1, which is

expressed on the surface of various different immune

cells, is paramount in both diseases and adaptive

immune responses. Xiaoguang Liu et al. first

confirmed that PD-1 plays an important role in

regulating cisplatin induced muscle atrophy (Liu,

2022) by regulating autophagy of skeletal muscle.

5 CONCLUSION

Cisplatin nephrotoxicity is a complex process caused

by multiple factors. Therefore, it is crucial to

understand how the several pathways combined to

cause cell dysfunction. This review focuses on two of

the pathways: the mitochondrial pathway and the

inflammatory pathway (figure 1), both originated

from DNA damage. In the mitochondrial pathway,

caspase-independent mechanism triggered by AIF

leads to apoptosis. In the inflammatory pathway,

ROS triggers the release of cytokines and

chemokines which leads to inflammation. These

contributes to the cisplatin intercellular cytotoxicity.

A fascinating area for future study is to compare the

different pathways to determine if there's generality

in these mechanisms. This may give new insight into

renoprotection during cisplatin treatment.

Cisplatin and Its Intercellular Cytotoxicity: Mechanism Derived from Different Pathway and Progression Targeting Toxicity Concern

REFERENCES

Bernal-Barquero, C. E., Vázquez-Zapién, G. J., et.al.

(2019). Review of alterations in gene expression and

apoptotic pathways caused in nephrotoxicity induced

by cisplatin. Revisión de las alteraciones en la

expresión génica y vías apoptóticas provocadas en la

nefrotoxicidad inducida por cisplatino. Nefrologia,

39(4), 362-371.

Beinke, S., & Ley, S. C. (2004). Functions of NF-kappaB1

and NF-kappaB2 in immune cell biology. The

Biochemical journal, 382(Pt 2), 393-409.

Cankara, F.N., Günaydın, C., et.al. Agomelatine confers

neuroprotection against cisplatin-induced hippocampal

neurotoxicity. Metabolic Brain Disease 36, 339-349

(2021).

Chakraborti, A., & Sahi, P. K. (2020). Vinblastine-induced

acral hyperpigmentation. Indian Pediatrics, 57(6), 581-

582.

Choi, A. R., Kim, J. H., et.al. (2014). Thioridazine

specifically sensitizes drug-resistant cancer cells

through highly increase in apoptosis and P-gp

inhibition. Tumour biology, 35(10), 9831–9838.

Dong, Z., & Atherton, S. S. (2007). Tumor necrosis factor-

alpha in cisplatin nephrotoxicity: a homebred foe.

Kidney international, 72(1), 5-7.

Fang, C. Y., Lou, D. Y., et.al. (2021). Natural products:

potential treatments for cisplatin-induced

nephrotoxicity. Acta pharmacologica Sinica, 42(12),

1951-1969.

Feldman, D. R., Bosl, G. J., et.al. (2008). Medical treatment

of advanced testicular cancer. JAMA, 299(6), 672-684.

Ghosh S. (2019). Cisplatin: The first metal based anticancer

drug. Bioorganic Chemistry, 88, 102925.

Hayden, M. S., & Ghosh, S. (2008). Shared principles in

NF-kappaB signaling. Cell, 132(3), 344-362.

Han, Y., Yin, W., et.al. (2018). Intracellular glutathione-

depleting polymeric micelles for cisplatin prodrug

delivery to overcome cisplatin resistance of cancers.

Journal of controlled release, 273, 30-39.

Holzer, A. K., Manorek, G. H.,et.al. (2006). Contribution

of the major copper influx transporter CTR1 to the

cellular accumulation of cisplatin, carboplatin, and

oxaliplatin. Molecular pharmacology, 70(4), 1390-

1394.

Kleih M, Böpple K, et.al. (2019). Direct impact of cisplatin

on mitochondria induces ROS production that dictates

cell fate of ovarian cancer cells. Cell Death &

Disease,10(11):851.

Li, Z., Zilberman, et.al. (2019). Electrochemical methods

for probing DNA damage mechanisms and designing

cisplatin-based combination chemotherapy.

BioTechniques, 66(3), 135-142.

Lawrence T. (2009). The nuclear factor NF-kappaB

pathway in inflammation. Cold Spring Harbor

Perspectives in Biology, 1(6), a001651.

Li, H., Wang, C., et.al. (2021). PARP1 Inhibitor Combined

With Oxaliplatin Efficiently Suppresses Oxaliplatin

Resistance in Gastric Cancer-Derived Organoids via

Homologous Recombination and the Base Excision

Repair Pathway. Frontiers in cell and developmental

biology, 9, 719192.

Liu, X., Xu, M., et.al. (2022). PD-1 Alleviates Cisplatin-

Induced Muscle Atrophy by Regulating Inflammation

and Oxidative Stress. Antioxidants (Basel,

Switzerland), 11(9), 1839.

Luyu Qi, Qun Luo, et.al. (2019). Chemical research in

toxicology 32,8:1469-1486

Lanjun Cheng, Chan Li, et.al. (2019). Cisplatin reacts with

histone H1 and the adduct forms a ternary complex

with DNA, Metallomics, 11,3:556-564

Manohar, S., & Leung, N. (2018). Cisplatin nephrotoxicity:

a review of the literature. Journal of nephrology, 31,1,

15-25

Paul, W., Flint, MD. (2021). Cummings otolaryngology:

head and neck surgery. Elsevier Inc. 18, 260-268.e2

Papich, M. (2016). Sauders handbook of veterinary drugs.

Pabla, N., & Dong, Z. (2008). Cisplatin nephrotoxicity:

mechanisms and renoprotective strategies. Kidney

international, 73(9), 994-1007.

Padgett, L. E., Broniowska, K. A., et.al. (2013). The role of

reactive oxygen species and proinflammatory

cytokines in type 1 diabetes pathogenesis. Annals of the

New York Academy of Sciences, 1281(1), 16-35.

Park, C. H., Lee, A. Y., et.al. (2019). Protective Effects of

Serotonin and its Derivatives, N-Feruloylserotonin and

N-(p-Coumaroyl) Serotonin, Against Cisplatin-

Induced Renal Damage in Mice. The American journal

of Chinese medicine, 47(2), 369-383.

Ramesh, G., & Brian Reeves, W. (2006). Cisplatin

increases TNF-alpha mRNA stability in kidney

proximal tubule cells. Renal Failure, 28(7), 583-592.

Santos, N., Ferreira, R. S., et.al. (2020). Overview of

cisplatin-induced neurotoxicity and ototoxicity, and the

protective agents. Food and Chemical Toxicology, 136,

111079.

Santos, N., Ferreira, R. S., et.al. (2020). Overview of

cisplatin-induced neurotoxicity and ototoxicity, and the

protective agents. Food and chemical toxicology, 136,

111079.

Volarevic, V., Djokovic, B., et.al. (2019). Molecular

mechanisms of cisplatin-induced nephrotoxicity: a

balance on the knife edge between renoprotection and

tumor toxicity. Journal of biomedical science, 26(1),

25.

Wang Langli, Li Na, et.al (2016). Research progress of

first-line chemotherapy drugs for non-small cell lung

cancer Chinese pharmacy, 27 (5), 4

Wellenberg, A., Brinkmann, V., et.al. (2021). Cisplatin-

induced neurotoxicity involves the disruption of

serotonergic neurotransmission. Pharmacological

research, 174, 105921.

Xiao, G., Harhaj, E. W., et.al. (2001). NF-kappaB-inducing

kinase regulates the processing of NF-kappaB2 p100.

Molecular Cell, 7(2), 401-409.

Xu, J., & Gewirtz, D. A. (2022). Is Autophagy Always a

Barrier to Cisplatin Therapy? Biomolecules, 12(3), 463.

Yimit, A., Adebali, O., et.al. Differential damage and repair

of DNA-adducts induced by anti-cancer drug cisplatin

across mouse organs. Nature Communications, 10, 309

FSB 2022 - The International Conference on Food Science and Biotechnology

(2019).

Zhang, Y., Chen, L., et.al. (2019). Gemcitabine and

cisplatin induction chemotherapy in nasopharyngeal

carcinoma. New England Journal of Medicine,

381(12), 1124-1135.

Zhang, B., Ramesh, G., et.al. (2007). Cisplatin-induced

nephrotoxicity is mediated by tumor necrosis factor-

alpha produced by renal parenchymal cells. Kidney

International, 72(1), 37-44.

Zhang Bicheng, & Zhu Bo (2018). Current status and

future of chemotherapy for advanced non-small cell

lung cancer Medical Guide, 37 (5), 5

Zheng, J. H., Viacava Follis, A., et.al. (2016). Discoveries

and controversies in BCL-2 protein-mediated

apoptosis. The FEBS journal, 283(14), 2690-2700.

Zhou, H., Liu, L., et.al. (2021). RIP1/RIP3/MLKL-

mediated necroptosis contributes to vinblastine-

induced myocardial damage. Molecular and Cellular

Biochemistry, 476(2), 1233-1243.

Zhu, H., Luo, H., et.al. (2016). Molecular mechanisms of

cisplatin resistance in cervical cancer. Drug design,

development and therapy, 10, 1885-1895.

Cisplatin and Its Intercellular Cytotoxicity: Mechanism Derived from Different Pathway and Progression Targeting Toxicity Concern