Advantages and Disadvantages of Therapeutically Inhibiting CDK5 in Cancer Patients and Alzheimer's Disease

This essay critically discusses the advantages and disadvantages of therapeutically inhibiting CDK5 in cancer patients and those suffering from Alzheimer's disease. It explores the impact on treatment outcomes and potential risks associated with CDK5 inhibition.

Critically discuss advantages
and disadvantages of
therapeutically inhibiting
CDK5 in cancer patients and
in those suffering from
Alzheimers disease

Table of Contents
INTRODUCTION......................................................................................................................3
MAIN BODY.............................................................................................................................3
CONCLUSION..........................................................................................................................7
REFERENCES...........................................................................................................................8
Books and journals.................................................................................................................8

INTRODUCTION
Biomedical sciences are a group of disciplines that utilise elements of natural science,
organised science, or both to establish information, interventions, or technologies for
healthcare and public health (Allnutt and et.al, 2020). Medical sciences include fields
including medical microbiology, clinical virology, clinical epidemiology, genetic
epidemiology, and biomedical engineering. Pathophysiology, on the other hand, may be
considered natural science when it comes to explaining biochemical pathways that operate in
pathological processes. This essay is based on discussion critically discuss advantages and
disadvantages of therapeutically inhibiting CDK5 in cancer patients and in those suffering
from Alzheimers disease.
MAIN BODY
Cancer is a term used to describe a category of diseases characterised by irregular cell
growth that has the ability to infiltrate or spread to other areas of the body. Benign cancers,
on the other hand, do not multiply. A lump, unusual bleeding, a persistent cough, sudden
weight loss, and a decrease in bowel movements are all possible signs and symptoms. While
these signs and symptoms can signify cancer, they may also indicate something else. Humans
are affected by over 100 different forms of cancer. On the other side, Alzheimer's disease is
an irreversible, cumulative brain disease that gradually erodes memories and cognitive
abilities, as well as the capacity to perform even the most basic activities. Symptoms occur in
the mid-60s in the majority of patients of the disease (those with the late-onset type). The
protein encoded by this gene is a prolife-directed serine/threonine kinase that belongs to the
cyclin-dependent kinase family (Brandt and Mansour, 2016). Contrary to other family
members, the protein encoded with the gene does not specifically regulate the regulation of
the cell cycle. Instead, the enzyme, often expressed in neurons of the postmitotical
mammalian central nervous system at high concentrations, acts in various processes such as
synaptic plasticity and neuronal migration through phosphorylation of the proteins required in
cytoskeletonal organisations, endocytosis, exocytosis and apoptosis. Although most CDK5
research has focused on the nervous system, its non-neuronal mechanisms have long been
neglected. CDK5 appears to control a wide range of functions outside of the nervous system,

including cell cycle progression, apoptosis, DNA damage response, metabolism,
angiogenesis, myogenesis, immune function, cell proliferation, invasion, and epithelial to
mesenchymal transformation.
The projected incidence of patient with cancer with our average rate among the male
was 94.1 as per 1 lakh and among female there is one 103 per 1 lakh for the year is taking the
survey is 2020. One in 68 cancer during their lifetime are usually reported and this is the
main incidence of the cancer in every sampling frame which may be stratified are counted as
a number of populations. The rate of new cases of cancer is 442 per 100000 men and women
per year the cancer death rate is 158 per 100000 and women per year based on the 2013 and
2017 dates. This is also analysing that the lung cancer is the most frequent cancer and create
the leading cause of death. Moreover, it followed by prostate and colorectal cancer for
incidence.
The Alzheimer and their incidence and prevalence are used to identify with their
approximate 5 to 8% of the individual over a 65 15 to 20% of the individual are over age
which is approximately 75% in this 25 to 50% of the individual are over the age of 85 in the
cell. The disease is the most common dementia accounting of 52 75% of the total with a
greater proportion and the higher age range.
Chemoresistance, tumour recurrence, and metastasis are all caused by tumour-
initiating cells (TICs), which are a significant concern in cancer treatment. However, there
are few techniques for dealing with TICs. Cdk5 has recently been linked to epithelial–
Mesenchymal transformation and has been identified as a potential candidate for anti-cancer
therapy in recent studies (EMT). Cdk5's function in TICs, on the other hand, has yet to be
established. Cdk5 expression has been analysed by staining a human tissue microarray in
human cancer tissue (TMA). In migration, invasion, cell death, and tumorsphere assays, as
well as tumour establishment in vivo, the functional effects of Cdk5 overexpression, genetic
knockdown by siRNA and shRNA, and pharmacologic inhibition by the small molecule
Roscovitine were investigated. Molecular biology techniques were used in the mechanistic
experiments (Cuttler, K). In particular, discovered a new mechanism for Cdk5 in TICs: Cdk5
knockdown and pharmacological inhibition inhibited Tumorsphere development and tumour
establishment in vivo. Cdk5 overexpression, on the other hand, facilitated Tumorsphere
development, which was consistent with increased Cdk5 expression in human breast cancer

tissues, as shown by staining of a human TMA. Here, in order to meet needs, researcher have
established a role for Cdk5 in detachment-induced cell death in order to better understand
how Cdk5 inhibition affects Tumorsphere formation: Cdk5 inhibition mediated apoptosis in
Tumorspheres by stabilising the transcription factor Foxo1, resulting in an improvement in
the pro-apoptotic protein Bim.
Scientific believe that the most of the people who is associated with the Alzheimer
disease are usually caused by the combination of genetic, lifestyle, and environmental factors
which affect the tendency of brain and their thinking pattern which can create the leading
causes of the Alzheimer disease less than 1% of the time. Alzheimer is caused by the specific
genetic changes which may be guaranteed to develop in the sense of disease. There are
various parameters in which the Alzheimer's disease are specified as per any damage in the
neurological body which reduce the neuron tendency. As per this, it creates hindrance in the
social parameters and individual usually isolated from the social and other groups.
TIC analysis has been heavily emphasised in recent years in order to identify
alternative ways for targeting TICs. Various pathways that lead to TIC generation and
survival have been identified. TIC generation has been linked to epithelial–mesenchymal
transformation (EMT), a cellular plasticity process that gives epithelial cells mesenchymal
properties. Epithelial cells undergo EMT as they change their appearance, develop strongly
migratory and invasive mesenchyme characteristics, and acquire stem-like properties. Cdk5 is
a serine/threonine kinase that is involved in neuronal development, synaptic plasticity, and
neurotransmission (Ganeshpurkar and et.al, 2019). It has also been linked to
neurodegenerative disorders such as Alzheimer's and Parkinson's disease. Important non-
neuronal roles of Cdk5 have been discovered in recent years. Research has shown that
endothelial Cdk5 is critical for lymphatic vessel growth and tumour angiogenesis, among
other things.
Cancer is a multifactorial disease which is usually caused by the effect of abnormal
cell growth which may be associated with the genetic and environmental factor the
environmental factor includes and genetic factor which is usually the over consumption of
alcohol and smoking lifestyle and infectious agent which can cause to lead the cancer.
Moreover, the hereditary influence of cancer and the modified nature of the environmental
factor which is preventable of the cancel the most important lifestyle which affect the

incidence and increase the mortality of Cancer. Usually, include tobacco, radiation and so on.
In this, the genetic factor is usually inherited mutation in the brca1 and brca2 gene which is
associated with the hereditary breast and ovarian cancer syndrome. In this, it is a disorder
marked by the increase lifestyle risk of the breast and ovarian cancer in the women.
CDK5 belongs to the family of cyclin-dependent kinases and is a proline-directed
serine/threonine kinase. CDK5 is a protein that is present in the nervous system and interacts
with a variety of substrates. CDK5 phosphorylation regulates cortical lamination and
morphology, which is important for the development of the mammalian nervous system
during embryogenesis (He, 2020). CDK5 is also needed for adult neuronal architecture
maintenance, synaptic plasticity, neurite outgrowth, and neuron migration. Neuronal
communication relies on the presynaptic terminal's operation. In this respect, CDK5 is a key
control point for neurotransmitter release modulation, and inhibiting CDK5 activation leads,
including the uncovering of silent synapses, to a considerable potential for presynaptic action.
CDK5's pivotal function is further supported by the discovery that it is rich in synaptosomes
with its physiological activator.
Cdk5 has been postulated that a neurofilament auto protein kinase based on the ability
to phosphorylate. These proteins are invitro in nature. Overall, the cdk5 inhibitor offered by
Santa cruz in a cdk5 and in some cases other cell cycle are also involve which is related with
the triglyceride phosphate or the phosphorylation related with the protein breakdown.
Furthermore, in vivo animal experiments have shown that conditional CDK5
knockout in adult mice improves hippocampal long-term potentiation, synaptic plasticity, and
spatial learning tasks due to increased levels of NR2B at the synapse triggered by the
breaking of the calpain/NR2B complex. Furthermore, enhanced basal excitability was
associated with improved memory and plasticity in mice, resulting in audio genic seizures
and epileptic activity, implying that CDK5 is involved in regulating synaptic plasticity and
managing neuronal and behavioural stimulus-induced excitability in neurons.
Much advancement has been made lately in the development of novel chemical
entities to inhibit the functions of various kinases. The development of Imatinib (brand name:
Gleevac) as a potent Abl-tyrosine-kinase inhibitor to treat multiple cancers, including chronic
myelogenous leukaemia, is perhaps the most notable of these. Imatinib inhibits the

Abltyrosine Kinase enzyme's ability to phosphorylate subsequent proteins and activate the
signalling cascade by selectively targeting the inactive conformation of Abl-tyrosine-kinase.
ALS is a lethal neurodegenerative disease that affects the brain and spinal cord's upper and
lower motor neurons (Kathirvel, 2021). Affected motor neurons grow protein-rich inclusions
containing ubiquitin and incorporating one or more ALS-associated proteins (e.g., superoxide
dismutase 1 (SOD1) and TAR DNA-binding protein 43 (TDP-43)) inside their cell bodies
and axons, resulting in irregular muscle tissue activity. These results in myasthenia,
dysphagia, atrophy, and, finally, the loss of function of all voluntary muscles.
Moreover, the selective aggregation of cyclin dependent kinase activity is highly
effective and create the strategy in order to action plan. Moreover, the atypical cdk and cdk5
has a long-term which play the role of neurodegenerative disease and become the target and
the best attractive drug for the cancer therapy.
In around 5% of ALS patients, front temporal dementia develops, while the rest of
ALS patients experience minor cognitive changes. TICs are also resistant to apoptosis by
modifying proteins in the apoptosis machinery. In Cdk5 knockdown tumorspheres (Figure
6A) or cells with pharmacologic Cdk5 inhibition, cell death was increased. Furthermore, the
pro-apoptotic BH3-only protein Bim, which is a known mediator of detachment-induced cell
death, was increased in Cdk5 knockdown cells (Saeidnia, 2015). Because Bim translocation
to mitochondria activates the intrinsic apoptosis machinery, we performed mitochondria
fractionation at different stages of cell detachment. It is discovered an increase in Bim mRNA
in Cdk5 knockdown cells when researching how Cdk5 knockdown affects Bim. Forkhead
transcription factor type O (Foxo) proteins control Bim transcription, and Cdk5 has
previously been related to Foxo1 in neurons. In particular, it is found that inhibiting or
knocking down Cdk5 increased Foxo1 in both the cytoplasm and the nucleus, while mRNA
transcription was unaffected. In conclusion, these findings indicate that Cdk5 controls cell
death in tumorspheres through Foxo1-mediated Bim transcription.
The targeting cdk5 in the cancer at the cellular level because the cdk5 is involve in the
regulation of the cell cycle and also, they are applicable in the cell proliferation by
phosphorylating tumour suppressor and transcription factors. Moreover, this is also analysed
that in the DNA damage response is upon exposure to genotoxic agent such as chemotherapy
and radiotherapy are more often used and they play emerging role as a cdk5 in the cancer.

The cyclin-dependent kinase which is cdk5 is usually recommended to play a vital role in the
tau phosphorylation. Moreover, they are also used to contribute their pathogenesis of
Alzheimer disease one of these the activator p25 is dramatically increasing the Alzheimer
disease which is associated with the brain, where p25 and cdk5 are colocalised with
neurofibrillary tangles in order to provide the drug treatment in the case of Alzheimer
disease.
It is discovered an increase in Bim mRNA in Cdk5 knockdown cells when
researching how Cdk5 knockdown affects Bim. Forkhead transcription factor type O (Foxo)
proteins control Bim transcription, and Cdk5 has previously been related to Foxo1 in
neurons. In particular, it is found that inhibiting or knocking down Cdk5 increased Foxo1 in
both the cytoplasm and the nucleus, while mRNA transcription was unaffected. In
conclusion, these findings indicate that Cdk5 controls cell death in Tumorspheres through
Foxo1-mediated Bim transcription (Yeh, C. Y., 2019). Indeed, CDK5/p25 induces
Hyperphosphorylation and excessive accumulation of the eurofilament protein NF-H, which
is a hallmark of ALS. Overexpression of NF-H in mutant SOD1 mice results in a longer life
span, suggesting that NF-H can serve as a competitive substrate for CDK5. This highlights
the promise of CDK5 inhibition as a treatment technique for ALS.
CONCLUSION
It can be concluded form the above that there is different impact of these has great
impact and advantages in treatment of different problems. This will also benefit in achieve in
positive results where the person can use it in effective way and achieve better results.

REFERENCES
Books and journals
Allnutt, A. B and et.al., 2020. Physiological and pathological roles of Cdk5: potential
directions for therapeutic targeting in neurodegenerative disease. ACS chemical
neuroscience, 11(9), pp.1218-1230.
Brandt, N. J. and Mansour, D. Z., 2016. Treatment of dementia: pharmacological approaches.
In Dementia Care (pp. 73-95). Springer, Cham.
Cuttler, K., Investigating the effect of LRP/LR and telomerase on tauopathy in alzheimer's
disease cell culture models (Doctoral dissertation).
Ganeshpurkar, A and et.al., 2019. Protein-protein interactions and aggregation inhibitors in
Alzheimer’s disease. Current topics in medicinal chemistry, 19(7), pp.501-533.
He, L., 2020. Computational tools for high-throughput drug combination screening, synergy
scoring and predictive modelling in cancer.
Kathirvel, P., 2021. Secondary Metabolites (Vol. 1). Darshan Publishers.
Saeidnia, S., 2015. New approaches to natural anticancer drugs. Springer International
Publishing.
Yeh, C. Y., 2019. Targeting Kv2. 1/Syntaxin Interaction for Neuroprotection (Doctoral
dissertation, University of Pittsburgh).