The Cell Cycle, Cyclins, Checkpoints and Cancer

 

Farha Fatma*, Anil Kumar

University Department of Botany, Ranchi University, Ranchi - 834008, Jharkhand, India.

*Corresponding Author E-mail: farhafatma78@gmail.com

 

ABSTRACT:

Cancer is a serious problem affecting the health of human and isone of the leading cause of mortality worldwide. A normal cell undergoes regulated cell division, differentiation and apoptosis (programmed cell death). When normal cell has lost the usual control over their division, differentiation and apoptosis they become tumor cells. Cancer arises mainly from mutations in somatic cells. Maintenance of genomic integrity is a pre-requisite for a safe and long lasting life. For this purpose, cell has quality control points, referred as checkpoints. The different mechanisms and multiple researchers involved in the field necessiatean understanding of the molecular mechanism to classify tumor and to assess the risk and treatment of disease. Certain therapeutic strategies exist and many more need to be explored. Different experimental therapies are currently in clinical trials and are raising hopes that a new class of anti-cancer drug may soon be available.

 

KEYWORDS: Cancer, apoptosis, cyclins, gene mutation, checkpoints.

 

 

 

INTRODUCTION:

For a safe and long lasting life, maintenance of genomic integrity is pre-requisite, whose instability leads to various diseases like cancer. Cancer has been known as a disease of dysregulation of cell growth. It is one of the leading cause of mortality worldwide.   DNA is damaged by various chemical and physical agents hence cell had number of surveillance mechanism that constantly monitor DNA integrity and cell cycle progression.

 

The process of replicating DNA and dividing cell is highly regulated and coordinated events called cell division cycle. This is ordered  series of events by which cell duplicates its genome and divides into daughtercells. Cell cycle has two main phases

·       M phase (mitosis)

·       The interphase

 

 

The interphase is further divided into:

G1 phase (Gap 1)- Period between end of mitosis and start of DNA replication.

 

S phase (Synthesis)- Period during which DNA synthesis occurs.

 

G2 Phase (Gap 2)- Gap period following DNA replication and preceding the initiation of mitotic prophase.

 

Cell may withdraw from cell cycle and enter into G0 phase or re-enter into cycle from it. The correct sequence of events is characteristic of cycle. If an early event is blocked then generally none of the later events is initiated, resulting cell arrest at G1 or G2 phase.

 

One of the hallmark of cancer is uncontrolled cell proliferation and genes are damaged that are involved in cell regulation. In a very well organized molecular events cell cycle give ability to the cell to produce exact copy of itself. DNA replication and segregation of replicated chromosomes are major events of cell cycle.

The Cell Cycle: Regulating balance between life and death:

The cell cycle is highly regulated process and responds to the specific needs of a certain tissue or cell type. There is a balance between cell death (programmed cell death or apoptosis) and proliferation (cell division) in the tissues producing a steady state. Disruption of this equilibrium by loss of cell cycle control may eventually lead to tumor development. The highly organized and regulated cell cycle process is responsible for duplication of the cell. Tight regulation and timing ensure that DNA is replicated once during the S phase (without errors), and that identical chromosomes are equally delivered to daughter cells during the M phase.

 

The cell cycle is, therefore, an alteration of two main processes: A) the “doubling” process (S = synthesis phase) where DNA is synthesized, and B) the “halving” process (M = mitosis phase) where the cell and its contents are divided equally into two daughter cells The periods between these processes are called gap periods (G phase).

 

Figure 1 : Cell cycle phases

 

Table 1: Cell cycle phase

Phase

Description

G1

Growth and preparation of the chromosomes for replication

S

Synthesis of DNA (Centrioles/ DNA replication)

G2

Preparation for mitosis

M

Mitosis

G0*

Temporary and permanent state of cell cycle exit. Post mitotic terminally differentiated.

* Exit from the cell cycle at G1, not occuring in every cell.

 

Cell cycle regulation:

Cell cycle progression is highly regulated by key regulatory proteins called CDK (Cyclin dependent kinases) which avoid the initiation of cell cycle before completion of preceding one. CDK has two subunits:

·       Cyclins

·       CDK protein kinase

 

Cyclin is regulatory component where as CDK is catalytic and acts as protein kinase. Cyclins undergo a cycle of synthesis and degradation in each cell division cycle hence called cyclins.

 

Major classes of Cyclins:

·       G1cyclins

·       S cyclins

·       M cyclins

 

Cyclins binds to CDK molecules and control their ability to phosphorylate appropriate target proteins. The rise and fall of cyclins level is primary determinant of CDK activity during the cell cycle. CDK activities are also regulated by several mechanisms at specific stages of cell cycle. They are-

·       Cyclin synthesis and degradation

·       Phosphorylation/ dephosphorylation

·       Binding of CDK inhibitor proteins (CKIs)

 

The cdks are a family of serine/threonine protein kinases that are activated at specific points of the cell cycle consisting of a catalytic subunit with a low intrinsic enzymatic activity and of a fundamental positive regulatory subunit called cyclin (Pavletich, 1999). Cyclin protein levels rise and fall during the cell cycle, activating the corresponding cdk, whereas the cdk protein levels are kept constant throughout the cell cycle. Once the complex cdk-cyclin is formed, it gets activated by the protein CAK (cdk activating protein) which phosphorylates the complex ensuring the subsequent phosphorylation of target gene products required for the progression of the cell through the cell cycle (Morgan, 1995).

 

When quiescent cells are stimulated by mitogen signals, CDK4 and CDK6 are activated by association with D type cyclins. These above cited cdk-cyclin complexes are important for the progression through the G1 phase and therestriction point preparing the cell to the replicative phase by phosphorylating the oncosuppressor protein pRb which causes the activation of the E2F family transcription factors. The activation of CDK4 andCDK6 is followed by the subsequent activation of CDK2 by cyclin E and cyclin A, which in turn initiatesDNA replication. As the DNA replication process finishes, the Cdk1/cyclin B complex is activatedleading to mitosis (Vermeulen et al., 2003; Sherr and Roberts, 1999). Until the end of G2 phase, CDK1 isphos-phorylated at Thr14 and Tyr15 by the kinases WEE1 and MYT1, resulting in inhibition of cyclin BCDK1 activity. Mitotic entry is ultimately initiated by dephosphorylation of these residues by the CDC25 family of phosphatases, initiating a positive feedback loop that stimulates cyclin B-CDK1 activity and entry into mitosis (Lindqvist et al., 2009). The activation status of the cdk-cyclin complexes is also monitored by negative regulation of the ATP binding site by phosphorylation in specific residues and subsequent reactivation by specific phosphatases which dephosphorylate the same residues.

 

Regulatory protein families:

Three distinct families of thesecyclin dependent kinase inhibitors (CKI) can be distinguished.

 

INK family:

The first one is called INK family and is composed by four members: p15, p16, p18 and p19. They regulate the G1-S transition of the cell cycle targeting to CDK4 and CDK6 by binding the cdk subunit and causing a conformational change of the kinases which become inactive precluding the cyclin binding.

Cip/Kip family:

The second family of inhibitors is the Cip/Kip family and consists of three members: p21cip1, p27kip1 and p57kip2. The components of this group negatively regulate the cdk2/cyclinA and cdk2/cyclinE complexes wherethey positively regulate the cdk4/6 cyclinD complexes by facilitating and stabilizing the association of cyclin and CDKs.

 

pRb protein family:

The final class of inhibitors is the pRb protein family which consists of two members: p107and p130. These proteins, better known as transcriptional inhibitors, act as potent cyclin E/A-cdk2 inhibitors by binding both to cyclin and to cdk sites (Vermeulen et al., 2003; Cobrinik, 2005).

 

 

Table 2: Cyclin –CDK complexes and their connection with cancer

 

 

Cell Cycle checkpoints:

The quality control points of the cell cycle are often referred as checkpoints. At checkpoints, there are important mechanisms sensing damaged DNA before the cell enters the S phase (G1 checkpoint) or the M phase (G2 checkpoint). One major molecular hallmark of checkpoint control is where transitions turn off the previous state and promote the future state of the cell cycle (irreversible progression). Loss of checkpoint control results in genomic instability, accumulation of DNA damage, uncontrolled cell proliferation, and, eventually, tumorigenesis. This has been implicated in the progression of many human cancers.

 

To understand the working of these checkpoints one must recognize the accelerators and brakes that control progression of cell cycle engine and then describe thesurveillance mechanisms that sense unfavorable conditionsand communicate halt signals to the engine Activation of a surveillance mechanism stops the cell cycle engine, allowing time for completion of a particular cell cycle event. The term checkpoint is used to refer to both the arrested state of the cell cycle engine and the signal transduction pathway that induces the arrested state. Checkpoint pathways are essential to cell survival under adverse conditions, when cells have difficulty meeting the requirements for successful proliferation.

 

Figure 2: Accelerators and brakes of the cell cycle engine

 

Core components of cell cycle engine:

The core components of the eukaryotic cell cycle engine are cyclin-dependent protein kinases (Cdks) and their regulatory subunits (cyclin).

 

cyclin–Cdk complexes fall into three general classes that have different substrate specificities andtherefore initiate different cell cycle events:

 

G1cyclin–Cdk complexes are important for progression through G1 phase and commitment to S phase;

 

S cyclin–Cdk complexes are responsible for initiating and completing DNA replication;

 

M cyclin–Cdk complexes drive eukaryotes into mitosis and restrain reentry into G1 phase.

 

Expression of Cdk genes plays only a minor role in regulating Cdk activity;

 

 

Table 3: Major components of the cell cycle engine

 

 

Regulatory events in cell cycle:

There are two main classes of regulatory mechanisms controlling, or driving, the cell cycle:

A) The intrinsic mechanisms appearing every cycle, and

B)  An extrinsic mechanism, which only acts when defects are detected.

 

The Main Intrinsic Actors of the Mammalian Cell Cycle:

The link between failure in checkpoint control and DNA instability was first evident in studies from the yeast Saccharomycescerevicia. The first cell cycle regulators (cdcs) were isolated and cloned from this organism, and temperature-sensitive cdc mutants from yeast have been valuable models for identification and isolation of mammalian homologues.

 

Figure 3: Regulation of cell cycle activity

 

Cyclins:

Cyclins are the second part of the Cdk holoenzyme and account for both substrate specificity and cell phase specificity of the Cdk/cyclin complex. The cyclins are important mediators of Cdk activity, and their level fluctuates throughout the cell cycle, some being more abundant in specific cell phases than others.

These cyclins have been divided into three classes: G1-S cyclins, S cyclins, and M cyclins. The cyclin level is primarily regulated by gene expression (transcriptional regulation) and protein degradation (proteolytic regulation, ubiquitination).

 

Cyclin-Dependent Kinases (Cdks):

Cdks that are required for cell cycle regulation consist of an active kinase subunit in complex with a regulatory subunit, or activator, commonly called cyclin. The Cdk/cyclin complex is subjected to several kinds of regulation, both positive and negative, for instance, by reversible protein phosphorylation. Phosphorylation at specific threonine residues by the Cdk activator kinase (CAK) and dephosphorylation at specific tyrosine residues by specific Cdk phosphatases ender the Cdk active.

 

Table 4 : Major cyclin classes involved in cell cycle control

Species

Class

Class

G1/S  

S

M

G1

S.cerevicia

Cln 1,2

Clb 5, 6

Clb1, 2, 3, 4

Cln 3

S.prombe

Pnc 1

Cig 2

Cdc 13

Puc 1

H.sapiens

Cyclin E

Cyclin A1, 2

Cyclin B, 1, 2

Cyclin D 1, 2, 3

 

Table 5: Cdks involved in mammalian cell cycle

Species

Name

Original name

Size(aa)

Function

S.cerevicia

Cdk 1

Cdc 28

298

All phases

S.prombe

Cdk 1

Ckc 2

297

All phases

H.sapiens

Cdk 1

Cdc 2

297

M

Cdk 2

298

G1, S

Cdk 4

303

G1

Cdk 6

326

G1

 

 

Figure 4: Schematic summary of the levels of regulation of the Cdks

 

Inhibitory proteins:

Inhibitory proteins also contribute to negatively regulate the cdks by forming either binary complexes with cdks or ternarycomplexes with cyclin cdk dimers. Threedistinct families of these so called cyclin dependentkinase inhibitors (CKI) can be distinguished. The first one is called INK family and is composed by fourmembers: p15, p16, p18 and p19. They mainly regulate the G1-S transition of the cell cycle targeting to CDK4 and CDK6 by binding the cdk subunit and causing a conformational change of the kinases which become inactive precluding the cyclin binding. The second family of inhibitors is the Cip/Kip family and consists of three members: p21cip1, p27kip1 and p57kip2. The components of this group negatively regulate the cdk2/cyclinA and cdk2/cyclinE complexes whereas they positively regulate the cdk4/6 cyclinD complexes by facilitating and stabilizing the association of cyclin and CDKs. The final class of inhibitors is the pRb protein family which consists of two members: p107 and p130. These proteins, better known as transcriptional inhibitors, act as potent cyclin E/A-cdk2 inhibitors by binding both to cyclin and to cdk sites (Vermeulen et al., 2003; Cobrinik, 2005).

 

p53

One of the protein critical in regulating the cell cycle is the tumor suppressor protein p53. p53 is a DNA-binding protein regulating the expression of genes involved in cell cycle arrest. It senses DNA damage and tells the cell to either stop growing (until damage is repaired) or to killitself by apoptosis (preventing unregulated cellular growth and formation of cancer), a typical extrinsic mechanism. p53 is the most frequently disrupted gene in human cancers. In fact, more than 50% of human cancers are associated with a p53 mutation, including cancers of the bladder, breast, cervix, colon, lung, liver, prostate, and skin. p53- related cancers are also very aggressive and have a high degree of lethality.

 

Cell cycle dysregulation:

Cell-cycle dysregulation is a hallmark of tumor cells. The ability of normal cells to undergo cell-cycle arrest after damage to DNA is crucial for the maintenance of genomic integrity. The biochemical pathways that stop the cellcycle in response to cellular stressors are called checkpoints. Defective checkpoint function results in geneticmodifications that contribute to tumorigenesis. The regulation of checkpoint signaling also has important clinical implications because the abrogation of checkpoint function can alter the sensitivity of tumor cells to chemotherapeutics.

 

G1-S checkpoint:

During G1, cells check whether their environment favours proliferation and whether their genome is ready to be replicated. This control point is called Start in yeast and the restriction point in mammals.

 

Inhibition of G1-phase cyclin–CDK complexes plays a key role in the function of the G1–S checkpoint. CDKs arenegatively regulated by a group of functionally related proteins called CDK inhibitors (CDKIs) of which there are two families, the INK4 inhibitors and the Cip/Kip inhibitors.

 

The INK4 family has four members:

p16INK4A (p16), p15INK4B (p15), p18INK4C (p18) and p19INK4D (p19); and the Cip/Kip family has three members: p21Waf1/Cip1 (p21), p27Kip1 (p27) and p57Kip2 (p57). The INK4 family inhibits CDK4 and CDK6 activity during G1 phase.

 

Cip/Kip family can inhibit CDK activity during all phases of the cell cycle. Both families of CDKI have important roles in the G1–S checkpoint.

 

Cells that meet the size and nutritional requirements commit to completing the cell cycle unless a specific threat to genome integrity is perceived. One major threat isDNA damage. Like nutrient or growth-factor sensing, DNA damage triggers a signaling network that arrests the cell cycle at specific places by inactivating Cdks (Walworth, 2000).

 

In mammalian cells, ionizing radiation produces double-stranded breaks in DNA, which trigger phosphorylation and consequent activation of ATM. ATMphosphorylates a number of substrates that function in DNA repair, apoptotic death and cell cycle arrest.

 

G2 Checkpoints:

Progression into M phase is dependent on cyclin Bdependent kinase activity, CycB–Cdk1, also called M phase-promoting factor (MPF). Before undergoing chromosome condensation and nuclear division, cells have to be sure that their DNA is fully replicated and undamaged.

 

After DNA damage, ATM (ataxia telangiectasia mutated)- and ATR (ATM and Rad3-related)-dependent signaling induces G2 cell-cycle arrest by inhibiting CDK1. ATM activates human checkpoint kinase 2 (Chk2) in cells that are exposed to ionizing radiation, whereas ATR signaling mediates activation of Chk1 in cells treated with ultraviolet radiation. Chk1 and Chk2 phosphorylate CDC25C, which generates a consensus binding site for 14–3–3 proteins. Binding of 14–3–3 proteins to CDC25C results in nuclear export and cytoplasmic sequestration of the phosphatase, with subsequent G2 arrest caused by inhibition of CDK1.

 

p53 maintains the G2 checkpoint by upregulating transcription of 14–3–3s and p21, which inhibit G2 progression bysequestrating CDK1 in the cytoplasm and by inactivating cyclin-B–CDK1 complexes, respectively. p21 can disrupt the interaction between proliferating cell nuclear antigen (PCNA) and CDC25C to induce G2 cell-cycle arrest.

 

DNA damage controls:

DNAdamage blocks the G2-M transition in fission yeast and mammals by blocking the action of Cdc25C. WhenCdc25C is phosphorylated by Chk1 and/or Chk2, it binds to the cytoskeletal protein 14-3-3 and becomes sequestered in the cytosol. Hence, it is unable to do its job on preMPF, which is nuclear. (Phosphorylation by Chk2 may also directly render Cdc25C less catalytically active.) Thus, Chk1 and Chk2 mediate cell cycle arrest in G1, S or G2 by tipping the balance toward phosphorylated, inactive, cyclin–Cdk dimers (Bartek and Lukas, 2001).

 

Mitotic spindle checkpoint:

The mitotic spindle checkpoint monitors the microtubule structure and chromosome attachments of the mitotic spindle and delays chromosome segregation during anaphase until defects in the mitotic spindle apparatus are corrected. The kinetochore-associated MAD2, BUBR1, BUB1 and BUB3 proteins are crucial constituents of the spindle-checkpoint pathway. MAD2 and BUBR1 regulate mitotic progression by direct interaction and inhibition of the APC machinery, which prevents anaphase entry in the presence of mitotic spindle dysfunction. BUB1 and BUB3 also mediate mitotic arrest after disruption of microtubules, because cells that lack either BUB1 or BUB3 do not undergo mitotic arrest when treated with spindle-disrupting agents.

 

Cell cycle dysregulation in human cancer:

The connection between the cell cycle and cancer is obvious: cell cycle machinery controls cell proliferation, and cancer is a disease of inappropriate cell proliferation. Fundamentally, all cancers permit the existence of too many cells. However, this cell number excess is linked in a vicious cycle with a reduction in sensitivity to signals that normally tell a cell to adhere, differentiate, or die. This combination of altered properties increases the difficulty of deciphering which changes are primarily responsible for causing cancer.

 

The malfunctioning genes can be broadly classified into three groups. The first group, called proto-oncogenes, produces protein products that normally enhance cell division or inhibit normal cell death. The mutated forms of these genes are called oncogenes. The second group, called tumor suppressors, makes proteins that normally prevent cell division or cause cell death. The third groupcontains DNA repair genes, which help prevent mutations that lead to cancer.

 

The products of cell cycle regulatory genes are critical determinants of cancer progression. The residue of transcriptional activator p53 are mutated in cancer cells, are critical for DNA binding.

 

Alterations in components of the cell-cycle machinery and checkpoint signaling pathways occur in most human tumors. Ultimately, these genetic modifications result in the dysregulation of oncogenes and tumor suppressor genes, which has important implications for the optimization of current therapeutic regimens and the selection of novel cell-cycle targets.

 

Alterations in components of cell cycle machinery:

Rb

Rb is a juvenile eye cancer that is caused by a mutation in the Rbgene, located on human chromosome 13. The main function of Rbis to connect the cell cycle clock to the transcriptional machinery (intrinsic mechanism). The Rb protein interacts with a protein called E2F, which is a nuclear transcription factor involved in cellular replication during the S phase. Interaction between Rb and E2F prevents E2F from functioning as a transcription factor. However, Rb is only able to bind E2F when it is unphosphorylated. It will not interact with E2F in its hyperphosphorylated state. Rb mutants, which are constitutively phosphorylated and cannot bind E2F, provide uncontrolled cell division at the S-phase restriction site and cells may become tumorigenic. In a subset of human cancers, growth advantage has been accomplished by direct mutation and/or loss of function of Rb [17, 18]. The “Rb pathway” is further discussed in view of the G1-S transition phase.

 

Alterations in checkpoints signaling proteins:

p53

One of the protein critical in regulating the cell cycle is the tumor suppressor protein p53. p53 is a DNA-binding protein regulating the expression of genes involved in cell cycle arrest. It senses DNA damage and tells the cell to either stop growing (until damage is repaired) or to kill itself by apoptosis (preventing unregulated cellular growth and formation of cancer), a typical extrinsic mechanism. p53 is the most frequently disrupted gene in human cancers. In fact, more than 50% of human cancers are associated with a p53 mutation, including cancers of the bladder, breast, cervix, colon, lung, liver, prostate, and skin. p53- related cancers are also very aggressive and have a high degree of lethality.

 

Cancer from molecular perspective:

Cancer results from a series of molecular events that fundamentally alter the normal properties of cells. The abnormalities in cancer cells usually result from mutations in protein-encoding genes that regulate cell division. Over time more genes become mutated.

 

Mutations begin to increase in the cell, causing further abnormalities in that cell and the daughter cells. Some of these mutated cells die, but other alterations may give the abnormal cell a selective advantage that allows it to multiply much more rapidly than the normal cells. Cancer cells in malignant tumors can often metastasize, sending cancer cells to distant sites in the body where new tumors may form.

 

Cancer occurs by a series of successive mutations in genes so that these mutations change cell functions. Chemical compounds have an obvious role of forming gene mutations and cancer cells. In addition, smoking involves several carcinogenic chemical compounds that lead to lung cancer Interestingly, environmental chemical substances with carcinogenic properties influence directly or indirectly the cytoplasm and nucleus of cells, and lead to genetic disorders and gene mutations. Viruses, bacteria and radiation rays are other carcinogenesis factors, comprising about 7% of all cancers. In general, cancer disrupts cellular relations and results in the dysfunction of vital genes. This disturbance is affective in the cell cycle, and leads to abnormal proliferation. Mutation in the p53 gene leads to formation of an unusual protein that has a prominent role in disturbance of molecular process related to p53. Abnormality of these molecular and biological events leads to formation of cancer cells; therefore, the p53gene has a complex relationship with cancer and it has been reported that p53 abnormality occurs in 60% of cancer cases. Under normal conditions, p53 plays an important role in cell division, cell death, senescence, angiogenesis, differentiation, and DNA metabolism.

 

Additionally, the majority of mutations related to the p53 gene occur in the DNA-binding position, and the disability of genes is controlled by p53 for replication. Cooperation of p53 with CDK1- P2 and CDC2 keeps cancer cells in G1 and G2 phases of cell cycle.

 

Hypomethylation in specific promoters can activate the ectopic expression of oncogens; for example, this condition occurs for MASPIN as a tumor suppressor gene in breast and prostate cancer.

 

Change in the distribution of histone methylation is mainly due to expression of histonemethyltransferases and histone demethylase. In addition, disabling mutations in SETD2 (a histone) and UTX (a histone demethylase) occurs during renal carcinoma. In leukemia, MLL oncoprotein leads to abnormal patterns of H3K4 and H3K29 methylation, and ultimately changes in the expression of the target genes of MLL. BRG1 and BRM (as subunits of ATPase related to SWI/SNF complex) are known as tumor suppressors that manifest a pivotal role in 15e20% of lung cancer.

 

 

Table 6: Some genes associated with cancer

 

 

CONCLUSION:

The cell cycle is very well organized molecular events thatgive the cell ability to produce exact itself’s copy. Any dysregulation in cell cycle progression lead to various diseases like cancer characterized by uncontrolled growth. Cell has number of surveillance mechanism to monitor DNA integrity and progression of cell cycle in theform of checkpoints. Identification of differences between normal cells and cancer cells is vital for continued development of anticancer agents that target cancer cells and minimize toxicity to normal tissues. Various studies to explore the epigenetic mechanisms and their relationship together with the development and progression of cancer is continuing. The field has significantly advanced in understanding mechanisms that underlie cell cycle, regulatory checkpoints, genetics of cancer and this is an exciting time for researchers and all those involved in and waiting for treatment and cure of cancer. Many therapeutic strategies exist and many more need to be explored and they will provide in the near future new effective tools for cancer therapy.

 

ACKNOWLEDGEMENT:

We are highly grateful to Dr. Jyoti Kumar, Head, University Department of Botany, Ranchi University, Ranchi, Jharkhand for his valuable suggestions in the improvement of this review paper.

 

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Received on 26.11.2020            Modified on 02.01.2021

Accepted on 15.02.2021      ©Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 2021; 11(2):175-183.

DOI: 10.52711/2231-5659.2021-11-2-14