Chromosomes are the structures in the cell that contain our DNA. These chromosomes are embedded in a structure called the mitotic spindle, which is created by a group of proteins called kinetochores.
During anaphase, the division of the mitotic spindle causes the chromosomes to move apart. If there were no movement, then the two sister chromatids would be separated and lost, which would be bad for cell function and survival.
Kinetochores are made up of many proteins that hold together the structure of the chromosome. Some of these proteins include Sad1 and Sad2 and Nucelophase Kinking Protein (NuKP). These help keep together both sister chromatids during anaphase through kinking and twisting.
There are drugs being researched that target these kinetochore proteins to disrupt movement of chromosomes during anaphase. This article will discuss this research further.
Microtubules
Another potential drug target is the microtubule network. Microtubules are long, thin structures that organize and move chromosomes during cell division.
Microtubules are made up of molecules called tubulin, and these molecules make up the structure of the microtubule. Cytokinectriole drugs target these tubulin molecules, disrupting the organization of the microtubules.
By doing so, it prevents the chromosomes from being properly organized and moved during anaphase. This results in aneuploidy in only some cells, instead of all cells having this abnormal cell number.
Cytokinectriole drugs have been shown to be effective in treating cancer by targeting this stage of mitosis. However, due to the risk of aneuploidy, they are only used when other treatments have failed.
Mitotic spindle
The movement of the chromosomes from one cell to two daughter cells is called anaphase. During this stage of mitosis, the chromosomes are rapidly separated so that each new cell receives a full set.
There are specific proteins in cells called kinetochores that attach the chromosome to the spindle structure that moves them. A drug targeted to these proteins would prevent anaphase.
Kinetochore drugs have been researched and tested, but none have yet been approved by the FDA for clinical use. There have been several trials conducted for non-cancer diseases though, with mixed results.
Generalized Systemic Scleroderma (GSS) is one disease that has had some clinical improvement with use of a kinetochore drug, but only in some patients. The drug did seem to reduce symptoms in these patients, however.
Kinetochores
A new study has found a way to stop the movement of chromosomes during anaphase, the stage of cell division when chromosomes separate.
The team, from Northwestern University in Evanston, IL, identified a key protein in the kinetochore — which is the structure that holds the chromosome together — that binds to drugs.
By finding a way to target this protein, called Ndc80 Complex Subunit 1 (NCC1), with drugs could stop anaphase. This would preserve the integrity of the entire cell and prevent death due to uncontrolled cell division.
Previous studies have shown that cancer cells have higher levels of NCC1. By targeting NCC1 with drugs, cancer cells could be killed while normal cells remain unaffected. This would reduce the risk of adverse side effects from such drugs.
Anaphase promoting complex (APC)
A drug that could prevent the movement of chromosomes during anaphase would be a significant discovery.
APC is a gene that codes for an enzyme. Enzymes are molecules that facilitate chemical reactions within our cells. The APC enzyme works by breaking down a special part of the cell called the cytoskeleton.
The cytoskeleton is essentially the framework of the cell. It functions to keep the cell intact and defines its shape.
By breaking down the cytoskeleton, APC allows the cell to divide into two new cells. By doing this, it ensures that each new cell will receive one copy of each chromosome, ensuring normal development.
If there was no APC or if it did not function correctly, then there could be an increased risk of developing cancer due to an improper number of chromosomes in each cell.
Histone proteins
As mentioned previously, chromatin is formed by DNA wrapped around histone proteins. These proteins can be altered by drugs, changing how easily chromosomes can be separated during anaphase.
Chromosomes cannot be separated until histone proteins are removed. Drugs that alter histones can prevent this process from happening. However, this may have negative side effects on the cell.
Because epigenetic regulators function at a cellular level, it is more difficult to target them with drugs than it is to target genes. This makes it harder to find ways to prevent cancer due to epigenetics than it is to prevent it due to genetics.
Drugs aimed at epigenetic regulators are still in development and continue to be tested for effectiveness and safety.
DNA damage and repair
A final theory on how anaphase is regulated is through DNA damage and repair. As chromosomes are being pulled apart in anaphase, if there were any mutations or damaged parts of the chromosome, it would allow the adjacent chromosomes to attach to each other. This would not be a safe situation, as the other half of the chromosome may be damaged or mutated.
A cell would not want to be in mitosis with a whole chromosome or part of a chromosome missing, so it would pull itself out of mitosis to repair this damage before moving onto the next stage.
This theory combines nicely with the drug hypothesis- by targeting drugs towards repairing any DNA damage that may be present in cells, cells will be more likely to move into anaphase without pulling back.
Cyclin-dependent kinase (CDK)
A possible drug target for preventing anaphase movement of the chromosomes is cyclin-dependent kinase (CDK). CDKs are a family of enzymes that play a critical role in cell division.
During G2 phase, CDKs activate the enzyme called kinase. This kinase activates another protein called Cyclin, which then activates another protein calledcdtoxiurilate-metlhyltransferase (CMCT).
Together, these proteins pull apart the paired chromosomes, moving them to opposite sides of the cell. Once separated, the cell enters Anaphase, where the centromere proteins pulling the chromosome apart are no longer active.
Therefore, without sufficient cyclin or cdtoxiurilate-metlhyltransferase (CMCT) activity, chromosomes cannot be properly separated into daughter cells during Anaphase. This could potentially be dangerous to the cell.
Cell cycle checkpoints
A cell cycle checkpoint is a protein signaling system that cells use to stop the cell division process until the cell has completed several processes.
These checkpoints include G1, S, and G2 phases. The G1 phase occurs when the cell grows and prepares to divide. The S phase occurs when the cell copies its DNA, and the G2 phase occurs when the cell prepares to divide.
Cell cycle checkpoints are activated when errors in any of these stages are detected. For example, if the DNA does not completely replicate, then the checkpoint will activate to prevent any further growth or division until it has been repaired.
Cytotoxic drugs target cancer cells by damaging their DNA. As a result, these drugs can disrupt cell cycle checkpoints by preventing replication of DNA during S phase.
