Abnormalities in the cell cycle are responsible for the majority of human neoplasms. A cell with no control, reproduced at an alarming rate, with polygenetic defects and / or polyepigenetic defects, in one or more chromosomes, producing abnormal proteins that add phosphate or methyl groups to other residues, changing completely the cellular homeostasis, completely unresponsive to the therapeutic protocols raised, although normal cells have defense mechanisms against cancer progression, in tumor cells different escape pathways are activated leading to tumor progression. I am forced to think that a cell under these conditions we must act at various points of the cell cycle, sequentially progressive and continuous. I just want to express, based on tests or existing protocols, and that I have reviewed, there is a total coincidence that the cell under conditions of malignancy should slow first entering G2 phase to M phase, immediately is necessary inhibit the catalytic action of 26S and 20S proteosome , and stick with antisense therapy to correct gene silencing resulting from aberrant DNA methylation, and I believe in a very personal way, and maybe that could be interpreted as a graphical approach, but under the rules of chemical kinetics, which cellular processes are developed, or in those chemical reactions involving breakage of links, in that the compounds act at a speed equal to one billionth of a second or is 1 picosecond (1 ps = 1 × 10-12 s), would allow us to better interpret the interaction enzyme - substrate, or identify better the protein - protein interactions within the interior of the cell system, which are the largest problems with the established therapies.
WE COULD TRY:
If we have to think in a traditional way, that the abnormal performance of the cell has a high degree of overlap in the different types of neoplasms and these become in differentiated pathways, depending on the cell decision to take to their ultimate goal which is to reproduce.
We should interpret that the first step to be taken after determining the gene expression profile of each case, is to try to slow or delay the entry of the cell from G2 phase to the M phase, because the goal here is, treat to delay arranging of the Factor Promoting M Phase (MPF) and trigger some level of apoptosis not dependent of ubiquitination.
The essay that I have reviewed (Targeting cyclin B1 Inhibits proliferation and sensitizes breast cancer cells to taxol. Authors:Ilija Androic †, † Andrea Krämer, Ruilan Yan, Franz Rödel, Regine Gätje, Manfred Kaufmann, Klaus Strebhardt † and Juping Yuan).
“Cyclin B1, the regulatory subunit of cyclin-dependent kinase 1 (Cdk1), is essential for the transition from G2 phase to mitosis. Cyclin B1 is very often found to be overexpressed in cancer cell lines.
In order to explore cyclin B1 as a potential target for cancer therapy, we studied the effect of small interfering RNA (siRNA) on different cancer cell lines by monitoring their proliferation rate, cell cycle profile, protein expression and activity, apoptosis induction and colony formation.
Downregulation of cyclin B1 inhibited proliferation of several cell lines including HeLa. After combining cyclin B1 siRNA with taxol, we observed an increased apoptotic rate accompanied by an enhanced antiproliferative effect in cancer cells. Furthermore, control HeLa cells were progressively growing, whereas the tumor growth of HeLa cells pre-treated with cyclin B1 siRNA was strongly inhibited, indicating that cyclin B1 is indispensable for tumor growth in vivo.
Our data support the notion of cyclin B1 being essential for survival and proliferation of cancer cells. Concordantly, knockdown of cyclin B1 inhibits proliferation in vitro as well as in vivo. Suggesting that specific cyclin B1 targeting is an attractive strategy for the combination with conventionally used agents in cancer therapy.
Uncontrolled cell proliferation, which is associated with the loss of the proper cell cycle control, is a prominent feature in cancers. The cell cycle is controlled by a highly conserved family of cyclin-dependent kinases (Cdks) and their regulatory subunits cyclins. Among the cyclins, cyclin B1 plays a pivotal role as a regulatory subunit for Cdk1, which is indispensable for the transition from G2 phase to mitosis. Overexpression of cyclin B1 has been reported in various human tumors, such as breast cancer, cervical cancer, gastric cancer, colorectal cancer, head and neck squamous cell carcinoma and non-small-cell lung cancer, indicating that overexpressed cyclin B1 could serve as one of the signals to initiate the communication between cancer cells and their microenvironment.
The mechanisms accounting for overexpressed cyclin B1 are not yet totally understood. It has been reported that the tumor suppressors p53 and BRCA1 negatively regulate the promoter of cyclin B1, whereas the oncogene c-Myc positively regulates the expression of cyclin B1 in cooperation with the loss of p53. The highly expressed cyclin B1, even in G1 phase, binds to its partner Cdk1, which phosphorylates a series of substrates regardless of the cell cycle phase and contributes to the aggressive proliferation in neoplastic tissues. This is consistent with the observation of cyclin B1 overexpression enabling cells to override the G2 DNA damage checkpoint. Nuclear cyclin B1, together with Cdk1AF, a Cdk1 mutant that cannot be phosphorylated at its inhibitory sites, induced a striking premature mitotic phenotype even after DNA damage, resulting in accumulation of genomic defects, one hallmark of neoplastic development. More strikingly, enforced expression of cyclin B1 induces tetraploidy, either after mitotic spindle inhibition of nocodazole or in the absence of such inhibition if cyclin B1 is coexpressed with c-Myc.
Taken together, deregulation of cyclin B1 is involved in neoplastic transformation and promotes proliferation of tumor cells. Conversely, downregulation of cyclin B1, consequently reducing the activity of Cdk1/cyclin B1, could block the aggressive proliferation of tumor cells. Indeed, our previous data confirm that interfering with cyclin B1 function inhibits proliferation of human tumor cells”.
what I want to say is that, if we could control the action of ciclin B1 between Phase G2 / M, without using the action of Taxol, and immediately try to inhibit the catalytic action of the proteosome,to try to slow or delay the entry of the cell from G2 phase to the M phase, with the coordination the deregulation of cyclin B1, and induced apoptosis by oxidative stress.
Other examples indicate the same, if we try to delay the entry of G2 phase to the M phase, with the regulating the synthesis of B1 through a flavoprotein inhibitor as diphenyleneiodonium.
The essay that I have reviewed (G2 cell cycle arrest, down-regulation of cyclin B, and induction of mitotic catastrophe by the flavoprotein inhibitor diphenyleneiodonium. Authors: Robin M. Scaife)
“Because proliferation of eukaryotic cells requires cell cycle–regulated chromatid separation by the mitotic spindle, it is subject to regulation by mitotic checkpoints. To determine the mechanism of the antiproliferative activity of the flavoprotein-specific inhibitor diphenyleneiodonium (DPI), I have examined its effect on the cell cycle and mitosis. Similar to paclitaxel, exposure to DPI causes an accumulation of cells with a 4N DNA content. However, unlike the paclitaxel-mediated mitotic block, DPI-treated cells are arrested in the cell cycle prior to mitosis. Although DPI-treated cells can arrest with fully separated centrosomes at opposite sides of the nucleus, these centrosomes fail to assemble mitotic spindle microtubules and they do not accumulate the Thr288 phosphorylated Aurora-A kinase marker of centrosome maturation. In contrast with paclitaxel-arrested cells, DPI impairs cyclin B1 accumulation. Release from DPI permits an accumulation of cyclin B1 and progression of the cells into mitosis. Conversely, exposure of paclitaxel-arrested mitotic cells to DPI causes a precipitous drop in cyclin B and Thr288 phosphorylated Aurora-A levels and leads to mitotic catastrophe in a range of cancerous and noncancerous cells. Hence, the antiproliferative activity of DPI reflects a novel inhibitory mechanism of cell cycle progression that can reverse spindle checkpoint-mediated cell cycle arrest.”
What I suggest a package that to block Cdk1 catalytic action has to be performed in two stages, first with siRNA1 transfection or siRNA3 and immediately try to inhibit the catalytic action 26S and 20S proteasome.
The degradation of cyclins, like many other molecules involved in cell cycle occurs in the 20S and 26S proteasome dependent phosphorylation after ubiquitination.
26S proteasome inhibition prevents lysis of several proteins involved in the cascade of signals within the cell, causing the death of this.

If there is a very selective pharmacological inhibition of the proteasome could be left free to degrade p21 and p27 CDK, preventing the formation of MPF and inducing apoptosis. A proteasome inhibition would prevent the destruction of IkB, and not separate NFkB and not release survival factors, producing apoptosis through these mechanisms of stress.
The essay that I have reviewed (Argyrin A Reveals a Critical Role for the Tumor Suppressor Protein p27kip1 in Mediating Antitumor Activities in Response to Proteasome Inhibition. Authors:Irina Nickeleit, Steffen Zender, Florenz Sasse, Robert Geffers, Gudrun Brandes, Inga Sörensen, Heinrich Steinmetz, Stefan Kubicka, Teresa Carlomagno, Dirk Menche, Ines Gütgemann, Jan Buer, Achim Gossler, Michael P. Manns, Markus Kalesse, Ronald Frank, Nisar P. Malek)
“A reduction in the cellular levels of the cyclin kinase inhibitor p27kip1 is frequently found in many human cancers and correlates directly with patient prognosis. In this work, we identify argyrin A, a cyclical peptide derived from the myxobacterium Archangium gephyra, as a potent antitumoral drug. All antitumoral activities of argyrin A depend on the prevention of p27kip1 destruction, as loss of p27kip1 expression confers resistance to this compound. We find that argyrin A exerts its effects through a potent inhibition of the proteasome. By comparing the cellular responses exerted by argyrin A with siRNA-mediated knockdown of proteasomal subunits, we find that the biological effects of proteasome inhibition per se depend on the expression of p27kip.”
Whether apoptosis occurs by reversible inhibition of the proteasome, either specific action on the catalytic core of the 20S proteasome, we continue to see in Phase G1 / S, aberrant DNA methylation, with gene silencing, by histone modification in regulatory regions of the promoter, making mandatory also act in G1 / S Phase, to try to stabilize a bit more persistent aberrant homeostasis, where the cyclin D plays an important role in the activation of this checkpoint, because, beyond this checkpoint, the cell becomes mitogenic stimuli independently and continuously without further ado to Phase S, and the new cycle will continue to present the same instability. Because the length of S phase varies with the total DNA; the rate of DNA synthesis, is fairly constant between cells and species, normally cells use 5 and 6 hours, (1.3888888888889E-15 and/ or 1.6666666666667E-15 picosecond), to complete the S phase.
The essay that I have reviewed (Antisense therapy in oncology: new hope for an old idea? Authors: Ingo Tamm, Bernd Dorken,Gunther Hartmann).
“Since antisense oligonucleotides inhibit gene expression in a sequence specific way, selective alteration of the expression of genes by use of closely related sequences is possible. The antisense strategy allows the detailed analysis of signal transduction pathways, which often comprise groups of highly homologous proteins.
Furthermore, research with oligonucleotides might lead to the identification of new therapeutic targets and provide a corresponding drug at the same time. Because most tumor cells have a different pattern of gene expression by comparison with normal cells, antisense oligonucleotides can theoretically be used to specifically target tumor associated genes, or mutated genes, without altering gene expression of normal cells.
Most of the proteins involved in the pathogenesis of cancer operate inside the cell, and are thus not accessible to protein-based drugs. To target the genes, which code for those proteins, by use of antisense oligonucleotides, requires a unique target sequence in the gene of interest and the design of a complementary oligonucleotide against the target sequence that confers biological activity.”
Currently there successful protocols to regulate aberrant DNA methylation, which depending on the case, they could be applied”.
In my opinion, is the rate at which chemical reactions are occurring, causing the instability and accumulation silencing gene mutations, Since approximately 100,000 cells, are produced every second by mitosis, and a similar number of cells die by apoptosis, in a normal cell cycle, we had expressed, the time in which a reaction occurs, (breaking and formation of new links), is of the order of 1 picosecond(1 ps = 1 × 10–12 s ) (If we say that the approximate time of 4 hours, lasting Mitosis, would have been used 1.1111111111111E-15 picoseconds, for each chemical reaction normally produced, For every minute, that we achieve delay the entry of a phase to another, would be decreasing approximately 1.6666666666667E-14 picoseconds in each reaction.), and considering that when reactions involving the breaking of covalent, are generally slower that they occur between particles found as ions, but, as we are facing atypical processes, that alter reaction kinetics, enzymes are acting as catalysts highly positive, further increasing the speed of the reactions and decreasing the activation energy produced, thus, the reaction rate will be higher, what cause, muting, or no expression of that part of the process, and what we are doing is to try to slow the cell cycle phases to produce an intermediate of high energy and short duration it would be an activated complex, that increase the activation energy and decrease the rate of reaction and occur altering the reaction in this way.
And so, we would have a cell that we could better manage.