The development of taxol and docetaxel into two of the worlds most important anticancer drugs (Taxol® and Taxotere®) has proven the stabilization of cellular microtubules to be a clinically relevant mechanistic principle.
Microtubule stabilization thus also provides a promising conceptual framework for the future discovery of new and improved antitumor agents and this is not in the least reflected in the significant number of new agents (taxane and non-taxane based) that are currently undergoing clinical evaluation in humans.
Until the recognition of the tubulin-polymerizing activity of epothilones in 1995, the capacity for microtubule stabilization appeared to be associated solely with taxol-like structures, but the last decade has witnessed the discovery of a number of new and structurally diverse microtubule stabilizing agents, which do not bear any structural resemblance with taxol.
These compounds are all characterized by the ability to induce tubulin polymerization in vitro and their gross cellular profiles are similar.
At the same time, it is becoming increasingly clear that not all microtubule stabilizers are made equal and that differences exist between individual agents with regard to their interactions with tubulin, in the way they affect the cellular microtubule network and in their effects on cell proliferation and the induction of apoptosis.
This includes, e.g., the discovery of compounds which do not bind to the taxol site on b-tubulin or the identification of
However, the majority of known anti-cancer drugs target normal cells as well. Methotrexate, formerly known as amethopterin, is an antimetabolite used in the treatment of some forms of cancer (Shacter and Law, 1956). It inhibits the function of dihydrofolate reductase (DHFR) by tightly binding to the enzyme. Following this slow interaction between methotrexate and DHFR, an enzyme-NADPH-inhibitor complex is formed (Stone et al., 1984). Therein, DHFR is rendered unable to catalyze the NADPH-dependent reduction of dihydrofolate to tetrahydrofolate (Anderson, 2017). Tetrahydrofolate is an important methyl group shuttle in the de novo synthesis of purine and pyrimidine nucleotides and some amino acids (Barbara and Hiroshi, 2002). Therefore, eliminating it from cells is a good therapeutic strategy against cancer cells, as it would limit the de novo synthesis of purines and pyrimidines (Lane and Fan, 2015). Inhibiting the function of DHFR by its competitive inhibitor methotrexate is one such good therapeutic strategy, as it would disable DHFR from converting dihydrofolate into tetrahydrofolate. However, some types of cancer cells had acquired some forms of resistance against methotrexate (Hans et al., 2011). Equally important, methotrexate should be administered in well established low doses, because it affects
Figure 4. We created a flow chamber in which kinesin was nonspecifically bound to a coverslip. As shown in (A), fluorescently-labeled microtubules were flowed in and the kinesin transported the microtubules. A sample timelapse set of images is shown in (B). None of the mutants were able to bind microtubules at our standard assay condition salt concentration of 50 mM NaCl. At lower salt concentrations, most L11 and L12 mutants had decreased velocities when compared to wildtype. However, P278L exhibited “rigor binding”, meaning kinesin was bound to microtubules, but there was no
Norcantharidin (NCTD), the demethylated analogue of cantharidin, has been used to treat human cancers in China since 1984. It was recently found to be capable of inducing apoptosis in human colon carcinoma, hepatoma and glioblastoma cells by way of an elusive mechanism.1 Norcantatharidins and their analogues are synthetic anticancer agents which have been used in various different procedures for the inducing growth arrest and apoptosis of tumour cells and also provide therapeutic and adjuvant therapeutic applications in the treatment of cancer agents.2 This report will discuss the various different NCTD that are currently being studied, highlighting the synthesis of these NCTD and their various biological pathways that are taken in order to inhibit the growth of the correspondent cancer cell. In particular NCTD induced apoptosis of the hepatoma cells will be considered and also highlighting the different views with the synthesis of the particular NCTD and also the effectiveness of the methodology and its observations in response to other NCTD and their mechanism in attacking the hepatoma cell site.
Niosomes can alter the metabolism; prolong circulation and half life of the drug, thus decrease the side effects of antineoplastic drugs. Niosomally entrapped methotrexate and doxorubicin showed beneficial effects over the free drug, such as decreased rate of proliferation of the tumor and higher plasma levels accompanied by slower elimination (9).
Vincristine is a cell-cycle specific chemotherapy drug that target the structural protein tubulin during mitosis in cell division. The anticancer property of vincristine is a result of its ability to inhibit cell division during early mitosis. The drug binds to tubulin monomers preventing the formation of spindle microtubules and therefore alter the microtubules structure and function resulting in chromosomes not separating. Vincristine stops the separation of the duplicated chromosome to form two daughter cells and hence prevent cell division (metaphase arrest).
as the cytosine at position 34, cytosine at position 12, and tyrosine at position 29. In
Docetaxel (doe-se-TAKS-sel) is a man-made antineoplastic chemotherapeutic agent developed to treat different types of cancers by stop cancer cell replication. Antimicrotubule agents such as docetaxel inhibit the microtubule structure of the cell ultimately results in the cells death. Microtubules are part of the cell's machinery for dividing and replicating itself. Belonging to the taxoid family Docetaxel is an antineoplastic. Also known as Taxotere its original trademarked brand name but is also available under these generic names from several manufacturers Pfizer, Sandoz, Hospira, Accord, and Activas. Docetaxel is used by itself or with other cancer medications prescribed. Docetaxel is most commonly used to treat breast, lung, prostate, stomach, and head cancers.
Hu, Jing, Hui Jing, and Hening Lin. “Sirtuin Inhibitors as Anticancer Agents.” Future medicinal chemistry 6.8 (2014): 945–966. PMC. Web. 9 Apr. 2017.
preventing the repair of cancer cell and tumor growth.8 However, This drug is under initial stage
In the studies being done, scientists realized that the BKM-120 inhibitor not only affects the PI3K/PKB/mTOR pathway, but the microtubule synthesis pathway, as well [5]. This dual activity found in the BMK-120 inhibitor was due to the structure of the inhibitor; Figure 5 illustrates how these two functions are possible (a) and what the ratio of microtubule inhibition and PI3K inhibition are in the cell (b) [5]. Through extensive studies on the BMK-120 inhibitor and other similar compound structures, researchers, like Bohancker et al., have been able to identify key structural components for the two activities. The Bohancker et al. found that additional nitrogen in the core of the molecule could help remove the tubulin inhibition, as well as, less symmetry in the BMK-120 overall structure [5]. In general, the research being done in these two examples, and the many other inhibitor synthesis experiments, show how the creation and modification of the phosphoinositide 3-kinases inhibitors is a huge part PI3K studies. From these developments, scientists can get a better sense of how the inhibitors will work in cells and treating diseases.
In vitro: cis-trismethoxy Resveratrol at 0.3 microM could exert a 80% growth inhibition of human colon cancer Caco-2 cells and arrest growth completely at 0.4 microM. The cis conformation of cis-trismethoxy Resveratrol was also 100-fold more potent than the trans isomer. cis-trismethoxy Resveratrol was able to cause cell cycle arrest at the G2/M phase transition and inhibit tubulin polymerization dose-dependently,
Nocodazole is a synthetic tubulin-binding agent. It inhibits mannose efflux by preventing and disrupting microtubule assembly and disassembly. This results in the prevention of mitosis and induction of apoptosis in tumor cells. The more nocodazole present, the more mannose efflux was inhibited. For example: in Figure 4a. efflux of mannose is over four times greater when there is no nocodazole than when there is 25 µM. The effects were also shown to increase as the amount of exposure time increase. At 30 minutes to efflux of mannose is around 20 cpm/µg. But at 60 minutes the efflux has risen to over 80 cpm/µg. It is concluded rapid efflux of mannose out of the Golgi Apparatus occurs through a nocodazole-sensitive transporter.
These findings are consistent with previous studies that report the effects of cytochalasin-D on fibroblasts. However, cytochalasin-D is not the only reagent that can disorganize the cortical layer of actin microfilaments. Cytochalasin-B has very similar effects on mouse fibroblasts and can disrupt organization of actin microfilaments as well (Domnina et al., 1982). This study indicates that cytochalasin-D and cytochalasin-B both alter certain characteristics of the actin cytoskeleton. Yet, cytochalasin-D can have this effect on any cell type that has actin because cytochalasin-D is altering the actin organization. Cytochalasin-D can also have clinical applications because the treatment of cells with cytochalasin-D activate the p53 protein (Rubtsova et al., 1998). This p53 protein plays a major role in the control of cell growth and in the cell’s response to various stress signals. More importantly, p53 is a gene that functions as a tumor suppressor, and if cytochalasin-D activates the p53 protein then there are possible cancer treatments that can be found. Moreover, phalloidin was used to prevent depolymerization by binding to
All reagents were of the highest quality available and were purchased either from Sigma Aldrich, Merck, Fluka, Scharlau Chemie, Roth, CALEDON, Gibco, Invitrogen or Biofil. N,N,N',N'-Tetramethyl-O-(benzotriazol-l-yl)Uronium Tetrafluoroborate (TBTU), Triisopropylsilane (TIS), 1-hydroxybenztriazole (HOBt), 5(6) Carboxyfluorescein (FAM), Potassium cyanide, Methotrexate and Ninhydrine were obtained from Sigma-Aldrich (St. Louis, MO, USA). 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) was from Roth (Karlsruhe, Germany). Piperidine was obtained from BDH Laboratory Supplies (England). Trifluoroacetic acid (TFA) was from Fluka (Buchs, Switzerland). N-ethyldiisopropylamine (DIPEA), Triethylamine (TEA), Dimethyl Sulfoxide (DMSO), Acetonitrile
It is notable that HDAC8 does not have an aromatic hydrophobic pocket corresponding to the one created by His-33 and Phe-155. In HDAC2 this region forms a nice groove, which is not observed in HDAC8, for the indole ring sit in. In HDAC8 the Lys-33 residue, while it has a hydrophobic chain, does not participate in staking interactions. The imidazole ring now adopts a T-shaped π-π stacking interaction between Phe-152 and Phe-208, whereas it was parallel displaced in HDAC2. This less favored double T-shaped interaction prevents the formation of a hydrogen bond in the core of HDAC8. ETS2 in HDAC8 also shows the shift of the indole ring to the right side of the gorge to now hydrogen bond with Gly-184, and the oxazole ring also adopts more of a T-shaped orientation with the Phe-208 in HDAC8 compared to a parallel π-π orientation. The oxazole ring is also less of an equal distance between the two Phe rings, favoring an interaction with Phe-208 over an interaction with Phe-152. Again the wider gorge size of HDAC8 decreases binding affinity of these compounds.