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Cytoskeletal drugs

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Cytoskeletal drugs are small molecules that interact with actin or tubulin. These drugs can act on the cytoskeletal components within a cell in three main ways. Some cytoskeletal drugs stabilize a component of the cytoskeleton, such as taxol, which stabilizes microtubules, or Phalloidin, which stabilizes actin filaments. Others, such as Cytochalasin D, bind to actin monomers and prevent them from polymerizing into filaments. Drugs such as demecolcine act by enhancing the depolymerisation of already formed microtubules. Some of these drugs have multiple effects on the cytoskeleton: for example, Latrunculin both prevents actin polymerization as well as enhancing its rate of depolymerization. Typically the microtubule targeting drugs can be found in the clinic where they are used therapeutically in the treatment of some forms of cancer.[1] As a result of the lack of specificity for specific type of actin (i.e. cannot distinguish between cardiac, smooth muscle, muscle and cytoskeletal forms of actin), the use of these drugs in animals results in unacceptable off-target effects. Despite this, the actin targeting compounds are still useful tools that can be used on a cellular level to help further our understanding of how this complex part of the cells' internal machinery operates. For example, Phalloidin that has been conjugated with a fluorescent probe can be used for visualizing the filamentous actin in fixed samples.

Cytochalasin D and Latrunculin are both understood to be toxins developed by certain fungi and sponges to promote the depolymerization of filaments. Specifically, Cytochalasin D is a fungal alkaloid while Latrunculin is a toxin that is secreted by sponges. Although they both result in depolymerization, they have different mechanisms. Cytochalasin D binds to the (+) end of F-actin and blocks the addition of subunits. Contrasting, Latrunculin binds to and sequesters G-actin, thus preventing it from adding to the filament end of F-actin. Upon addition to live cells, Cytochalasin D and Latrunculin disassemble the actin cytoskeleton and inhibit cell movements such as locomotion.[2]

Other toxins secreted by sponges, such as jasplakinolide and phalloidin (phallotoxins), isolated from Amanita phalloides (the “death cap” mushroom[3]), contrasts the function of Cytochalasin D and Latrunculin. Jasplakinolide binds to and stabilizes actin dimers by enhancing nucleation[2] (one of the first phases of G-actin polymerization,[4]) and thus lowering the critical concentration, or the minimum concentration needed to form filaments.[5] Phalloidin prevents filaments from polymerizing by binding between subunits in F-actin and locking them together. The presence of phalloidin in a cell paralyzes it, killing the cell.[2]

Phallotoxins have been isolated from A. phalloides, a type of mushroom, and have been involved in fatal cases of mushroom poisoning. The liver and kidneys of humans are most commonly affected by ingestion of the toxin, and can cause symptoms such as jaundice and seizures to name a few, ultimately resulting in death. Three classes of toxins can be isolated from A. phalloides: amatoxins, phallotoxins, and virotoxins. These toxins can cause deaths within 2-8 hours. Similarly to the phallotoxins, the virotoxins interact with actin and prevent filament depolymerization. Ultimately, these toxins disrupt the functions of the cytoskeleton, paralyzing susceptible cells[3].

A cancer cell that was fixed and stained with phalloidin to visualize the actin cytoskeleton.
Drug Name Target cytoskeletal component Effect Applications
Colchicine[6] Microtubule Prevents polymerization Used to treat gout
Cytochalasins[7] Actin Prevents polymerization None
Demecolcine[8] Microtubule Depolymerizes Chemotherapy
Latrunculin[9] Actin Prevent polymerization, enhance depolymerisation None
Jasplakinolide[10][11] Actin Enhances polymerization None
Nocodazole[12] Microtubule Prevents polymerization None
Paclitaxel (taxol)[13] Microtubule Stabilizes microtubules and therefore prevents mitosis Chemotherapy
Phalloidin[14] Actin Stabilizes filaments None
Swinholide[15] Actin Sequesters actin dimers None
Vinblastine[1] Microtubule Prevents polymerization Chemotherapy
Rotenone[16] Microtubule Prevents polymerization Pesticide

See also

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References

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  1. ^ a b Jordan MA, Wilson L (April 2004). "Microtubules as a target for anticancer drugs". Nature Reviews. Cancer. 4 (4): 253–65. doi:10.1038/nrc1317. PMID 15057285. S2CID 10228718.
  2. ^ a b c Lodish H (2016). Molecular Cell Biology. Macmillan Learning. pp. 791–792. ISBN 978-1-464-18745-2.
  3. ^ a b Garcia J, Costa VM, Carvalho A, Baptista P, de Pinho PG, de Lourdes Bastos M, Carvalho F (December 2015). "Amanita phalloides poisoning: Mechanisms of toxicity and treatment". Food and Chemical Toxicology. 86: 41–55. doi:10.1016/j.fct.2015.09.008. hdl:10198/17717. PMID 26375431.
  4. ^ Lodish H (2016). Molecular Cell Biology. Macmillan Learning. p. 781. ISBN 978-1-464-18745-2.
  5. ^ Lodish H (2016). Molecular Cell Biology. Macmillian Learning. p. 782. ISBN 978-1-464-18745-2.
  6. ^ Vandecandelaere A, Martin SR, Engelborghs Y (April 1997). "Response of microtubules to the addition of colchicine and tubulin-colchicine: evaluation of models for the interaction of drugs with microtubules". The Biochemical Journal. 323 ( Pt 1) (Pt 1): 189–96. doi:10.1042/bj3230189. PMC 1218294. PMID 9173881.
  7. ^ Cooper JA (October 1987). "Effects of cytochalasin and phalloidin on actin" (PDF). The Journal of Cell Biology. 105 (4): 1473–8. doi:10.1083/jcb.105.4.1473. PMC 2114638. PMID 3312229.
  8. ^ Jordan MA, Wilson L (April 2004). "Microtubules as a target for anticancer drugs". Nature Reviews. Cancer. 4 (4): 253–65. doi:10.1038/nrc1317. PMID 15057285. S2CID 10228718.
  9. ^ Yarmola EG, Somasundaram T, Boring TA, Spector I, Bubb MR (September 2000). "Actin-latrunculin A structure and function. Differential modulation of actin-binding protein function by latrunculin A". The Journal of Biological Chemistry. 275 (36): 28120–7. doi:10.1074/jbc.M004253200. PMID 10859320.
  10. ^ Sasse F, Kunze B, Gronewold TM, Reichenbach H (October 1998). "The chondramides: cytostatic agents from myxobacteria acting on the actin cytoskeleton". Journal of the National Cancer Institute. 90 (20): 1559–63. doi:10.1093/jnci/90.20.1559. PMID 9790549.
  11. ^ Bubb MR, Spector I, Beyer BB, Fosen KM (February 2000). "Effects of jasplakinolide on the kinetics of actin polymerization. An explanation for certain in vivo observations". The Journal of Biological Chemistry. 275 (7): 5163–70. doi:10.1074/jbc.275.7.5163. PMID 10671562.
  12. ^ Vasquez RJ, Howell B, Yvon AM, Wadsworth P, Cassimeris L (June 1997). "Nanomolar concentrations of nocodazole alter microtubule dynamic instability in vivo and in vitro". Molecular Biology of the Cell. 8 (6): 973–85. doi:10.1091/mbc.8.6.973. PMC 305707. PMID 9201709.
  13. ^ Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT (May 1971). "Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia". Journal of the American Chemical Society. 93 (9): 2325–7. doi:10.1021/ja00738a045. PMID 5553076.
  14. ^ Buchwalow, Igor B.; Böcker, Werner (2010). Immunohistochemistry: Basics and Methods. Springer. pp. 92. ISBN 978-3-642-04608-7.
  15. ^ Bubb MR, Spector I, Bershadsky AD, Korn ED (February 1995). "Swinholide A is a microfilament disrupting marine toxin that stabilizes actin dimers and severs actin filaments". The Journal of Biological Chemistry. 270 (8): 3463–6. doi:10.1074/jbc.270.8.3463. PMID 7876075.
  16. ^ Heinz S, Freyberger A, Lawrenz B, Schladt L, Schmuck G, Ellinger-Ziegelbauer H (April 2017). "Mechanistic Investigations of the Mitochondrial Complex I Inhibitor Rotenone in the Context of Pharmacological and Safety Evaluation". Scientific Reports. 7: 45465. Bibcode:2017NatSR...745465H. doi:10.1038/srep45465. PMC 5379642. PMID 28374803.
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