A spindle poison, also known as a spindle toxin, is a poison that disrupts cell division by affecting the protein threads that connect the centromere regions of , known as spindles. Spindle poisons effectively cease the production of new cells by interrupting the mitosis phase of cell division at the spindle assembly checkpoint (SAC). However, as numerous and varied as they are, spindle poisons are not yet 100% effective at ending the formation of tumors (neoplasms).[Wood KW, Cornwell WD, Jackson JR. (2001) Past and future of the mitotic spindle as an oncology target. Current Opinion in Pharmacology. 1:370–377. PubMed] Although not 100% effective, substantive therapeutic efficacy has been found in these types of chemotherapeutic treatments. The mitotic spindle is composed of microtubules (polymerized tubulin) that aid, along with regulatory proteins, each other in the activity of appropriately segregating replicated chromosomes. Certain compounds affecting the mitotic spindle have proven highly effective against solid tumors and hematological malignancies.
Two specific families of antimitotic agents — vinca alkaloids and taxanes — interrupt the cell’s division by the agitation of microtubule dynamics. The vinca alkaloids work by causing the inhibition of the polymerization of tubulin into microtubules, resulting in the G2/M arrest within the cell cycle and eventually cell death. In contrast, the taxanes arrest the mitotic cell cycle by stabilizing microtubules against depolymerization. Even though numerous other spindle proteins exist that could be the target of novel chemotherapeutics, tubulin-binding agents are the only types in clinical use. Agents that affect the motor protein kinesin are beginning to enter clinical trials.[Noelle S. Williams, Anthony W. G. Burgett, Ashley S. Atkins, Xiaodong Wang, Patrick G. Harran, and Steven L. McKnight. Proceedings of the National Academy of Sciences – U.S.A. 2007 February 13; 104(7): 2074–2079.] Another type, paclitaxel, acts by attaching to tubulin within existing microtubules. Next, it stabilizes the polymer.
Spindle assembly checkpoint (SAC)
Normally, cells duplicate their genetic material and then produce two equal daughter cells. Tampering with this tightly monitored distribution system can result in the production of irregular
chromosome content, within each cell, commonly referred to as
aneuploidy. Cells have developed various checkpoints to carry out
mitosis with great accuracy. Early research concluded that spindle poisons, inserted to cells, caused a considerable reduction in the number of cells that exited
mitosis, while the number of cells that entered
mitosis dramatically increased. The SAC was found to be the key signaling pathway to the mitotic arrest. The precise division of
chromosomes is the primary responsibility of SAC. Its origin stems from
kinetochores, proteins that aid in joining
DNA and
microtubules on the
chromatids. Only one unattached
kinetochore is required to fuel a response that ultimately blocks cell cycle progression. The end result is each
chromosome is attached to the spindle in the initial stage of
anaphase.
Mitosis
During normal
mitosis, the SAC is active for a short duration of minutes. During this period, spindle microtubules attach to
chromosomes and rectify any improper attachments. High
cyclin B levels are also maintained through inhibition of an E3
ubiquitin ligase that normally seeks out
cyclin B for degradation. This particular
ligase is referred to as (APC/C) anaphase promoting complex or
cyclosome. When the APC/C is inhibited, cyclin B levels are kept high by the SAC and it ultimately protects cyclin-dependent kinase (CDK1).
Mitosis is prompted by the activation of (CDK1) by cyclin B. After confirmation of proper attachment of all chromosomes, the SAC is turned off and degradation of cyclin B occurs by way of the (APC/C). Spindle poisons, in contrast, inhibit
kinetochores during
mitosis and prevent them from forming proper attachments to spindle microtubules. Permanent activation of the SAC ensues along with a mitotic arrest that lasts several hours. These cells will either exit
mitosis by a different pathway not normal to
mitosis or they will
apoptose.
[Matson, Daniel R. and Stukenberg, P. Todd (2011). Spindle Poisons and Cell Fate: A Tale of Two Pathways. Molecular Inventions April 2011, 11(2): 141-50.]
Examples
Some spindle poisons:
See also
