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Relationship: 1833

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Binding of MSAs to microtubules leads to Disturbance in microtubule dynamic instability

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes. Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Microtubule interacting drugs lead to peripheral neuropathy adjacent Not Specified Not Specified Arthur Author (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

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Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

Evidence Collection Strategy

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Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

It is well known that the binding of taxol and MSAs like epothilones and discodermolide to microtubules stabilizes microtubules thereby promoting polymerization and concomitantly suppressing depolymerisation. Therefore, they directly disturb microtubule dynamic instability. [1-9]

It is assumed that the M-Loop, which is part of the taxane pocket, undergoes conformational changes and gets more structured as a short helix is formed upon MSA binding. This structuring promotes the assembly and stabilization of microtubules as it is needed for lateral tubulin interactions. [10, 11]

Mutations in the β-tubulin gene were identified in patients with taxol-resistant non-small-cell lung cancer. Patients with β-tubulin mutations did not respond to taxol-treatment, whereas patients without β-tubulin mutations had complete or partial responses and survived longer. β-tubulin mutations were therefore identified as predictor of taxol-response thereby confirming β-tubulin as the binding and interaction site of taxol. [12]

In two taxol-resistant ovarian cancer cell lines, two point mutations were identified in the β-tubulin gene. Taxol-driven polymerization was shown to be impaired in these cells. Taxol-resistant cells did not exhibit microtubule polymerization upon taxoll treatment whereas the parental cells show increasing tubulin-polymerization with increasing doses of taxol. [13]

In two epothilone-resistant ovarian carcinoma cell lines two point mutations were identified in the β-tubulin gene. Epothilone- as well as taxol-driven polymerization was shown to be impaired in these cells while parental cells exhibit dose-dependent increase in tubulin polymerization upon epothilone A- and taxol-treatment. [14]

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

The binding of MSAs to microtubules is extensively studies and well established. Its impact of this interaction on microtubule dynamic instability is addressed in numerous studies and the findings are largely consistent in the point of stabilization of microtubules accompanied by the disturbance of microtubule dynamic instability.

It has to be noted that microtubule destabilizing agents like the vinca alkaloids are known to bind to microtubules and disturb microtubule dynamic instability as well. However, vinca alkaloids differ in their mode of action as they bind to the end of microtubules and, in case of stoichiometric binding, promote depolymerization. [19]

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

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References

List of the literature that was cited for this KER description. More help

1. Schiff, P.B., J. Fant, and S.B. Horwitz, Promotion of microtubule assembly in vitro by taxol. Nature, 1979. 277(5698): p. 665-667.

2. Bollag, D.M., et al., Epothilones, a New Class of Microtubule-stabilizing Agents with a Taxol-like Mechanism of Action. Cancer Research, 1995. 55(11): p. 2325-2333.

3. Hung, D.T., J. Chen, and S.L. Schreiber, (+)-Discodermolide binds to microtubules in stoichiometric ratio to tubulin dimers, blocks taxol binding and results in mitotic arrest. Chemistry & Biology, 1996. 3(4): p. 287-293.

4. Kowalski, R.J., et al., The Microtubule-Stabilizing Agent Discodermolide Competitively Inhibits the Binding of Paclitaxel (Taxol) to Tubulin Polymers, Enhances Tubulin Nucleation Reactions More Potently than Paclitaxel, and Inhibits the Growth of Paclitaxel-Resistant Cells. Molecular Pharmacology, 1997. 52(4): p. 613-622.

5. ter Haar, E., et al., Discodermolide, A Cytotoxic Marine Agent That Stabilizes Microtubules More Potently Than Taxol. Biochemistry, 1996. 35(1): p. 243-250.

6. Derry, W.B., L. Wilson, and M.A. Jordan, Substoichiometric Binding of Taxol Suppresses Microtubule Dynamics. Biochemistry, 1995. 34(7): p. 2203-2211.

7. Dumontet, C. and M.A. Jordan, Microtubule-binding agents: a dynamic field of cancer therapeutics. Nature Reviews. Drug Discovery, 2010. 9(10): p. 790-803.

8. Jordan, M.A. and L. Wilson, Microtubules as a target for anticancer drugs. Nature Reviews Cancer, 2004. 4: p. 253.

9. Carozzi, V.A., A. Canta, and A. Chiorazzi, Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett, 2015. 596: p. 90-107.

10. Prota, A.E., et al., Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science, 2013. 339(6119): p. 587-590.

11. Snyder, J.P., et al., The binding conformation of Taxol in β-tubulin: A model based on electron crystallographic density. Proceedings of the National Academy of Sciences, 2001. 98(9): p. 5312-5316.

12. Monzó, M., et al., Paclitaxel Resistance in Non–Small-Cell Lung Cancer Associated With Beta-Tubulin Gene Mutations. Journal of Clinical Oncology, 1999. 17(6): p. 1786-1786.

13. Giannakakou, P., et al., Paclitaxel-resistant Human Ovarian Cancer Cells Have Mutant β-Tubulins That Exhibit Impaired Paclitaxel-driven Polymerization. Journal of Biological Chemistry, 1997. 272(27): p. 17118-17125.

14. Giannakakou, P., et al., A common pharmacophore for epothilone and taxanes: Molecular basis for drug resistance conferred by tubulin mutations in human cancer cells. Proceedings of the National Academy of Sciences, 2000. 97(6): p. 2904-2909.

15. Witte, H., D. Neukirchen, and F. Bradke, Microtubule stabilization specifies initial neuronal polarization. The Journal of Cell Biology, 2008. 180(3): p. 619-632.

16. Jordan, M.A., et al., Mechanism of mitotic block and inhibition of cell proliferation by taxol at low concentrations. Proceedings of the 

National Academy of Sciences of the United States of America, 1993. 90(20): p. 9552-9556.

17. Kowalski, R.J., P. Giannakakou, and E. Hamel, Activities of the Microtubule-stabilizing Agents Epothilones A and B with Purified Tubulin and in Cells Resistant to Paclitaxel (Taxol®). Journal of Biological Chemistry, 1997. 272(4): p. 2534-2541.

18. Risinger, A.L. and S.L. Mooberry, Cellular studies reveal mechanistic differences between taccalonolide A and paclitaxel. Cell Cycle, 2011. 10(13): p. 2162-2171.

19. Dumontet, C. and B.I. Sikic, Mechanisms of Action of and Resistance to Antitubulin Agents: Microtubule Dynamics, Drug Transport, and Cell Death. Journal of Clinical Oncology, 1999. 17(3): p. 1061-1061.