Development
of Resistance to Vinca Alkaloids
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Vinca alkaloids,
such as vinblastine and vincristine, are important
chemotherapeutic agents derived from the Madagascar
periwinkle plant (Catharanthus
roseus).
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They exert
their cytotoxic effects primarily by interfering
with microtubule dynamics, binding to tubulin dimers
and inhibiting their polymerization, which
ultimately leads to cell cycle arrest at metaphase
and apoptosis [1].
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Despite their
efficacy, the development of drug resistance is a
major obstacle limiting their clinical utility.
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Resistance
to vinca alkaloids can arise through several complex
mechanisms, often involving multiple pathways
simultaneously.
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Key Mechanisms of Resistance:
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Increased Drug Efflux:
This is one of the most well-characterized
mechanisms of resistance to vinca alkaloids and many
other chemotherapy drugs.
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Alterations in Tubulin:
Since tubulin is the direct target of vinca
alkaloids, changes in tubulin structure or
expression can confer resistance.
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Tubulin Mutations:
Mutations in the genes encoding β-tubulin (TUBB)
can alter the drug-binding site, reducing the
affinity of vinca alkaloids for tubulin [5].
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Changes in Tubulin Isotype Expression:
Mammalian cells express multiple isotypes of α-
and β-tubulin.
-
Alterations in the relative expression
levels of these isotypes, particularly an
increase in class III β-tubulin (βIII-tubulin
or TUBB3), have been strongly associated
with resistance to vinca alkaloids and other
microtubule-targeting drugs [6, 7].
-
β III-tubulin
containing microtubules appear to be less
sensitive to depolymerization by these
agents and may possess different dynamic
properties [7].
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Altered Microtubule Dynamics:
Even without direct mutations or isotype shifts,
cancer cells can develop resistance by altering
the overall regulation of microtubule dynamics,
making them less dependent on the specific
processes inhibited by vinca alkaloids [1].
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Defects in Apoptotic Pathways:
Vinca alkaloids ultimately trigger cell death
through apoptosis.
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Understanding these resistance mechanisms
is crucial for developing strategies to overcome or
circumvent resistance, such as using P-gp inhibitors
(though clinical success has been limited), developing
drugs that are poor substrates for efflux pumps,
targeting specific tubulin isotypes, or combining vinca
alkaloids with agents that modulate apoptotic pathways.
References
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1.
Jordan, M. A., & Wilson, L. (2004).
Microtubules as a target for anticancer drugs.
Nature
Reviews Cancer,
4(4),
253–265.
https://doi.org/10.1038/nrc1317
-
2. Gottesman, M.
M., Fojo, T., & Bates, S. E. (2002). Multidrug
resistance in cancer: role of ATP–binding cassette
transporters.
Nature Reviews Cancer,
2(1),
48–58.
https://doi.org/10.1038/nrc7
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3.
Ambudkar, S. V., Kimchi-Sarfaty, C.,
Sauna, Z. E., & Gottesman, M. M. (2003). P-glycoprotein:
from genomics to mechanism.
Oncogene,
22(47),
7468–7485.
https://doi.org/10.1038/sj.onc.1206948
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4. Cole, S. P.,
Bhardwaj, G., Gerlach, J. H., Mackie, J. E., Grant, C.
E., Almquist, K. C., ... & Deeley, R. G. (1992).
Overexpression of a transporter gene in a multidrug-resistant
human lung cancer cell line.
Science,
258(5088),
1650–1654.
https://doi.org/10.1126/science.1360704
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5.
Kavallaris, M. (2010). Microtubules and resistance to
tubulin-binding agents.
Nature Reviews Cancer,
10(3),
194–204.
https://doi.org/10.1038/nrc2803
-
6. Giannakakou,
P., Sackett, D. L., Kang, Y. K., Zhan, Z., Buters, J.
T., Fojo, T., & Poruchynsky, M. S. (1997). 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,
94(17),
9116-9121.
https://pubmed.ncbi.nlm.nih.gov/10688884/(Note:
While focusing on epothilones/taxanes, it discusses
tubulin mutations conferring broad resistance).
-
7. Ferlini, C.,
Raspaglio, G., Mozzetti, S., Cicchillitti, L.,
Filippetti, F., Fattorusso, C., ... & Scambia, G.
(2005). The seco-taxane IDN5390 is able to overcome
P-glycoprotein-mediated multidrug resistance and targets
class III β-tubulin.
Cancer Research,
65(6),
2397-2405.
https://pubmed.ncbi.nlm.nih.gov/15781655/ (Note:
Discusses βIII-tubulin's role in resistance).
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8. Fulda, S.
(2010). Tumor resistance to apoptosis.
International
Journal of Cancer,
127(7),
1509-1514.
https://pubmed.ncbi.nlm.nih.gov/19003982/ (Note:
General review on apoptosis resistance in cancer).
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