Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Vinca Alkaloids

  • Overview Continued:

    • Semisynthetic Vinca Alkaloid Analogues and Derivatives:

      • Vinorelbine (Nevelbine, VRL)

      •  

        Vinflunine (Javlor, bifluorinated agent)

         

      • Vindesine (Eldisine, VDS)

       

      • Resistance that develops to the antineoplastic actions of vinca alkaloid drugs:¹

       

      • Resistance to Antineoplastic Activity of Vinca Alkaloids such as Vinblastine, Vincristine etc.

        (Google Gemini AI Assisted, April 30, 2025)

        Development of Resistance to Vinca Alkaloids Vinca alkaloids, such as vinblastine and vincristine, are important chemotherapeutic agents derived from the Madagascar periwinkle plant (Catharanthus roseus). 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]. Despite their efficacy, the development of drug resistance is a major obstacle limiting their clinical utility. Resistance to vinca alkaloids can arise through several complex mechanisms, often involving multiple pathways simultaneously. Key Mechanisms of Resistance: Increased Drug Efflux: This is one of the most well-characterized mechanisms of resistance to vinca alkaloids and many other chemotherapy drugs. Resistance involves the overexpression of ATP-binding cassette (ABC) transporters, particularly P-glycoprotein (P-gp), which is encoded by the MDR1 (ABCB1) gene [2]. P-gp functions as an energy-dependent efflux pump, actively transporting vinca alkaloids and other structurally diverse hydrophobic compounds out of the cancer cell, thereby reducing intracellular drug accumulation and preventing the drug from reaching its target concentration [2, 3]. Other ABC transporters, like the Multidrug Resistance-associated Protein 1 (MRP1, encoded by ABCC1), can also contribute to vinca alkaloid efflux, although P-gp is often considered the primary player [4]. Alterations in Tubulin: Since tubulin is the direct target of vinca alkaloids, changes in tubulin structure or expression can confer resistance. 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]. Specific mutations have been identified in resistant cell lines and clinical samples that decrease the effectiveness of microtubule-targeting agents [5, 6]. 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]. 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]. This effect can involve changes in the expression or activity of microtubule-associated proteins (MAPs) that regulate microtubule stability and function. Defects in Apoptotic Pathways: Vinca alkaloids ultimately trigger cell death through apoptosis. Resistance can arise if cancer cells acquire defects in the apoptotic signaling pathways downstream of microtubule disruption [8]. These can involve mutations in key apoptotic regulators like p53 or alterations in the balance of pro-apoptotic (e.g., Bax) and anti-apoptotic (e.g., Bcl-2) proteins, allowing cells to survive despite drug-induced damage [8]. 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 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 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 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 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). 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).

      • As will be noted in subsequent sections, the various vinca alkaloids exhibit differences in clinical effectiveness and characteristics.¹ 

        • However, these agents exhibit cross-resistance.¹ 

          • Should resistance develop against the antineoplastic activity of one agent, such resistance is likely to apply to other vinca alkaloids as well.⁹ 

          • Antitumor effects of the vinca alkaloids are mediated by a multidrug-resistant system, Pgp, which is also known as the "multidrug-resistant protein 1" or MDR1.⁹ 

            • This system is further described as the "ATP-binding cassette sub-family B member 1.

              • PgP pumps foreign substances out of cells utilizing an ATP -dependent efflux pump.

                • Pgp is described as a 170 kDa transmembrane glycoprotein.

                • Pgp is found in cell types found in liver, kidney, colon, jejunum and pancreas as well as in brain capillary endothelial cells.⁹

                  • Mouse P-glycoprotein structure¹⁰  

                    Attribution:  Boghog2 [Public domain], from Wikimedia Commons Mouse P-glycoprotein structure as described by PDB coordinates. https://commons.wikimedia.org/wiki/File:MDR3_3g5u.png

              • Abnormalities in chromosomal structure suggestive of gene amplification with associated elevated Pgp levels have been described in cells resistant to the action of vinca alkaloids in cell culture systems.¹

                • Resistance may also occur to the antineoplastic activity of vinca alkaloids due to β-tubulin mutations or in differential β-tubulin isoform expression which prevents effective binding of inhibitors to target sites.¹