Medical Pharmacology Chapter 33-34:  Anticancer Drugs

• Natural Products:  Vinca Alkaloids

  • Overview:

    • Microtubules represent an important element of the cellular cytoskeleton.⁹ 

      • The structures are made of cytoplasmic tubes and may exhibit significant length.

      • Each tube is formed from 13 longitudinally arranged protofilaments made up of two very similar proteins, α-tubulin and β-tubulin.

      • Initially tubulin dimers form the basis of subsequent assembly into protofilaments which associate to form parallel sheets and ultimately cylinders.

        • Assembly requires the presence of GTP.⁹

      •  Thus ssembly of tubulin molecules into microtubules first involve forming linear microtubule "protofilaments" which align around a central, hollow core.

        • The β-subunit of one dimer is situated in head to tail and contact with the α-subunit of the next.

          • Formation of Microtubule Structure⁸

            Attribution: adapted from Figure 11.1 of reference 8. Step  1: "Heterodimers of α-tubulin and  β-tubulin to form a short microtubule nucleus."8 Step 2: "nucleation is followed by elongation of the microtubular both ends to form a cylinder that is composed of tubulin heterodimers arranged head to tail in 13 protofilaments."8

          •  

            Microtubule Structure¹⁰

            Attribution:  Thomas Splettstoesser (www.scistyle.com) [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)], from Wikimedia Commons "Diagram showing a microtubule and the alpha/beta-tubulin heterodimer." 16 June 2015 https://commons.wikimedia.org/wiki/File:Microtubule_structure.png

         

        • Microtubule Function:

          • Tubulin polymerization is a requirement for proper microtubule assembly and support of mitotic spindle activity needed for cell replication.³   

            • As a result, microtubules are essential given their importance in ensuring proper mitotic spindle function in support of chromosomal separation or segregation as duplicate sets of chromosomes are provided to daughter cells during cellular division.⁸ 

              • In order for cells to pass appropriately through cell-cycle checkpoints, mitotic spindle integrity is necessary.

                • When chromosomal segregation errors are detected, checkpoint proteins are activated leading to apoptosis (programmed cell death).⁸ 

                  • During other cell-cycle "phases" such as interphase a principal role of microtubules is manifest in:

                    • Determining cell shape

                    • Providing scaffolding for both attachment and movement of cell organelles as well as

                    • Supporting secretory processes, neurotransmission as well as intracellular signaling.⁸

            • Antimicrotubule drugs such as the vinca alkaloids inhibit tubulin polymerization.

              • Within the cell cycle then, antimicrotubule agents target the M phase.

            • In addition to supporting cellular replication, microtubules are important in maintaining cellular shape and provide a basis for cell motility.

              • Furthermore, intracellular protein transport is often microtubule dependent.

              • Therefore inhibition of microtubule formation is detrimental to many essential cellular activities.³

      • Vinca Alkaloids:

        • Vinca alkaloids were identified as products extracted from the periwinkle plant (Catharanthus roseus).

          • Periwinkle: Catharanthus roseus flower

            Attribution: Photo: Joydeep / Wikimedia Commons "Catharanthus roseus flower" https://commons.wikimedia.org/wiki/File:Catharanthus_roseus24_08_2012_(1).JPG

             

        • Some extracts of this plant were associated with various medicinal applications including management of hemorrhage, toothache, and diabetes, in this latter case because of possible beneficial effects on chronic wound healing.

          • Anticancer properties were eventually noted associated with vinca alkaloids.

             

            • Vinca Alkaloid Structure Example:  Vincristine (Oncovin)

              Attribution:  Fvasconcellos [Public domain], via Wikimedia Commons Vinca Alkaloid Structure Example (Vincristine, Oncovin) https://commons.wikimedia.org/wiki/File:Vincristine.svg

          • Prominent anticancer drugs, naturally occurring, include:

            •  Vinca alkaloids

              • Vincristine (Oncovin,VCR)

              • Vinblastine (Velban,VBL).

            • Semisynthetic analogs or derivatives of these agents including:

              • Vinorelbine (Nevelbine, VRL)

                • Vinorelbine (Navelbine)¹¹

                  Attribution: Eori L Duchatellier C Ermina-Makapedua D Fabian J Eno S Vinorelbine https://www.youtube.com/watch?v=UuaiYuJ9pqY

              • Vinflunine (Javlor, bifluorinated agent, VFL) and

              • Vindesine (Eldisine, VDS).

        • Differences between Vinca Alkaloids:

          • Vinca alkaloids have similarities with other drugs that are also cell-cycle-specific blockers of mitosis.

            • These other agents include:

              • Colchicine

              • Podophyllotoxin

              • Taxanes, and

              • Epothilones.

        • As described earlier, vinca alkaloids bind to β-tubulin preventing a polymerizing interaction with α-tubulin, resutling in microtubule formation.

        • Vinca Alkaloid Structures:

          • Vincristine (Oncovin,VCR)

          •  

            Vinblastine (Velban,VBL)