PerspectivesAre you interested in submitting a Perspective Article? Be sure to read The Science Advisory Board's Editorial Guides for Perspective Articles. Click here. Microtubule-targeted drugs for cancer chemotherapy by Manu Lopus, Research Scholar Powai, Mumbai, India  Faithful segregation of chromosomes during cell division ensures continuity of life. The cell cycle that regulates the segregation of chromosomes into daughter cells is under stringent checkpoint-mediated control. Deregulation of the cell cycle is central to hyperproliferative disorders (1) Microtubules are dynamic, hollow, cylindrical, cytoskeletal polymers whose structural, mechanical, and polymerization properties are vital for cell division, maintenance of cell structure, and intracellular transport in eukaryotes (1-3). Microtubules are formed from alpha-beta tubulin protein heterodimers. As key regulators of cell division, microtubules form effective targets for a number of anti-cancer drugs (4 & 5). By interfering with the polymerization-depolymerization properties of microtubules, these drugs prevent cell cycle progression and induce the cells to undergo programmed cell death (6 & 7). Numerous tubulin ligands with anti-mitotic properties and anti-cancer potential have been discovered in recent years. Several of these drugs have played seminal roles in experiments probing the basic mechanism of mitosis. Though chemically diverse, all of these compounds, are characterized by their ability to perturb the mitotic spindle and thereby inhibit cell division at the metaphase/anaphase transition. With the advent of instruments like Differential Interphase Contrast microscopes (DIC), it has been observed that there are a number of drugs that inhibit cell proliferation by interfering with the dynamic instability and treadmilling properties of microtubules, rather than directly inhibiting or stabilizing microtubules. Drugs like paclitaxel (Taxol) inhibit cancer cell proliferation by stabilizing the microtubules (7). On the other hand, vinblastine and their analogs inhibit cell proliferation by depolymerizing the microtubules (7). Most of the drugs that target microtubules, including nocodazole, vinblastine, noscapine analogs, benomyl and griseofulvin, inhibit cell cycle progression at mitosis [8-12] and induce them to undergo programmed cell death. However, compounds like sanguinarine, halogenated derivatives of acetamido benzoyl ethyl ester, etc. were found to depolymerize cellular microtubules and to arrest cells at the G1/S transition and kill them through apoptosis (13 & 14). Interestingly, many of these anti-microtubule drugs are found to be less toxic toward normal cells, signifying their potential utility in clinical settings (9). In fact, a number of microtubule drugs (like Taxol and vinblastine analogs) are in clinical use. The success of microtubule-targeted drugs in cancer chemotherapy largely depends on their preferential targeting of cancer cells and tolerable side effects on patients. Differential dynamic behavior and isotype composition in microtubules in cancer cells make them selective targets for microtubule-targeting anti-cancer agents (6). References: 1. Lodish H, Berk A, Zipursky SL, Matsudaira P, Baltimore D & Darnell J (2000) Molecular Cell Biology, 4th edn. W.H. Freeman and company, New York. 2. McIntosh JR, Grishchuk, E & West RR (2002) Chromosome-microtubule interactions during mitosis. Annu Rev Cell Dev Biol 18, 193-219. 3. Gunderson GG & Cook TA (1999) Microtubules and signal transduction. Curr Opin Cell Biol 11, 81-94. 4. Wilson L, Panda D, & Jordan MA (1999) Modulation of microtubule. dynamics by drugs: A paradigm for the actions of cellular regulators. Cell Struct Funct 24, 329-335. 5. Downing KH (2000) Structural basis for the interaction of tubulin with proteins and drugs that affects microtubule dynamics. Ann Rev Cell Dev Biol 16, 89-111. 6. Jordan MA (2002) Mechanism of action of antitumor drugs that interacts with microtubules and tubulin. Curr Med Chem Anti-Can Agents 2,1-17. 7. Jordan MA & Wilson L (2004) Microtubules as a target for anticancer drugs. Nat Rev Cancer 4, 253-265. Hamel E (1996) Antimitotic natural products and their interactions with tubulin. Med Res Rev 16, 207-231. 8. Panda D, Jordan MA, Chu KC & Wilson L (1996) Differential effects of vinblastine on polymerization and dynamics at opposite microtubule ends. J Biol Chem 271, 29807-29812. 9. Aneja, R, Lopus M, Zhou J, Vangapandu SN, Ghaleb A, Yao J, Nettles JH, Zhou B, Gupta M, Panda D, Chandra R and Joshi, HC (2006) Rational design of a microtubule targeting anti-breast cancer drug, EM015. Cancer Research 66, 3782-3791. 10. Gupta K, Bishop J, Peck A, Brown J, Wilson L& Panda D (2004 Jordan MA, Thrower D & Wilson L (1991) Mechanism of inhibition of cell proliferation by Vinca alkaloids. Cancer Res 51, 2212-2222. 11. Gupta K, Bishop J, Peck A, Brown J, Wilson L & Panda D (2004) Antimitotic antifungal compound benomyl inhibits brain microtubule polymerization and dynamics and cancer cell proliferation at mitosis, by binding to a novel site in tubulin. Biochemistry 43, 6645-6655. 12. Panda D, Rathinasamy K, Santra MK & Wilson L (2005) Kinetic suppression of Microtubule dynamic instability by griseofulvin: Implications for its possible use in the treatment of cancer. Proc Natl Acad Sci USA 102, 9878-9883. 13. Lopus M and Panda D (2006) The benzophenanthridine alkaloid sanguinarine perturbs microtubule assembly dynamics through tubulin binding: a possible mechanism for its antiproliferative activity. FEBS Journal (in press) 14. Davis A, Jiang JD, Middleton KM, Wang Y, Weisz I, Ling YH & Bekesi JG (1999) Novel suicide ligands of tubulin arrest cancer cells in S-phase. Neoplasia 1, 498_507. ### << Previous Next >> [ View All Perspectives ] |
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