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Mechanism of action of antimitotic drugs: A new hypothesis based on the role of cellular calcium

Gupta, R.S., Dudani, A.K.·1989·Medical Hypotheses
DOI 10.1016/0306-9877(89)90154-0
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Abstract

The antimitotic drugs such as colchicine, podophyllotoxin, etc. are currently believed to exert their cytotoxic and antimitotic effects due to binding of the drug-tubulin complex to the growing ends of microtubules (MTs), leading to an "end-capping or poisoning" effect. However, to account for a number of apparently puzzling observations regarding antimitotic drugs (which cannot be readily explained by the current model) and the mitotic process, a new hypothesis regarding the mechanism of action of antimitotic drugs is proposed. The key observations in this context are as follows: (i) The antimitotic drugs bind specifically to free tubulin. (ii) Cell growth by these drugs is specifically blocked in metaphase, and interphase microtubules do not seem to play any role in the drugs' cytotoxic or antimitotic effects. (iii) Tubulin is specifically associated with a number of membranous organelles (viz. mitochondria, plasma membranes, endoplasmic reticulum) which are responsible for intracellular Ca+2 homeostasis. (iv) Fluorescent derivatives of antimitotic drugs also bind to the above membranous organelles and not to MTs. (v) Ca+2 plays a central role in the control of MT assembly/disassembly in vivo and a Ca+2 pulse is necessary for the metaphase to anaphase transition. (vi) Cellular mutants which exhibit specific resistance to various antimitotic drugs are altered in either tubulin(s) or mitochondrial matrix proteins. To account for these observations, it is suggested that free t…

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Research works printed but not linked: 87

  1. Mareel, 1984, Effect of microtubule inhibitors on invasion and on related activities of tumor cells, Int. Rev. Cytol, 90, 125, 10.1016/S0074-7696(08)61489-8 · DOI
  2. Manfredi, 1984, Taxol: An antimitotic agent with a new mechanism of action, Pharmac. Ther., 25, 83, 10.1016/0163-7258(84)90025-1 · DOI
  3. Kirschner, 1978, Microtubule assembly and nucleation, Int. Rev. Cytol., 1, 54
  4. Soifer, 1986, Dynamic aspects of microtubule biology, Ann. N.Y. Acad Sci., 466, 1, 10.1111/j.1749-6632.1986.tb38378.x · DOI
  5. Brinkley, 1985, Microtubule organizing centers, Ann. Rev. Cell Biol., 1, 145, 10.1146/annurev.cb.01.110185.001045 · DOI
  6. Timasheff, 1980, In vitro assembly of cytoplasmic microtubules, Ann. Rev. Biochem., 49, 565, 10.1146/annurev.bi.49.070180.003025 · DOI
  7. Wiche, 1985, High molecular weight microtubule associated proteins (MAPS): A ubiquitous family of cytoskeletal connecting links, TIBS, 10, 67
  8. Borisy, 1967, The mechanism of action of colchicine. Binding of colchicine 3H to cellular protein, J. Cell Biol., 34, 525, 10.1083/jcb.34.2.525 · DOI
  9. Cortese, 1977, Podophyllotoxin as a probe for the colchicine binding site of tubulin, J. Biol. Chem., 254, 1134, 10.1016/S0021-9258(17)40631-4 · DOI
  10. Margolis, 1978, Opposite end assembly and disassembly of microtubules at steady state in vitro, Cell, 13, 1, 10.1016/0092-8674(78)90132-0 · DOI
  11. Margolis, 1981, Microtubule treadmillspossible molecular machinery, Nature, 293, 705, 10.1038/293705a0 · DOI
  12. Caplow, 1982, Incorporation of radioactive tubulin into microtubules at steady state: Experimental and theoretical analysis of the effect of podophyllotoxin, J. Biol. Chem., 256, 5608, 10.1016/S0021-9258(19)69247-1 · DOI
  13. Manso-Martinez, 1982, Podophyllotoxin poisoning of microtubules at steady state. Effect of substoichiometric and superstoichiometric concentrations of drug, Mol. Cell Biochem., 45, 3, 10.1007/BF01283158 · DOI
  14. Bergen, 1983, Tubulin colchicine complex inhibits microtubule elongation at both plus and minus ends, J. Biol. Chem., 258, 4190, 10.1016/S0021-9258(18)32604-8 · DOI
  15. Luduena, 1986, Interaction of vinblastine and maytansine with tubulin, Ann. N.Y. Acad. Sci., 466, 718, 10.1111/j.1749-6632.1986.tb38454.x · DOI
  16. Salmon, 1984, Rapid rate of tubulin dissociation from microtubules in the mitotic spindle in vivo-measured by blocking polymerization with colchicine, J. Cell Biol., 99, 1066, 10.1083/jcb.99.3.1066 · DOI
  17. Hays, 1982, The action of colchicine on microtubules on isolated mitotic spindles, J. Cell Biol., 95, 306a
  18. Mitchison, 1984, Dynamic instability of microtubule growth, Nature, 312, 237, 10.1038/312237a0 · DOI · Paper page
  19. Gupta, 1981, Resistance to the microtubule inhibitor podophyllotoxin: Selection and partial characterization of mutants in CHO cells, Som. Cell Genet., 7, 59, 10.1007/BF01544748 · DOI
  20. Gupta, 1982, Podophyllotoxin resistant mutants of Chinese hamster ovary cells: Alteration in a microtubule associated protein, J. Biol. Chem., 257, 1071, 10.1016/S0021-9258(19)68309-2 · DOI
  21. Gupta, 1983, Podophyllotoxin resistant mutants of Chinese hamster ovary cells: Cross resistance studies with various microtubule inhibitors and podophyllotoxin analogs, Cancer Res., 43, 505
  22. Bech-Hansen, 1976, Pleiotropic phenotype of colchicine-resistant CHO cells: Crossresistance and collateral sensitivity, J. Cell. Physiol., 88, 23, 10.1002/jcp.1040880104 · DOI
  23. Beck, 1983, Vinca alkaloid-resistant phenotype in cultured human leukemic Lymphoblasts, Cancer Treat. Rep., 67, 875
  24. Biedler, 1983, Drug resistance in Chinese hamster lung and mouse tumor cells, Cancer Treat. Rep., 67, 859
  25. Gupta, 1985, Cross-resistance of vinblastine and taxolresistant mutants of Chinese hamster ovary cells to other anticancer drugs, Cancer Treat. Rep., 69, 515
  26. Gupta, 1984, Mutants of Chinese hamster ovary cells affected in two different microtubule-associated proteins: Genetic and biochemical studies, J. Biol. Chem., 259, 1882, 10.1016/S0021-9258(17)43490-9 · DOI
  27. Gupta, 1985, Genetic and biochemical studies with mutants of mammalian cells affected in microtubule-related proteins other than tubulin: Mitochondrial localization of a microtubule-related protein, Can. J. Biochem. Cell Biol., 63, 489, 10.1139/o85-068 · DOI
  28. Gupta, 1987, Mitochondrial binding of a protein affected in a mutant resistant to the microtubule inhibitor podophyllotoxin, Eur. J. Cell Biol.
  29. Gupta, 1986, Mitochondrial localization of a microtubule related protein, Ann. N.Y. Acad. Sci., 466, 854, 10.1111/j.1749-6632.1986.tb38471.x · DOI
  30. Gupta, 1988, Mitochondrial matrix localization of the protein altered in mutants resistant to the microtubule inhibitor podophyllotoxin, Eur. J. Cell. Biol.
  31. Gupta, 1986, Cross resistance of nocodazole-resistant mutants of CHO cells towards other microtubule inhibitors: Similar mode of action benzimidazole carbamate derivatives and NSC 181928 and TN16, Mol. Pharmacol., 30, 142
  32. Cabral, 1980, CHO mutants resistant to colchicine, colcemid or griseofulvin have an altered β-tubulin, Cell, 20, 29, 10.1016/0092-8674(80)90231-7 · DOI
  33. Schibler, 1985, Maytansine resistant mutants of CHO cells with an alteration in α-tubulin, Can. J. Biochem. Cell Biol., 63, 503, 10.1139/o85-069 · DOI
  34. Schibler, 1986, Taxol-dependent mutants of Chinese hamster ovary cells with alterations in α-and β-tubulins, J. Cell Biol., 102, 1522, 10.1083/jcb.102.4.1522 · DOI
  35. Ratan, 1986, Calcium and the regulation of mitotic events, TIBS, 11, 456
  36. Weisenberg, 1972, Microtubule formation in vitro in solutions containing low calcium concentrations, Science, 177, 1104, 10.1126/science.177.4054.1104 · DOI
  37. Kiehart, 1981, Studies on the in vivo sensitivity of spindle microtubules to calcium ions and evidence for a vesicular calcium sequestering system, J. Cell Biol., 88, 604, 10.1083/jcb.88.3.604 · DOI
  38. Keith, 1983, Microinjection of Ca++ calmodulin causes a localized depolymerization of microtubules, J. Cell Biol., 97, 1918, 10.1083/jcb.97.6.1918 · DOI
  39. Izant, 1983, The role of calcium ions during mitosis. Calcium participates in the anaphase trigger, Chromosoma (Berlin), 88, 1, 10.1007/BF00329497 · DOI
  40. Kakiuchi, 1981, Ca2+ and calmodulin-dependent flip-flop mechanism in microtubule assembly-disassembly, FEBS Letts., 132, 141, 10.1016/0014-5793(81)80448-6 · DOI
  41. Lee, 1984, Calmodulin binds to both microtubule-associated protein 2 and T proteins, J. Biol. Chem., 259, 1226, 10.1016/S0021-9258(17)43592-7 · DOI
  42. Yamamoto, 1985, Ca2+, calmodulin-dependent regulation of microtubule formation via phosphorylation of microtubule-associated protein 2, T factor, and tubulin, and comparison with the cAMP-dependent phosphorylation, J. Neurochem., 44, 759, 10.1111/j.1471-4159.1985.tb12880.x · DOI
  43. Harris, 1975, The role of membranes in the organization of the mitotic apparatus, Exp. Cell Res., 94, 409, 10.1016/0014-4827(75)90507-8 · DOI
  44. Helper, 1984, Membranes in the mitotic apparatus: Their structure and function, Int. Rev. Cytol., 90, 169, 10.1016/S0074-7696(08)61490-4 · DOI
  45. Silver, 1980, Isolation of mitotic apparatus containing vesicles with calcium-sequestering activity, Cell, 19, 505, 10.1016/0092-8674(80)90525-5 · DOI
  46. Helper, 1985, Calcium restriction prolongs metaphase in dividing Tradescantia stamen hair cells, J. Cell Biol., 100, 1363, 10.1083/jcb.100.5.1363 · DOI
  47. Wolniak, 1983, Ionic changes in the mitotic apparatus at the metaphase/anaphase transition, J. Cell Biol., 96, 598, 10.1083/jcb.96.3.598 · DOI
  48. Keith, 1985, Local cytoplasmic calcium gradients in living mitotic cells, Nature, 316, 848, 10.1038/316848a0 · DOI
  49. Poenie, 1986, Calcium rises abruptly and briefly throughout the cell at the onset of anaphase, Science, 233, 886, 10.1126/science.3755550 · DOI
  50. Schrek, 1976, Inhibition by ionophore A23187 of the cytoxicity of vincristine, colchicine and x-rays to leukemic lymphocytes, Oncology, 33, 132, 10.1159/000225126 · DOI
  51. Conter, 1983, Impairment by ruthenium red of anticancer drug cytotoxicity in CCRF-CEM cells, Biochem. Pharmacol., 32, 723, 10.1016/0006-2952(83)90502-6 · DOI
  52. Nicholls, 1982, Mitochondrial calcium transport, Biochim. Biophys. Acta., 683, 57, 10.1016/0304-4173(82)90013-1 · DOI
  53. Irvine, 1986, Calcium transients: Mobilization of intracellular Ca++, Brit. Med. Bull., 42, 369, 10.1093/oxfordjournals.bmb.a072154 · DOI
  54. Carafoli, 1986, Membrane transport in the cellular homeostasis of calcium, J. Cardiovasc. Pharmacol., 8, 53, 10.1097/00005344-198600088-00002 · DOI
  55. Nicholls, 1986, Intracellular calcium homeostasis, Brit. Med. Bull., 42, 353, 10.1093/oxfordjournals.bmb.a072152 · DOI
  56. Denton, 1980, Role of calcium ions in the regulation of intramitochondrial metabolism. Effects of Na+, Mg2+ and ruthenium red on the Ca2+ stimulated oxiglutarate and pyruvate dehydrogenease activity in intact rat heart mitochondria, Biochem. J., 190, 107, 10.1042/bj1900107 · DOI
  57. McCormack, 1986, Ca2+ as a second messenger within mitochondria, TIBS, 11, 258
  58. Pratt, 1984, ATPases in mitotic spindles, Int. Rev. Cytol., 87, 83, 10.1016/S0074-7696(08)62440-7 · DOI
  59. Cande, 1982, Nucleotide requirements for anaphase chromosome movements in permeabilized mitotic cells — anaphase B but not anaphase A requires ATP, Cell, 28, 15, 10.1016/0092-8674(82)90370-1 · DOI
  60. Helper, 1985, Metabolic inhibitors block anaphase A in vivo, J. Cell Biol., 102, 1995
  61. Brinkley, 1974, Rotenone inhibition of spindle microtubule assembly in mammalian cells, Exp. Cell Res., 85, 41, 10.1016/0014-4827(74)90210-9 · DOI
  62. Maro, 1982, In vivo and in vitro effects of the mitochondrial uncoupler FCCP on microtubules, EMBO Journal, 11, 1347, 10.1002/j.1460-2075.1982.tb01321.x · DOI
  63. Pickett-Heaps, 1982, Studies on kinetochore function in mitosis II. The effects of metabolic inhibitors on mitosis and cytoskeleton in the diatom Hantzschia amohioxys, Eur. J. Cell Biol., 28, 83
  64. Bhattacharya, 1975, Membrane-bound tubulin in brain and thyroid tissue, J. Biol. Chem., 249, 7639, 10.1016/S0021-9258(19)40863-6 · DOI
  65. Zenner, 1976, Microtubular proteins in pigeon erythrocyte membranes, Eur. J. Biochem., 71, 177, 10.1111/j.1432-1033.1976.tb11104.x · DOI
  66. Soifer, 1980, Association of newly synthesized tubulin with brain microsomal membranes, J. Neurochem., 35, 1128, 10.1111/j.1471-4159.1980.tb07868.x · DOI
  67. Bernier-Valentin, 1982, Interaction of tubulin with rat liver mitochondria, J. Biol. Chem., 257, 7092, 10.1016/S0021-9258(18)34541-1 · DOI
  68. Rubin, 1982, Tubulin as a major cell surface protein in human lumphoid cells of leukemic origin, Cancer Res., 42, 1384
  69. Bernier-Valentin, 1983, Evidence for tubulin binding sites on cellular membranes-plasma membranes, mitochondria membranes and secretory granule membranes, J. Cell Biol., 97, 209, 10.1083/jcb.97.1.209 · DOI
  70. Wiedenmann, 1983, Tubulin is a major protein constituent of bovine brain coated vesicles, Biochem. Biophys. Res. Commun., 115, 303, 10.1016/0006-291X(83)91004-5 · DOI
  71. Pfeffer, 1983, Identification of 3 coated vesicle components and alpha-tubulin and beta-tubulin-linked to a phosphorylated 50,000 dalton polypeptide, J. Cell Biol., 97, 40, 10.1083/jcb.97.1.40 · DOI
  72. Hargeaves, 1985, Localization and characterization of tubulin-like proteins associated with brain mitochondria: The presence of a membrane-specific isoform, J. Neurochem., 45, 490, 10.1111/j.1471-4159.1985.tb04015.x · DOI
  73. Moll, 1982, Fluorescent deacetylcolchicine. New aspects of its activity and localization in PtK-1 cells, Exp. Cell Res., 141, 211, 10.1016/0014-4827(82)90083-0 · DOI
  74. Clark, 1978, Fluorescein colchicine, Synthesis, purification and biological activity, J. Cell Biol., 76, 619, 10.1083/jcb.76.3.619 · DOI
  75. Denton, 1986, The calcium sensitive dehydrogenases of vertebrate mitochondria, Cell Calcium, 7, 377, 10.1016/0143-4160(86)90040-0 · DOI
  76. Kennedy, 1979, Inhibitors of microtubule assembly enhance beta-adrenergic and prostaglandin El-stimulated cAMP accumulation in S49 lymphoma cells, Mol. Pharmacol., 16, 215
  77. Rachamilewitz, 1980, Effect of colchicine on jejunal adenylate cyclase activity, PGE2 and cAMP contents, Eur. J. Pharmacol., 67, 235, 10.1016/0014-2999(80)90503-8 · DOI
  78. Berridge, 1984, Inositol triphosphate and diacylglycerol as second messengers, Biochem. J., 220, 345, 10.1042/bj2200345 · DOI
  79. Berridge, 1985, The molecular basis of communication within the cell, Scient. Amer., 253, 142, 10.1038/scientificamerican1085-142 · DOI
  80. Carafoli, 1985, The Calcium Signal, Scient. Amer., 253, 70, 10.1038/scientificamerican1185-70 · DOI
  81. Murray, 1951, Specific inhibition by meso-inositol of the colchicine effect on rat fibroblasts, Exp. Cell Res., 11, 165, 10.1016/0014-4827(51)90082-1 · DOI
  82. Lymberopoulos, 1980, Inhibition by myoinositol of the antimitotic effect of colchicine on rat fibroblasts and rat intestinal mucosa, Exp. Cell Res., 129, 409, 10.1016/0014-4827(80)90509-1 · DOI
  83. Schellenberg, 1980, Effects of colchicine, vinblastine, griseofulvin and deuterium oxide upon phospholipid metabolism in concanavallin A-stimulated lymphocytes, Biochim. Biophys. Acta., 619, 522, 10.1016/0005-2760(80)90104-6 · DOI
  84. Cherremont-Comhaire, 1953, Action du lithium sur la croissance et la mitose dans les cultures de fibroblastes et myoblastes, Arch. Biol., 64, 295
  85. Forer, 1987, The role of the phosphatidyl inositol cycle in mitosis in sea urchin zygotes. Lithium inhibition is overcome by myo-inositol but not by other cyclitols or sugars, Exp. Cell Res., 170, 42, 10.1016/0014-4827(87)90115-7 · DOI
  86. Teng, 1977, Synergism between antimicrotubule agents and growth stimulants in enhancement of cell cycle traverse, Nature, 268, 739, 10.1038/268739a0 · DOI
  87. Galwain, 1981, Prevention of colchicine toxicity to rat hepatocytes by glucagon, hydrocortisone and insulin, Exp. Cell Res, 131, 379, 10.1016/0014-4827(81)90241-X · DOI

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Metadata

Authors
Gupta, R. S., & Dudani, A. K.
Venue
Medical Hypotheses
Publisher
Elsevier BV
Published
1989-01
Volume
28
Issue
1
Pages
57-69
ISSN
0306-9877
DOI
10.1016/0306-9877(89)90154-0
Cited by
9
References
0
Language
en
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)

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