title: A synthetic dolastatin 10 analogue suppresses microtubule dynamics, inhibits cell proliferation, and induces apoptotic cell death.
abstract: We have synthesized eight analogues (D1-D8) of dolastatin 10 containing several unique amino acid subunits. Of these agents, D5 was found to be most effective in inhibiting both HeLa cell proliferation and microtubule assembly in vitro. At low nanomolar concentrations, D5 inhibited the proliferation of several types of cancer cells in culture. D5 bound to tubulin with a dissociation constant of 29.4 ± 6 μM. D5 depolymerized microtubules in cultured cells and produced mulitpolar spindles. At its half-maximal inhibitory concentration (15 nM), D5 strongly suppressed the dynamics of individual microtubules in live MCF-7 cells. D5 increased the accumulation of checkpoint proteins BubR1 and Mad2 at the kinetochoric region and caused G2/M block in these cells. The blocked cells underwent apoptosis with the activation of Jun N-terminal kinase. The results suggested that D5 exerts its antiproliferative action by dampening microtubule dynamics.
authors: CSIR-Central Drug Research Institute, Lucknow 226 001 India.
authors: Praveen Kumar
authors: PK
authors: Gajula
authors: Jayant
authors: J
authors: Asthana
authors: Dulal
authors: D
authors: Panda
authors: Tushar Kanti
authors: TK
authors: Chakraborty
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000494:pharmacology; D047630:Depsipeptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004347:Drug Interactions; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020558:GTP Phosphohydrolases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D018386:Kinetochores / Q000187:drug effects / Q000378:metabolism; D061986:MCF-7 Cells; D008870:Microtubules / Q000187:drug effects* / Q000378:metabolism*; D008938:Mitosis / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects; D020836:Protein Structure, Quaternary; D014404:Tubulin / Q000737:chemistry / Q000378:metabolism; D014747:Vinblastine / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047630:Depsipeptides; D014404:Tubulin; D014747:Vinblastine; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D020558:GTP Phosphohydrolases; C064570:dolastatin 10; D003078:Colchicine