title: Dietary antioxidant curcumin inhibits microtubule assembly through tubulin binding.
abstract: Curcumin, a component of turmeric, has potent antitumor activity against several tumor types. However, its molecular target and mechanism of antiproliferative activity are not clear. Here, we identified curcumin as a novel antimicrotubule agent. We have examined the effects of curcumin on cellular microtubules and on reconstituted microtubules in vitro. Curcumin inhibited HeLa and MCF-7 cell proliferation in a concentration-dependent manner with IC(50) of 13.8 +/- 0.7 microm and 12 +/- 0.6 microm, respectively. At higher inhibitory concentrations (> 10 microm), curcumin induced significant depolymerization of interphase microtubules and mitotic spindle microtubules of HeLa and MCF-7 cells. However, at low inhibitory concentrations there were minimal effects on cellular microtubules. It disrupted microtubule assembly in vitro, reduced GTPase activity, and induced tubulin aggregation. Curcumin bound to tubulin at a single site with a dissociation constant of 2.4 +/- 0.4 microm and the binding of curcumin to tubulin induced conformational changes in tubulin. Colchicine and podophyllotoxin partly inhibited the binding of curcumin to tubulin, while vinblastine had no effect on the curcumin-tubulin interactions. The data together suggested that curcumin may inhibit cancer cells proliferation by perturbing microtubule assembly dynamics and may be used to develop efficacious curcumin analogues for cancer chemotherapy.
authors.affiliation: School of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai, India.
authors.forename: Kamlesh K
authors.initials: KK
authors.lastname: Gupta
authors.forename: Shubhada S
authors.initials: SS
authors.lastname: Bharne
authors.forename: Krishnan
authors.initials: K
authors.lastname: Rathinasamy
authors.forename: Nishigandha R
authors.initials: NR
authors.lastname: Naik
authors.forename: Dulal
authors.initials: D
authors.lastname: Panda
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D003474:Curcumin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005455:Fluorescent Antibody Technique; D020558:GTP Phosphohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D008870:Microtubules / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D013997:Time Factors; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000975:Antioxidants; D014404:Tubulin; D050257:Tubulin Modulators; D006160:Guanosine Triphosphate; D020558:GTP Phosphohydrolases; D003474:Curcumin