TY - JOUR
T1 - Nakiterpiosin targets tubulin and triggers mitotic catastrophe in human cancer cells
AU - Wei, Jen Hsuan
AU - Seemann, Joachim
PY - 2010/12
Y1 - 2010/12
N2 - Agents that interfere with mitotic progression by perturbing microtubule dynamics are commonly used for cancer chemotherapy. Here, we identify nakiterpiosin as a novel antimitotic drug that targets microtubules. Nakiterpiosin induces mitotic arrest and triggers mitotic catastrophe in human cancer cells by impairing bipolar spindle assembly. At higher concentration, it alters the interphase microtubule network andsuppresses microtubule dynamics. In the presence of nakiterpiosin, microtubules are no longer arranged in a centrosomal array and centrosome-mediated microtubule regrowth after cold depolymerization is inhibited. However, centrosome organization, the ultrastructure of Golgi stacks, and protein secretion are not affected, suggesting that the drug has minimal toxicity toward other cellular functions. Nakiterpiosin interacts directly with tubulin, inhibits microtubule polymerization in vitro, and decreases polymer mass in cells. Furthermore, it enhances tubulin acetylation and reduces viability of paclitaxel-resistant cancer cells. In conclusion, nakiterpiosin exerts antiproliferative activity by perturbing microtubule dynamics during mitosis that activates the spindle assembly checkpoint and triggers cell death. These findings suggest the potential use of nakiterpiosin as a chemotherapeutic agent.
AB - Agents that interfere with mitotic progression by perturbing microtubule dynamics are commonly used for cancer chemotherapy. Here, we identify nakiterpiosin as a novel antimitotic drug that targets microtubules. Nakiterpiosin induces mitotic arrest and triggers mitotic catastrophe in human cancer cells by impairing bipolar spindle assembly. At higher concentration, it alters the interphase microtubule network andsuppresses microtubule dynamics. In the presence of nakiterpiosin, microtubules are no longer arranged in a centrosomal array and centrosome-mediated microtubule regrowth after cold depolymerization is inhibited. However, centrosome organization, the ultrastructure of Golgi stacks, and protein secretion are not affected, suggesting that the drug has minimal toxicity toward other cellular functions. Nakiterpiosin interacts directly with tubulin, inhibits microtubule polymerization in vitro, and decreases polymer mass in cells. Furthermore, it enhances tubulin acetylation and reduces viability of paclitaxel-resistant cancer cells. In conclusion, nakiterpiosin exerts antiproliferative activity by perturbing microtubule dynamics during mitosis that activates the spindle assembly checkpoint and triggers cell death. These findings suggest the potential use of nakiterpiosin as a chemotherapeutic agent.
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U2 - 10.1158/1535-7163.MCT-10-0305
DO - 10.1158/1535-7163.MCT-10-0305
M3 - Article
C2 - 21139045
AN - SCOPUS:78650439892
SN - 1535-7163
VL - 9
SP - 3375
EP - 3385
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 12
ER -