Mitotic spindle checkpoint inactivation by trichostatin A defines a mechanism for increasing cancer cell killing by microtubule-disrupting agents

• DOI: 10.4161/cbt.4.2.1441
• Publication Date: 2010-07-15T16:05:23Z
• Authors: Melissa L. Dowling; K. Ranh Voong; Mijin Kim; Michael K. Keutmann; Eleanor Harris; Gary D. Kao
• Keywords: Nocodazole; Trichostatin A; Spindle checkpoint; Histone deacetylase inhibitor

Microtubule-disrupting agents such as the taxanes comprise some of most clinically useful chemotherapeutic and invoke spindle checkpoint in proliferating cells. A robust turn may forestall mitotic catastrophe, potentially providing a mechanism that permits cancer cells to survive transient exposure these drugs. Previous reports on G2-M cell cycle progression by histone deacetylase inhibitors suggested potential role modulating therapeutic efficacy microtubule-disrupting agents. As both classes are generally administered clinical trials pulse treatments, we investigated human effects brief treatments with inhibitor trichostatin (TSA) alone or nocodazole paclitaxel (Taxol) checkpoint. Treatment synchronized 200 ng/ml TSA for eight hours completely block class I II HDACs did not interfere into mitosis chromosomal condensation confirmed MPM-2 expression. treatment at this concentration surprisingly formation centrosomal separation, but instead led missegregation chromosomes, suggesting Consistent hypothesis, abrogated phosphorylation kinetochore localization protein BubR1 H3 after treatment. These rapid death considerably reduced clonogenic survival. results together suggest inactivating checkpoint, can potentiate lethal drugs, strategy might be usefully exploited optimizing anticancer therapy.