Arsenic trioxide suppresses paclitaxel-induced mitotic arrest

To understand if there exists a functional interaction between arsenic trioxide and paclitaxel in vitro. HeLa and HCT116 (rho 53(+/+) and rho 53(-/-)) cells were treated with As2O3 and/or paclitaxel for various times. Treated cells were collected for analyses using a combination of flow cytometry, fluorescence microscopy and Western blotting. Because As2O3 is capable of inhibiting tubulin polymerization and inducing mitotic arrest, we examined whether there existed any functional interaction between As2O3 and paclitaxel, a well-known microtubule poison. Flow cytometry and fluorescence microscopy revealed that although As2O3 alone caused a moderate level of mitotic arrest, it greatly attenuated paclitaxel-induced mitotic arrest in cells with p53 deficiency. Western blot analysis showed that As2O3 significantly blocked phosphorylation of BubR1, Cdc20, and Cdc27 in cells treated with paclitaxel, suggesting that arsenic compromised the activation of the spindle checkpoint. Our further studies revealed that the attenuation of paclitaxel-induced mitotic arrest by As2O3 resulted primarily from sluggish cell cycle progression at S phase but not enhanced mitotic exit. The observations that As2O3 has a negative impact on the cell cycle checkpoint activation by taxol should have significant clinical implications because the efficacy of taxol in the clinics is associated with its ability to induce mitotic arrest and subsequent mitotic catastrophe.