Arsenic trioxide suppresses paclitaxel-induced mitotic arrest

Objectives:  To understand if there exists a functional interaction between arsenic trioxide and paclitaxel in vitro.
Materials and methods:  HeLa and HCT116 ( ρ 53^+/+ and ρ 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.
Results:  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.
Conclusion:  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.