Arsenic trioxide suppresses paclitaxel-induced mitotic arrest.
OBJECTIVE
To understand if there exists a functional interaction between arsenic trioxide and paclitaxel in vitro.


METHODS
HeLa and HCT116 (rho53(+/+) and rho53(-/-)) 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 As(2)O(3) is capable of inhibiting tubulin polymerization and inducing mitotic arrest, we examined whether there existed any functional interaction between As(2)O(3) and paclitaxel, a well-known microtubule poison. Flow cytometry and fluorescence microscopy revealed that although As(2)O(3) 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 As(2)O(3) 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 As(2)O(3) resulted primarily from sluggish cell cycle progression at S phase but not enhanced mitotic exit.


CONCLUSIONS
The observations that As(2)O(3) 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.
Duan
Q
Q
Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Komissarova
E
E
Dai
W
W
D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D002460:Cell Line; D005434:Flow Cytometry; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000187:drug effects*; D010087:Oxides / Q000494:pharmacology*; D017239:Paclitaxel / Q000494:pharmacology*
D001152:Arsenicals; D010087:Oxides; D017239:Paclitaxel; D000077237:Arsenic Trioxide