P. Giannakakou et al., Low concentrations of paclitaxel induce cell type-dependent p53, p21 and G1/G2 arrest instead of mitotic arrest: molecular determinants of paclitaxel-induced cytotoxicity, ONCOGENE, 20(29), 2001, pp. 3806-3813
Paclitaxel (PTX), a microtubule-active agent, blocks cell proliferation by
inhibiting mitotic progression leading to mitotic and postmitotic arrest an
d cell death. Here we demonstrate for the first time that very low concentr
ations of PTX (3-6 nM) can completely inhibit cell proliferation without ar
resting cells at mitosis, At these low concentrations that are insufficient
to inhibit mitotic progression, PTX induced both p53 and p21 causing CI an
d G2 arrest in A549. In contrast, low PTX concentrations failed to induce G
1 and G2 arrest in A549/E6 cells, that do not express p53, Furthermore, we
observed that the levels of p53 and p21 induced by adriamycin and by low co
ncentrations of PTX in A549 cells were comparable. This observation led us
to conclude that tow concentrations of PTX can induce p53 and p21 sufficien
tly to cause G1 and G2, Many other cell lines, including HCT116 cells, do n
ot readily upregulate p53 in response to PTX, and therefore undergo exclusi
vely mitotic and postmitotic arrest after PTX treatment. At low concentrati
ons that do not cause mitotic arrest, PTX did not significantly inhibit pro
liferation of these cells. In HCT116 cells, loss of p53 (HCT/p53(-/-)) or p
21 (HCT/p21(-/-)) affects both Bar and Bcl-2 expression. In cells lacking p
53, levels of Bar and p21 were decreased. In cells lacking p21, levels of w
t p53 were highly increased to compensate for the loss of p21, This in turn
results in upregulation of Bar and downregulation of Bcl-2 resulting in an
increase of the apoptotic Bax/Bcl2 ratio consistent with increased sensiti
vity of these cells to apoptotic stimuli, High levels of p53 and Bax/Bcl-2
ratio can also explain why loss of p21 is rarely found in human cancer.