Zoledronic acid determines S-phase arrest but fails to induce apoptosis in cholangiocarcinoma cells

Abstract

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Chloroquine exerts antitumor effects on NB4 acute promyelocytic leukemia cells and functions synergistically with arsenic trioxide

“…In the present study, CQ treatment induced a significant increase in the number of cells in the S phase and a decrease in the number of cells in the G 0 /G 1 phase in a concentration-dependent manner. S phase arrest accompanied with a decrease in the number of cells in G 0 /G 1 phase following treatment with antitumor drugs has also been reported in a number of other studies (31)(32)(33), and does not appear to affect the antitumor effect of these drugs. One potential explanation for this is that the inhibition of cell proliferation is associated with cell cycle arrest, but the phase at which the cells are arrested depends on the anticancer drugs and the antitumor cells involved.…”

The BH3-mimetic ABT-737 targets the apoptotic machinery in cholangiocarcinoma cell lines resulting in synergistic interactions with zoledronic acid

“…The overexpression of BCL-2 observed in EGI-1 cells is in striking contrast with the results showed by Okaro [16], where the EGI-1 and TFK-1 cells were negative for BCL-2. The overexpression of BCL-2 and BCL-XL family members of the BCL-2 subfamily have been associated in our previous study [14] with the resistance of the TFK-1 and EGI-1 cholangiocarcinoma cells to the ZOL induced apoptosis, and making mandatory the setting up of combination therapies with molecules that target BCL-2. As observed by cytofluorimetric analysis ZOL determined moderate triggering of apoptotic machinery as revealed by a shift of fluorescence, index of loss of mitochondrial potential.…”

“…In our previous paper [14] the large constitutive expression of BCL-XL proteins in both TFK-1 and EGI-1 cells has prompt us to speculate a potential involvement of pro-survival BCL-2 family members in ZOL-induced apoptosis resistance. As shown in Figure 1A, BCL-2 protein is significantly expressed in both cell lines with higher level in EGI-1 cells.…”

“…Considering that ZOL, a third-generation of biphosphonates, facilitates the dislocation of RAS from cell membrane to cytosol by inhibiting post-translational prenylation and its membrane-anchorage, affects the activation of the downstream ERK and AKT signaling pathways [13], we have investigated this inhibitor in cholangiocarcinoma cell lines [14]. Our results indicated that ZOL-treatment determines S-phase arrest but fails to induce apoptosis even at concentrations above IC50.…”

“…In our previous report [14] we hypothesized that the failure of ZOL to induce apoptosis in cholangiocarcinoma cell lines could be linked to mechanisms such as an altered expression of prosurvival or pro-apoptotic proteins, and/or a constitutive expression of heat shock proteins. In this work we sought to determine whether direct targeting of BCL-2 by using the selective inhibitor ABT-737 could cooperate with ZOL to complete the apoptosis process in TFK-1 and EGI-1 cholangiocarcinoma cell lines.…”