Epothilone-paclitaxel resistant leukemic cells CEM/dEpoB300 are sensitive to albendazole: Involvement of apoptotic pathways.
Altered or deficient activation of apoptosis signalling pathways may contribute to drug resistance. Here, we assess the role of apoptotic mediators in eliciting an anti-proliferative response to paclitaxel (PTX) in a T cell acute lymphoblastic leukemia (ALL) cell line CEM and its epothilone-paclitaxel resistant sub-line CEM/dEpoB300. Furthermore, the cellular response to PTX was compared to those elicited by cells in response to treatment with albendazole (ABZ; a microtubule depolymerizing agent). In cell proliferation studies, CEM cells were sensitive to both PTX and ABZ, while the CEM/dEpoB300 cells were highly resistant to PTX (IC(50) 2.86 nM versus 30.26 nM, respectively). In contrast, the resistant cells showed a 2-fold increase in sensitivity to ABZ (0.32 microM in CEM compared to 0.16 microM in CEM/dEpoB300). Analysis of caspase-3 activity and cytochrome c release in response to PTX or ABZ treatment (24, 48 and 72 h) revealed that, compared to the parent cells, the resistant cells have diminished response to PTX and enhanced response to ABZ. A similar pattern was observed for the pro-apoptotic protein Bax. Levels of the anti-apoptotic protein Bcl-2 was highly elevated in CEM/dEpoB300 cells and in these cells, ABZ was more effective in lowering the Bcl-2 levels than PTX. Similarly, ABZ treatment led to profound down regulation of the Mcl-1 protein. These results reveal for the first time, the changes in apoptotic mediators following development of resistance to PTX in an ALL cell and the significantly increased sensitivity of these PTX resistant cells to ABZ.
Khalilzadeh
Azita
A
Cancer Research Laboratories, University of New South Wales, Department of Surgery, St. George Hospital, Sydney, NSW 2217, Australia.
Wangoo
Kiran T
KT
Morris
David L
DL
Pourgholami
Mohammad H
MH
D015766:Albendazole / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D045304:Cytochromes c / Q000378:metabolism; D017931:DNA Primers; D034261:Epothilones / Q000494:pharmacology*; D006801:Humans; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D017931:DNA Primers; D034261:Epothilones; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; D045304:Cytochromes c; D053148:Caspase 3; D015766:Albendazole; D017239:Paclitaxel