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Epothilone-paclitaxel resistant leukemic cells CEM/dEpoB300 are sensitive to albendazole: Involvement of apoptotic
Azita Khalilzadeh1, Kiran T Wangoo, David L Morris
1Cancer Research Laboratories, University of New South Wales, Department of Surgery, St. George Hospital, Sydney, NSW 2217, Australia.
Abstract:
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.
Insights
Paclitaxel-resistant T-cell leukemia cells show reduced apoptosis. These resistant cells become more sensitive to albendazole, indicating a potential new treatment strategy for drug-resistant leukemia.
Area of Science:
- Oncology
- Cell Biology
- Pharmacology
Background:
- Drug resistance in T cell acute lymphoblastic leukemia (ALL) is a significant clinical challenge.
- Apoptosis signaling pathways play a crucial role in the efficacy of chemotherapy drugs like paclitaxel (PTX).
- Understanding the molecular mechanisms underlying drug resistance is vital for developing alternative therapeutic strategies.
Purpose of the Study:
- To investigate the role of apoptotic mediators in paclitaxel (PTX) resistance in a T-cell ALL cell line (CEM) and its resistant counterpart (CEM/dEpoB300).
- To compare the cellular response to PTX and albendazole (ABZ), a microtubule depolymerizing agent, in both sensitive and resistant cells.
- To elucidate the changes in apoptotic signaling pathways associated with acquired PTX resistance.
Main Methods:
- Cell proliferation assays were performed to determine drug sensitivity (IC50 values) to PTX and ABZ.
- Caspase-3 activity and cytochrome c release were analyzed to assess apoptosis induction.
- Western blot analysis was used to evaluate the expression levels of key apoptotic proteins, including Bax, Bcl-2, and Mcl-1.
Main Results:
- CEM/dEpoB300 cells exhibited significant resistance to PTX but showed increased sensitivity to ABZ compared to CEM cells.
- PTX treatment resulted in diminished caspase-3 activity and cytochrome c release in resistant cells, while ABZ treatment enhanced these apoptotic markers.
- Resistant cells displayed elevated levels of the anti-apoptotic protein Bcl-2, which were more effectively reduced by ABZ than PTX. ABZ also downregulated Mcl-1.
Conclusions:
- Acquired paclitaxel resistance in T-cell ALL is associated with alterations in apoptotic mediator function.
- PTX-resistant ALL cells demonstrate significantly increased sensitivity to albendazole.
- Albendazole represents a promising therapeutic agent for overcoming paclitaxel resistance in T-cell ALL.
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