AML sensitivity to YM155 is modulated through AKT and Mcl-1
Rosalia de Necochea-Campion1, Carlos J Diaz Osterman2, Heng-Wei Hsu1
1Department of Internal Medicine, Division of Hematology and Medical Oncology & Biospecimen Laboratory, Loma Linda University, Loma Linda, CA 92350, USA.
Cancer Letters
|June 30, 2015
Summary
YM155 effectively treats acute myeloid leukemia (AML) cells by inducing apoptosis. Combining YM155 with Akt inhibitors enhances efficacy in resistant AML cells by targeting Akt signaling.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Acute myeloid leukemia (AML) remains a significant challenge, necessitating novel therapeutic strategies.
- YM155, a survivin suppressant, has shown variable efficacy in AML cell lines.
- Understanding resistance mechanisms is crucial for optimizing YM155 treatment.
Purpose of the Study:
- To investigate the differential sensitivity of HL60 and U937 AML cell lines to YM155.
- To elucidate the molecular mechanisms underlying YM155-induced apoptosis and resistance.
- To evaluate the potential of combining YM155 with Akt inhibitors for enhanced AML therapy.
Main Methods:
- Differential sensitivity assessment of HL60 and U937 cells to YM155.
- Apoptosis induction analysis using Annexin V/PI staining and caspase-3 activity assays.
- Western blot analysis for apoptosis-related proteins (XIAP, Bcl-2, Mcl-1) and Akt signaling.
- Combination therapy studies with YM155 and the Akt inhibitor MK-2206.
Main Results:
- HL60 cells exhibited sensitivity to YM155-induced apoptosis, while U937 cells showed resistance.
- YM155 downregulated survivin transcription and inhibited total Akt protein in HL60 cells.
- U937 cells maintained Akt activity (pAkt-Ser473) despite YM155 treatment, potentially stabilizing anti-apoptotic proteins.
- Combination therapy with MK-2206 sensitized resistant U937 cells to YM155 cytotoxicity.
Conclusions:
- Akt signaling plays a critical role in mediating YM155 response in AML.
- Differential expression of apoptosis regulators and Akt pathway activation contribute to YM155 resistance.
- Combination therapy targeting both survivin and Akt signaling offers a promising strategy to overcome YM155 resistance in AML.
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