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Antileukemic activity of the HSP70 inhibitor pifithrin-μ in acute leukemia
Abstract:
Heat shock protein (HSP) 70 is aberrantly expressed in different malignancies and has emerged as a promising new target for anticancer therapy. Here, we analyzed the in vitro antileukemic effects of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70, in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines, as well as in primary AML blasts. PFT-μ significantly inhibited cell viability at low micromolar concentrations in all cell lines tested, with IC50 values ranging from 2.5 to 12.7 μ, and was highly active in primary AML blasts with a median IC50 of 8.9 μ (range 5.7-37.2). Importantly, higher IC50 values were seen in normal hematopoietic cells. In AML and ALL, PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent fashion. PFT-μ also led to an increase of the active form of caspase-3 and reduced the intracellular concentrations of AKT and ERK1/2 in NALM-6 cells. Moreover, PFT-μ enhanced cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib in NALM-6, TOM-1 and KG-1a cells. This is the first study demonstrating significant antileukemic effects of the HSP70 inhibitor PFT-μ, alone and in combination with different antineoplastic drugs in both AML and ALL. Our results suggest a potential therapeutic role for PFT-μ in acute leukemias.
Insights
Pifithrin-μ, an inhibitor of heat shock protein 70 (HSP70), shows significant anti-leukemic effects in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) cell lines. This HSP70 inhibitor also enhances the efficacy of common chemotherapy drugs.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Heat shock protein (HSP) 70 is frequently overexpressed in various cancers, making it a potential therapeutic target.
- Targeting HSP70 offers a novel strategy for developing anticancer therapies.
Purpose of the Study:
- To investigate the in vitro antileukemic activity of pifithrin-μ (PFT-μ), an inhibitor of inducible HSP70.
- To evaluate the efficacy of PFT-μ as a single agent and in combination with other anticancer drugs against acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL).
Main Methods:
- In vitro analysis of PFT-μ effects on AML and ALL cell lines and primary AML blasts.
- Assessment of cell viability, apoptosis, cell cycle arrest, and caspase-3 activation.
- Evaluation of PFT-μ's impact on AKT and ERK1/2 signaling pathways.
- Combination studies with standard chemotherapeutic agents.
Main Results:
- PFT-μ demonstrated significant inhibition of cell viability in AML and ALL cell lines and primary AML blasts at low micromolar concentrations.
- PFT-μ induced apoptosis and cell cycle arrest in a dose-dependent manner.
- PFT-μ enhanced the cytotoxicity of cytarabine, 17-(allylamino)-17-desmethoxygeldanamycin, suberoylanilide hydroxamic acid, and sorafenib.
Conclusions:
- PFT-μ exhibits potent antileukemic effects in vitro against both AML and ALL.
- PFT-μ shows a favorable safety profile with higher IC50 values in normal hematopoietic cells compared to leukemic cells.
- PFT-μ holds promise as a therapeutic agent for acute leukemias, both as a monotherapy and in combination regimens.
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