Piceatannol, a Structural Analog of Resveratrol, Is an Apoptosis Inducer and a Multidrug Resistance Modulator in HL-60 Human Acute Myeloid Leukemia Cells.

Kamila Siedlecka-Kroplewska,Zbigniew Kmieć,Agata Wrońska

doi:10.3390/ijms221910597

Kamila Siedlecka-Kroplewska, Zbigniew Kmieć + Show 1 more

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https://doi.org/10.3390/ijms221910597

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Abstract

Acute myeloid leukemia is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells. Despite recent advances in the treatment of this disease, the prognosis and overall long-term survival for patients remain poor, which drives the search for new chemotherapeutics and treatment strategies. Piceatannol, a polyphenolic compound present in grapes and wine, appears to be a promising chemotherapeutic agent in the treatment of leukemia. The aim of the present study was to examine whether piceatannol induces autophagy and/or apoptosis in HL-60 human acute myeloid leukemia cells and whether HL-60 cells are able to acquire resistance to piceatannol toxicity. We found that piceatannol at the IC90 concentration of 14 µM did not induce autophagy in HL-60 cells. However, it induced caspase-dependent apoptosis characterized by phosphatidylserine externalization, disruption of the mitochondrial membrane potential, caspase-3 activation, internucleosomal DNA fragmentation, PARP1 cleavage, chromatin condensation, and fragmentation of cell nuclei. Our findings also imply that HL-60 cells are able to acquire resistance to piceatannol toxicity via mechanisms related to MRP1 activity. Our results suggest that the use of piceatannol as a potential chemotherapeutic agent may be associated with the risk of multidrug resistance, warranting its use in combination with other chemotherapeutic agents.

Highlights

Acute myeloid leukemia (AML) is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells that accumulate mainly in the bone marrow and blood [1]
Since the calculation of inhibit growth of HL-60 cells by 50% (IC50) and IC90 values is recommended to evaluate the cytotoxic potency of studied compounds [66], we calculated these values for piceatannol
We found that treatment of HL-60 cells with piceatannol at the IC90 concentration was not accompanied by the cell cycle arrest (Figure 2A,B)

Summary

Introduction

Acute myeloid leukemia (AML) is characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells that accumulate mainly in the bone marrow and blood [1]. The backbone of initial induction chemotherapy has not changed for several decades and is based mainly on a combination of cytarabine and anthracyclines [6,7]. Another important therapeutic strategy recently introduced for AML treatment is based on the use of hypomethylating agents (HMA) such as decitabine [8]. The major problems of chemotherapy of AML are treatment-related toxicity and mortality, cellular heterogeneity, as well as the occurrence of multidrug resistance (MDR) [5,6,7,8,9,10]. The overexpression of ABC transporters in cancer cells may lead to increased drug efflux resulting in resistance to chemotherapy [13,14]. Accumulating evidence suggests that P-gp, MRP1 and BCRP expression may be involved in multidrug resistance in AML [9,10,28,29,30,31,32,33]

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