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Drug Des Devel Ther. 2016 Feb 4;10:557-70. doi: 10.2147/DDDT.S92687. eCollection 2016.

Curcumin enhances the cytogenotoxic effect of etoposide in leukemia cells through induction of reactive oxygen species.

Author information

1
Department of Cytobiology, Jagiellonian University Medical College, Krakow, Poland.
2
Department of Medical Diagnostic, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
3
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
4
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Department of Clinical Immunology, Institute of Pediatrics, Krakow, Poland.
5
Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.
6
Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland; Malopolska Centre of Biotechnology, Jagiellonian University, Krakow, Poland.

Abstract

Curcumin may exert a more selective cytotoxic effect in tumor cells with elevated levels of free radicals. Here, we investigated whether curcumin can modulate etoposide action in myeloid leukemia cells and in normal cells of hematopoietic origin. HL-60 cell line, normal myeloid progenitor cluster of differentiation (CD)-34(+) cells, and granulocytes were incubated for 4 or 24 hours at different concentrations of curcumin and/or etoposide. Brown Norway rats with acute myeloid leukemia (BNML) were used to prove the influence of curcumin on etoposide action in vivo. Rats were treated with curcumin for 23 days and etoposide was administered for the final 3 days of the experiment. Curcumin synergistically potentiated the cytotoxic effect of etoposide, and it intensified apoptosis and phosphorylation of the histone H2AX induced by this cytostatic drug in leukemic HL-60 cells. In contrast, curcumin did not significantly modify etoposide-induced cytotoxicity and H2AX phosphorylation in normal CD34(+) cells and granulocytes. Curcumin modified the cytotoxic action of etoposide in HL-60 cells through intensification of free radical production because preincubation with N-acetyl-l-cysteine (NAC) significantly reduced the cytotoxic effect of curcumin itself and a combination of two compounds. In contrast, NAC did not decrease the cytotoxic effect of etoposide. Thus, oxidative stress plays a greater role in the cytotoxic effect of curcumin than that of etoposide in HL-60 cells. In vitro results were confirmed in a BNML model. Pretreatment with curcumin enhanced the antileukemic activity of etoposide in BNML rats (1.57-fold tumor reduction versus etoposide alone; P<0.05) and induced apoptosis of BNML cells more efficiently than etoposide alone (1.54-fold change versus etoposide alone; P<0.05), but this treatment protected nonleukemic B-cells from apoptosis. Thus, curcumin can increase the antileukemic effect of etoposide through reactive oxygen species in sensitive myeloid leukemia cells, and it is harmless to normal human cells.

KEYWORDS:

ROS; acute myeloid leukemia; apoptosis; curcumin; etoposide; γ-H2AX

PMID:
26893544
PMCID:
PMC4745860
DOI:
10.2147/DDDT.S92687
[Indexed for MEDLINE]
Free PMC Article

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