Cytotoxicity of arsenic trioxide is enhanced by (-)-epigallocatechin-3-gallate via suppression of ferritin in cancer cells

Journal Article · Sat Jan 01 00:00:00 EST 2011 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/j.taap.2010.10.005· OSTI ID:21535204

Lee, Te-Chang ^[1]; Cheng, I-Cheng ^[2]; Shue, Jun-Jie ^[1]

---

1. Institute of Biomedical Sciences, Academia Sinica, Taiwan (China)
2. Institute of Cellular and Organismic Biology, Academia Sinica, Taiwan (China)

Arsenic trioxide (ATO) treatment is a useful therapy against human acute promyelocytic leukemia (APL), however, it concomitantly brings potential adverse consequences including serious side effect, human carcinogenicity and possible development of resistance. This investigation revealed that those problems might be relaxed by simultaneous application with (-)-epigallocatechin-3-gallate (EGCG), one of the major components from green tea. EGCG significantly lowered down the ATO concentration required for an effective control of APL cells, HL-60. The simultaneous treatment of ATO with EGCG induced a mitochondria-dependent apoptosis in HL-60 cells significantly, which accounted for more than 70% of the cell death in the treatment. The mechanism of apoptosis induction was elucidated. EGCG in HL-60 cells acted as a pro-oxidant enhancing intracellular hydrogen peroxide significantly. ATO, on the other hand, induced heme oxygenase-1 (HO-1) to catalyze heme degradation, thereby provided ferrous iron for EGCG-induced hydrogen peroxide to precede Fenton reaction, which in turn generated deleterious reactive oxygen species to damage cell. In addition, EGCG inhibited expression of ferritin, which supposedly to sequester harmful ferrous iron, thereby augmented the occurrence of Fenton reaction. This investigation also provided evidence that ATO, since mainly acted to induce HO-1 in simultaneous treatment with EGCG, could be replaced by other HO-1 inducer with much less human toxicity. Furthermore, several of our preliminary investigations revealed that the enhanced cytotoxicity induced by combining heme degradation and Fenton reaction is selectively toxic to malignant but not non-malignant cells.

• OSTI ID: 21535204
• Journal Information: Toxicology and Applied Pharmacology, Vol. 250, Issue 1; Other Information: DOI: 10.1016/j.taap.2010.10.005; PII: S0041-008X(10)00381-9; Copyright (c) 2010 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
ARSENIC
FERRITIN
HEME
HUMAN POPULATIONS
HYDROGEN PEROXIDE
IRON
LEUKEMIA
OXYGENASES
THERAPY
TOXICITY
CARBOXYLIC ACIDS
COMPLEXES
DISEASES
ELEMENTS
ENZYMES
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
HYDROGEN COMPOUNDS
IMMUNE SYSTEM DISEASES
IRON COMPLEXES
MEDICINE
METALLOPROTEINS
METALS
NEOPLASMS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
OXIDOREDUCTASES
OXYGEN COMPOUNDS
PEROXIDES
PIGMENTS
POPULATIONS
PORPHYRINS
PROTEINS
SEMIMETALS
TRANSITION ELEMENT COMPLEXES
TRANSITION ELEMENTS