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Arsenic trioxide induces apoptosis in human gastric cancer cells through up‐regulation of P53 and activation of caspase‐3
Author(s) -
Jiang XiaoHua,
ChunYu Wong Benjamin,
Yuen SiuTsan,
Jiang ShiHu,
Cho ChiHin,
Lai KamChuen,
Lin Marie C.M.,
Kung HsiangFu,
Lam ShiuKum
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/1097-0215(200002)9999:9999<::aid-ijc1039>3.0.co;2-d
Subject(s) - apoptosis , arsenic trioxide , poly adp ribose polymerase , caspase , microbiology and biotechnology , dna fragmentation , cancer cell , biology , caspase 3 , programmed cell death , chemistry , cancer research , biochemistry , cancer , dna , polymerase , genetics
Abstract Arsenic trioxide (As 2 O 3 ) can induce clinical remission in patients suffering from acute promyelocytic leukemia, through induction of apoptosis and activation of caspases. We investigated the potential use of As 2 O 3 in human gastric cancer and its possible mechanisms. Human gastric cancer cell lines AGS and MKN‐28 were treated with various concentrations (0.1 to 100 μM) of As 2 O 3 for 24 to 72 hr. Apoptosis was determined by acridine orange staining, flow cytometry and DNA fragmentation. Protein levels of p53, p21 waf1/cip1 , c‐myc, bcl‐2 and bax were detected by Western blotting. Effects of As 2 O 3 on caspase‐3 protease activity, its protein concentration and cleavage of poly(ADP)‐ribose polymerase (PARP) were also studied. As 2 O 3 inhibited cell growth and induced apoptosis in both cell lines, though AGS cells were more sensitive. As 2 O 3 induced apoptosis in AGS cells in a concentration‐ and time‐dependent manner. Treatment resulted in a marked increase in p53 protein levels as early as 4 hr. Co‐incubation with p53 anti‐sense oligo‐nucleotide suppressed As 2 O 3 ‐induced intracellular p53 over‐expression and apoptosis. As 2 O 3 increased the activity of caspase‐3, with appearance of its 17 kDa peptide fragment, and cleavage of PARP, with appearance of the 85 kDa cleavage product, both in parallel with the induction of apoptosis. Both the tripeptide caspase inhibitor zVAD‐fmk and the specific caspase‐3 inhibitor DEVD‐fmk partially suppressed As 2 O 3 ‐induced caspase‐3 activation and apoptosis. As 2 O 3 inhibits cell growth and induces apoptosis in gastric cancer cells, involving p53 over‐expression and activation of caspase‐3. The potential use of this compound in the treatment of gastric cancer is worth further investigation. © 2001 Wiley‐Liss, Inc.