Aspirin inhibits camptothecin-induced p21(CIP1) levels and potentiates apoptosis in human breast cancer cells

Alfonso, Lloyd F., Srivenugopal, Kalkunte S., Arumugam, Thirua V., Abbruscato, Thomas J., Weidanz, Jon A. and Bhat, G. Jayarama (2009) Aspirin inhibits camptothecin-induced p21(CIP1) levels and potentiates apoptosis in human breast cancer cells. International Journal of Oncology, 34 3: 597-608. doi:10.3892/ijo_00000185


Author Alfonso, Lloyd F.
Srivenugopal, Kalkunte S.
Arumugam, Thirua V.
Abbruscato, Thomas J.
Weidanz, Jon A.
Bhat, G. Jayarama
Title Aspirin inhibits camptothecin-induced p21(CIP1) levels and potentiates apoptosis in human breast cancer cells
Formatted title
Aspirin inhibits camptothecin-induced p21 CIP1 levels and potentiates apoptosis in human breast cancer cells
Journal name International Journal of Oncology   Check publisher's open access policy
ISSN 1019-6439
1791-2423
Publication date 2009-03
Sub-type Article (original research)
DOI 10.3892/ijo_00000185
Volume 34
Issue 3
Start page 597
End page 608
Total pages 12
Place of publication Athens, Greece
Publisher Spandidos Publications
Collection year 2010
Language eng
Formatted abstract
The ability of aspirin to trigger apoptosis in cancer
cells is well known and is consistent with the clinical and
epidemiological evidence on its chemopreventive effects in
curtailing epithelial cancers, including breast cancer. We
hypothesized that the anticancer effects of aspirin may involve
acetylation of the tumor suppressor protein p53, a known
regulator of apoptosis. In the present study, we determined
if aspirin at the physiologically achievable concentration of
100 μM acetylates p53 and modulates the expression of
p21CIP1, a protein involved in cell cycle arrest, and Bax, a
pro-apoptotic protein. Using MDA-MB-231 human breast
cancer cells, we demonstrate that aspirin at 100 μM concentration
markedly acetylated the p53 protein, which was
primarily localized to the nucleus. Aspirin induced p21CIP1
protein levels in a transient fashion in contrast to the sustained
induction of Bax. The induction of p21CIP1 protein levels began
at 3 h and was maximal at 6-8 h; however, it decreased to
control levels by 30 h. In contrast, the anticancer drug,
camptothecin (CPT) induced a steady accumulation of p21CIP1
protein. Remarkably, when cells were co-treated with aspirin
and CPT, p21CIP1 levels were drastically downregulated, and
this phenomenon was observed in many cancer cell lines.
Incubation of recombinant p21 with cytoplasmic extracts
from aspirin-treated cells caused its degradation suggesting
the involvement of proteases in the disappearance of p21CIP1.
Consistent with this data, aspirin decreased the survival of
CPT-treated cells and greatly increased the extent of apoptosis.
Our observation that aspirin has the ability to inhibit p21CIP1
after its initial induction has important implications in chemotherapy,
and suggests its potential use to increase the efficacy
of anticancer agents.
Keyword Aspirin
Chemoprevention
Chemotherapy
Breast cancer
Apoptosis
Gene expression
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: Faculty of Health and Behavioural Sciences -- Publications
 
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Created: Tue, 17 Nov 2009, 12:19:42 EST