Ovarian
Depression
Diabetes
Alzheimer
hepatocellular carcinoma
Int J Mol Med. 2006 Jul;18(1):41-7. Mol Ther. 2006 Mar 29; [Epub
ahead of print] Clin Cancer Res. 2006 Mar 15;12(6):1686-92.
COX-2 inhibitors sensitize human hepatocellular carcinoma cells to TRAIL-induced
apoptosis.
Yamanaka
Y, Shiraki K, Inoue
T, Miyashita
K, Fuke H, Yamaguchi
Y, Yamamoto
N, Ito
K, Sugimoto
K, Nakano
T.
First Department of Internal Medicine,
Cyclooxygenase (COX)-2 is upregulated
in a variety of human cancers, including in hepatocellular
carcinoma (HCC), whereas it is undetectable in most normal tissue. Evidence
suggests that COX-2 is likely to be involved in hepatocarcinogenesis
and, thus, COX-2 may be involved in an early process in carcinogenesis,
dedifferentiation. To address this possibility, we investigated the effect
of COX-2 inhibitors on TNF-related apoptosis, inducing ligand
(TRAIL) sensitivity and its molecular mechanisms, with special attention to
anti-apoptotic proteins. We used the highly selective COX-2 inhibitors,
NS398 and CAY10404. We also used the MTT assay and cytological analysis of
DAPI-stained DNA to assess viability and apoptosis in two HCC cells
(SK-Hep1 and HLE). In order to ask what led to increased sensitivity to
TRAIL in HCC cells, cell surface expression of TRAIL and TRAIL-receptors
was investigated using flow cytometry analysis.
Expression of survivin, X-chromosome-linked IAP
(XIAP), Bcl-xL, AKT and phospho-AKT
was also investigated using immunoblotting. COX-2
inhibitors resulted in a concentration-dependent decrease in cell viability
in the two HCC cell lines tested. Subtoxic levels
of COX-2 inhibitors did not significantly augment TNFalpha-induced
apoptosis but did dramatically enhance TRAIL-induced apoptosis in both cell
lines. TRAIL receptor 2/death receptor 5 (TRAIL-R2/DR5) expression
was significantly up-regulated in SH-Hep1 and HLE cells. TRAIL receptor
1/death receptor 4 (TRAIL-R1/DR4) expression was
up-regulated only in SK-Hep1. Expression of survivin
and Bcl-xL was down-regulated in SK-Hep1 and HLE
cells in the presence of CAY10404 but XIAP was not affected. Expression of survivin, Bcl-xL and XIAP was
down-regulated in SK-Hep1 cells in the presence of NS398. Survivin expression was also down-regulated in the
presence of NS398 in HLE cells. Finally, NS398 also decreased phospho-AKT in SK-Hep1 cells. These results demonstrate
that COX-2 inhibitors can induce apoptosis and augment TRAIL sensitivity by
up-regulation of TRAIL receptors and down-regulation of both survivin and AKT signaling.
PMID: 16786154 [PubMed - in process]
Triple-Targeted Oncolytic
Adenoviruses Featuring the Cox2 Promoter, E1A Transcomplementation,
and Serotype Chimerism for Enhanced Selectivity
for Ovarian Cancer Cells.
Bauerschmitz
GJ, Guse
K, Kanerva
A, Menzel
A, Herrmann I,
Desmond RA,
Yamamoto M,
Nettelbeck
DM, Hakkarainen
T, Dall
P, Curiel
DT, Hemminki
A.
Division of Human Gene Therapy, Department of Medicine, Department of
Pathology, Department of Surgery, Gene Therapy Center, University of
Alabama at Birmingham, Birmingham, AL 35294, USA; Department of Obstetrics
and Gynecology, Duesseldorf University Medical
Center, Heinrich-Heine University, 40225 Duesseldorf, Germany; Rational Drug Design Program, Biomedicum Helsinki, University of Helsinki, 00014
Helsinki, Finland; Department of Oncology, Helsinki University Central
Hospital, 00029 Helsinki, Finland.
Conditionally replicating adenoviruses (CRAd's)
feature selective replication in and killing of tumor cells. Initial
clinical studies with relatively attenuated early generation agents have
resulted in promising safety and efficacy data. Nevertheless, increased
specificity may be advantageous for an emerging generation of
infectivity-enhanced CRAd's. Further, increased
specificity could translate into a larger tolerated dose. An approach for
increasing specificity is dual control of E1A expression. We constructed
six CRAd's featuring two variants of the cyclo-oxygenase 2 (cox2) promoter, combined with three
versions of E1A. Transcriptional targeting was supplemented with transductional targeting utilizing the serotype 3 knob. In vivo and in vitro results suggest that cox2 can
be utilized for enhancing the specificity of E1A deletion mutants and that
combination with the Delta24 mutation increases specificity without
reducing potency. Combination with Delta2-Delta24 was specific but somewhat
attenuated. The promoter variants behaved similarly, although the longer
1554-bp version displayed a trend for improved specificity. Transcriptional
modifications were compatible with transductional
targeting and resulted in up to 100,000-fold increase in the therapeutic
window for Ad5/3cox2Ld24 vs wild-type adenovirus.
Thus, the proposed triple-targeting strategy may be useful for increasing
the safety and efficacy of adenoviral gene therapy for ovarian cancer.
PMID: 16580264 [PubMed - as supplied by
publisher]
Cyclooxygenase 2 expression in colorectal
cancer with DNA mismatch repair deficiency.
Castells A,
Paya A, Alenda C, Rodriguez-Moranta
F, Agrelo R, Andreu M, Pinol V, Castellvi-Bel S,
Jover R, Llor X, Pons E, Elizalde JI,
Bessa X, Alcedo J, Salo J, Medina E, Naranjo A,
Esteller M,
Pique JM; Gastrointestinal
Oncology Group of the Spanish Gastroenterological Association.
Department of Gastroenterology, Institut
de Malalties Digestives, Hospital Clinic, Institut d'Investigacions Biomediques August Pi i Sunyer,
BACKGROUND: Cyclooxygenase 2
(COX-2) overexpression is a frequent but
not universal event in colorectal cancer. It has been suggested that COX-2
protein expression is reduced in colorectal cancer with a defective
mismatch repair (MMR) system, a phenomenon commonly associated with
hereditary nonpolyposis colorectal cancer (HNPCC)
but also present in up to 15% of sporadic tumors. Aim: To assess COX-2
expression in a large series of fully characterized colorectal cancer
patients with respect to the MMR system and to dissect the mechanisms
responsible for altered COX-2 expression in this setting. PATIENTS AND
METHODS: MMR-deficient colorectal cancer were
identified in a nationwide, prospective, multicenter
study (EPICOLON project). Control MMR-proficient colorectal cancer patients
were randomly selected. COX-2 expression was evaluated by immunohistochemistry. Personal and familial
characteristics, as well as MSH2/MLH1 expression and germ line mutations,
were evaluated. RESULTS: One hundred fifty-three patients, 46 with MMR
deficiency and 107 with MMR proficiency, were included in the analysis.
Overall, tumor COX-2 overexpression was observed
in 107 patients (70%). COX-2 overexpression was
observed in 85 patients (79%) with a MMR-proficient system, but only in 22
patients (48%) with a MMR-deficient colorectal cancer (P < 0.001). The
lack of COX-2 overexpression was independently
associated with a MMR-deficient system (odds ratio, 3.89; 95% confidence
interval, 1.78-8.51; P = 0.001) and a poor degree of differentiation (OR,
3.83; 95% CI, 1.30-11.31; P = 0.015). In the subset of patients with a
MMR-deficient colorectal cancer, lack of COX-2 overexpression
correlated with a poor degree of differentiation, no fulfillment of
Amsterdam II criteria, absence of MSH2/MLH1 germ line mutations, presence
of tumor MSH2 expression, and lack of tumor MLH1 expression. CpG island promoter hypermethylation
of COX2 was observed in 6 of 18 (33%) tumors lacking COX-2 expression in
comparison with 2 of 28 (7%) tumors expressing this protein (P = 0.04).
CONCLUSIONS: Up to half of MMR-deficient colorectal cancer
do not show COX-2 overexpression, a fact
observed almost exclusively in patients with sporadic forms. COX2 hypermethylation seems to be responsible for gene
silencing in one third of them. These results suggest the potential utility
of nonsteroidal anti-inflammatory drugs in HNPCC
chemoprevention and may explain the lack of response of this approach in
some sporadic tumors.