REIC/Dkk-3-encoding adenoviral vector as a potentially effective therapeutic             agent for bladder cancer.
Bladder cancer is one of the most common urogenital malignancies. The intravesical             instillation of anticancer agents is an attractive strategy to treat a superficial             lesion or floating/disseminated cancer cells after transurethral operation. An             adenovirus carrying REIC/Dkk-3, a tumor suppressor gene (Ad-REIC), exhibits cancer-specific             apoptotic effects in various types of cancer cells. The aim of the present study             was to examine the potential of Ad-REIC as a therapeutic agent for bladder cancer.             KK47 and RT4 human bladder cancer cells were sensitive to the Ad-REIC treatment             for apoptosis induction, but some human bladder cancer cell lines (T24, J82 and             TccSup) were resistant. Significant cell growth inhibition was observed when these             resistant cancer cell lines were treated with Ad-REIC in a condition of floating             cells, which is clinically observed after transurethral operation and becomes             a cause of intravesical cancer dissemination. The therapeutic potential of Ad-REIC             for the treatment of multidrug-resistant bladder cancer was investigated. The             adriamycin-resistant KK47 bladder cancer cells (KK47/ADM), which also present             multidrug resistance, showed induction of significant apoptosis following Ad-REIC             treatment. The Ad-REIC treatment induced downregulation of P-glycoprotein in KK47/ADM             cells and restored the sensitivity to doxorubicin (adriamycin). Ad-REIC suppressed             P-glycoprotein expression in a c-Jun-NH2-kinase (JNK)-dependent manner. Therefore,             the current study indicated two therapeutic aspects of the Ad-REIC agent against             human bladder cancer cells, as an apoptosis inducer/cell growth inhibitor and             as a sensitizer of chemotherapeutic agents in multidrug-resistant cancer cells.             The intravesical instillation of Ad-REIC could be an attractive therapeutic method             in human bladder cancer where the treatment of superficial lesions and floating/disseminated             or multidrug-resistant cancer cells is necessary.
Department of Urology,Okayama University, Okayama, Japan.
Takeshi
T
Hirata
Masami
M
Watanabe
Haruki
H
Kaku
Yasuyuki
Y
Kobayashi
Hiroshi
H
Yamada
Masakiyo
M
Sakaguchi
Kohji
K
Takei
Nam-Ho
NH
Huh
Yasutomo
Y
Nasu
Hiromi
H
Kumon
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000256:Adenoviridae / Q000235:genetics*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D018925:Chemokines; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000628:therapy*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D048868:Adaptor Proteins, Signal Transducing; D000903:Antibiotics, Antineoplastic; D018925:Chemokines; C498624:DKK3 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases