BioKnife, a uPA activity-dependent oncolytic Sendai virus, eliminates pleural spread of malignant mesothelioma via simultaneous stimulation of uPA expression.
Malignant pleural mesothelioma (MPM) is highly intractable and readily spreads throughout the surface of the pleural cavity, and these cells have been shown to express urokinase-type plasminogen activator receptor (uPAR). We here examined the potential of our new and powerful recombinant Sendai virus (rSeV), which shows uPAR-specific cell-to-cell fusion activity (rSeV/dMFct14 (uPA2), named "BioKnife"), for tumor cell killing in two independent orthotopic xenograft models of human. Multicycle treatment using BioKnife resulted in the efficient rescue of these models, in association with tumor-specific fusion and apoptosis. Such an effect was also seen on both MSTO-211H and H226 cells in vitro; however, we confirmed that the latter expressed uPAR but not uPA. Of interest, infection with BioKnife strongly facilitated the uPA release from H226 cells, and this effect was completely abolished by use of either pyrrolidine dithiocarbamate (PDTC) or BioKnife expressing the C-terminus-deleted dominant negative inhibitor for retinoic acid-inducible gene-I (RIG-IC), indicating that BioKnife-dependent expression of uPA was mediated by the RIG-I/nuclear factor-κB (NF-κB) axis, detecting RNA viral genome replication. Therefore, these results suggest a proof of concept that the tumor cell-killing mechanism via BioKnife may have significant potential to treat patients with MPM that is characterized by frequent uPAR expression in a clinical setting.
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yosuke
Y
Morodomi
Tokujiro
T
Yano
Hiroaki
H
Kinoh
Yui
Y
Harada
Satoru
S
Saito
Ryoichi
R
Kyuragi
Kumi
K
Yoshida
Mitsuho
M
Onimaru
Fumihiro
F
Shoji
Tsukihisa
T
Yoshida
Kensaku
K
Ito
Yasunori
Y
Shikada
Riichiroh
R
Maruyama
Mamoru
M
Hasegawa
Yoshihiko
Y
Maehara
Yoshikazu
Y
Yonemitsu
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D051379:Mice; D050504:Oncolytic Viruses / Q000235:genetics / Q000502:physiology*; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D029082:Sendai virus / Q000235:genetics / Q000502:physiology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
D034741:RNA, Small Interfering; D055293:Receptors, Urokinase Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator