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Antigene peptide nucleic acid specifically inhibits MYCN expression in human neuroblastoma cells leading to cell growth inhibition and apoptosis
Roberto Tonelli,Stefania Purgato,Consuelo Camerin,Raffaele Fronza,Fabrizio Bologna,Simone Alboresi,Monica Franzoni,Roberto Corradini,Stefano Sforza,Andrea Faccini,Jason M. Shohet,Rosangela Marchelli,and Andrea Pession Department of Pediatrics, University of Bologna,Sant’Orsola-Malpighi Hospital, Bologna, Italy; Department of Organic and Industrial Chemistry, University of Parma, Parma,Italy; and 3Center for Cell and Gene Therapy, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas
Abstract
We developed an antigene peptide nucleic acid (PNA) for
selective inhibition of MYCN transcription in neuroblastoma
cells, targeted against a unique sequence in the
antisense DNA strand of exon 2 of MYCN and linked at
its NH2 terminus to a nuclear localization signal peptide.
Fluorescence microscopy showed specific nuclear delivery
of the PNA in six human neuroblastoma cell lines: GI-LIN
and IMR-32 (MYCN-amplified/overexpressed); SJ-NKP
and NB-100 (MYCN-unamplified/low-expressed);
and GI-CA-N and GI-ME-N (MYCN-unamplified/unexpressed).
Antiproliferative effects were observable at
24 hours (GI-LI-N, 60%; IMR-32, 70%) and peaked at
72 hours (GI-LI-N, 80%; IMR-32, 90%; SK-N-KP, 60%;
NB-100, 50%); no reduction was recorded for GI-CA-N
and GI-ME-N (controls). In MYCN-amplified/overexpressed
IMR-32 cells and MYCN-unamplified/lowexpressed
SJ-N-KP cells, inhibition was recorded of
MYCN mRNA (by real-time PCR) and N-Myc (Western
blotting); these inhibitory effects increased over 3 days
after single treatment in IMR-32. Antigene PNA induced
G1-phase accumulation (39–53%) in IMR-32 and apoptosis
(56% annexin V–positive cells at 24 hours in
IMR-32 and 22% annexin V–positive cells at 48 hours
in SJ-N-KP). Selective activity of the PNA was shown
by altering three point mutations, and by the observation
that an antigene PNA targeted against the noncoding
DNA strand did not exert any effect. These findings
could encourage research into development of an
antigene PNA–based tumor-specific agent for neuroblastoma
(and other neoplasms) with MYCN expression.
[Mol Cancer Ther 2005;4(5):779–86]
Antigene peptide nucleic acid specifically inhibits MYCN expression in human neuroblastoma cells leading to cell growth inhibition and apoptosis
Roberto Tonelli,Stefania Purgato,Consuelo Camerin,Raffaele Fronza,Fabrizio Bologna,Simone Alboresi,Monica Franzoni,Roberto Corradini,Stefano Sforza,Andrea Faccini,Jason M. Shohet,Rosangela Marchelli,and Andrea Pession Department of Pediatrics, University of Bologna,Sant’Orsola-Malpighi Hospital, Bologna, Italy; Department of Organic and Industrial Chemistry, University of Parma, Parma,Italy; and 3Center for Cell and Gene Therapy, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, Texas
Abstract
We developed an antigene peptide nucleic acid (PNA) for
selective inhibition of MYCN transcription in neuroblastoma
cells, targeted against a unique sequence in the
antisense DNA strand of exon 2 of MYCN and linked at
its NH2 terminus to a nuclear localization signal peptide.
Fluorescence microscopy showed specific nuclear delivery
of the PNA in six human neuroblastoma cell lines: GI-LIN
and IMR-32 (MYCN-amplified/overexpressed); SJ-NKP
and NB-100 (MYCN-unamplified/low-expressed);
and GI-CA-N and GI-ME-N (MYCN-unamplified/unexpressed).
Antiproliferative effects were observable at
24 hours (GI-LI-N, 60%; IMR-32, 70%) and peaked at
72 hours (GI-LI-N, 80%; IMR-32, 90%; SK-N-KP, 60%;
NB-100, 50%); no reduction was recorded for GI-CA-N
and GI-ME-N (controls). In MYCN-amplified/overexpressed
IMR-32 cells and MYCN-unamplified/lowexpressed
SJ-N-KP cells, inhibition was recorded of
MYCN mRNA (by real-time PCR) and N-Myc (Western
blotting); these inhibitory effects increased over 3 days
after single treatment in IMR-32. Antigene PNA induced
G1-phase accumulation (39–53%) in IMR-32 and apoptosis
(56% annexin V–positive cells at 24 hours in
IMR-32 and 22% annexin V–positive cells at 48 hours
in SJ-N-KP). Selective activity of the PNA was shown
by altering three point mutations, and by the observation
that an antigene PNA targeted against the noncoding
DNA strand did not exert any effect. These findings
could encourage research into development of an
antigene PNA–based tumor-specific agent for neuroblastoma
(and other neoplasms) with MYCN expression.
[Mol Cancer Ther 2005;4(5):779–86]
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