TY - JOUR
T1 - The Bioactivity of D-/L-Isonucleoside- and 2′-Deoxyinosine-Incorporated Aptamer AS1411s Including DNA Replication/MicroRNA Expression
AU - Fan, Xinmeng
AU - Sun, Lidan
AU - Li, Kunfeng
AU - Yang, Xiantao
AU - Cai, Baobin
AU - Zhang, Yanfen
AU - Zhu, Yuejie
AU - Ma, Yuan
AU - Guan, Zhu
AU - Wu, Yun
AU - Zhang, Lihe
AU - Yang, Zhenjun
N1 - Publisher Copyright:
© 2017 The Author(s)
PY - 2017/12/15
Y1 - 2017/12/15
N2 - In this study, chemical modification of 2′-deoxyinosine (2′-dI) and D-/L-isothymidine (D-/L-isoT) was performed on AS1411. They could promote the nucleotide-protein interaction by changing the local conformation. Twenty modified sequences were obtained, FCL-I and FCL-II showed the most noticeable activity improvement. They stabilized the G-quadruplex, remained highly resistant to serum degradation and specificity for nucleolin, further inhibited tumor cell growth, exhibited a stronger ability to influence the different phases of the tumor cell cycle, induced S-phase arrest, promoted the inhibition of DNA replication, and suppressed the unwound function of a large T antigen as powerful as AS1411. The microarray analysis and TaqMan PCR results showed that FCL-II can upregulate the expression of four breast-cancer-related, lowly expressed miRNAs and downregulate the expression of three breast-cancer-related, highly expressed miRNAs (>2.5-fold). FCL-II resulted in enhanced treatment effects greater than AS1411 in animal experiments (p < 0.01). The computational results further proved that FCL-II exhibits more structural advantages than AS1411 for binding to the target protein nucleolin, indicating its great potential in antitumor therapy.
AB - In this study, chemical modification of 2′-deoxyinosine (2′-dI) and D-/L-isothymidine (D-/L-isoT) was performed on AS1411. They could promote the nucleotide-protein interaction by changing the local conformation. Twenty modified sequences were obtained, FCL-I and FCL-II showed the most noticeable activity improvement. They stabilized the G-quadruplex, remained highly resistant to serum degradation and specificity for nucleolin, further inhibited tumor cell growth, exhibited a stronger ability to influence the different phases of the tumor cell cycle, induced S-phase arrest, promoted the inhibition of DNA replication, and suppressed the unwound function of a large T antigen as powerful as AS1411. The microarray analysis and TaqMan PCR results showed that FCL-II can upregulate the expression of four breast-cancer-related, lowly expressed miRNAs and downregulate the expression of three breast-cancer-related, highly expressed miRNAs (>2.5-fold). FCL-II resulted in enhanced treatment effects greater than AS1411 in animal experiments (p < 0.01). The computational results further proved that FCL-II exhibits more structural advantages than AS1411 for binding to the target protein nucleolin, indicating its great potential in antitumor therapy.
KW - 2'-deoxyinosine
KW - AS1411
KW - biological regulation
KW - isonucleoside
KW - tumor suppressor
UR - http://www.scopus.com/inward/record.url?scp=85041846438&partnerID=8YFLogxK
UR - https://www.sciencedirect.com/science/article/pii/S2162253117302603?via%3Dihub
U2 - 10.1016/j.omtn.2017.09.010
DO - 10.1016/j.omtn.2017.09.010
M3 - Journal article
AN - SCOPUS:85041846438
SN - 2162-2531
VL - 9
SP - 218
EP - 229
JO - Molecular Therapy Nucleic Acids
JF - Molecular Therapy Nucleic Acids
ER -