miR-221 silencing blocks hepatocellular carcinoma and promotes survival.
Patients with advanced hepatocellular carcinoma (HCC) face a dismal prognosis because of a lack of any effective therapies. To address this situation, we conducted a preclinical investigation of the therapeutic efficacy of oligonucleotides directed against the oncogenic microRNA miR-221, which has been implicated in HCC. Of 9 chemistries evaluated, we determined that a 2'-O-methyl phosphorothioate-modified anti-miR-221 oligonucleotide was most effective at reducing proliferation in vitro. A cholesterol-modified isoform of anti-miR-221 (chol-anti-miR-221) exhibited improved pharmacokinetics and liver tissue distribution compared with unmodified oligonucleotide. Chol-anti-miR-221 significantly reduced miR-221 levels in liver within a week of intravenous administration and in situ hybridization studies confirmed accumulation of the oligonucleotide in tumor cells in vivo. Within the same period, chol-anti-miR-221 reduced tumor cell proliferation and increased markers of apoptosis and cell-cycle arrest, elevating the tumor doubling time and increasing mouse survival. Taken together, our findings offer a preclinical proof of efficacy for chol-anti-miR-221 in a valid orthotopic mouse model of HCC, suggesting that this targeted agent could benefit treatment for patients with advanced HCC.
College of Pharmacy, Ohio State University, Columbus, Ohio 43210, USA.
Jong-Kook
JK
Park
Takayuki
T
Kogure
Gerard J
GJ
Nuovo
Jinmai
J
Jiang
Lei
L
He
Ji Hye
JH
Kim
Mitch A
MA
Phelps
Tracey L
TL
Papenfuss
Carlo M
CM
Croce
Tushar
T
Patel
Thomas D
TD
Schmittgen
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015152:Blotting, Northern; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002784:Cholesterol / Q000737:chemistry; D005260:Female; D020868:Gene Silencing; D006801:Humans; D017403:In Situ Hybridization; D053208:Kaplan-Meier Estimate; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014162:Transfection / Q000379:methods; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
C548375:MIRN22 microRNA, human; D035683:MicroRNAs; D016376:Oligonucleotides, Antisense; D002784:Cholesterol