Armoring CRAds with p21/Waf-1 shRNAs: the next generation of oncolytic adenoviruses.
Conditionally replicating adenoviruses (CRAds) represent a promising modality for the treatment of neoplastic diseases, including Prostate Cancer. Selectively replicating viruses can be generated by placing a tissue or cancer-specific promoter upstream of one or more of the viral genes required for replication (for example, E1A, E1B). We have previously reported multiple cellular processes that can attenuate viral replication, which in turn compromises viral oncolysis and tumor kill. In this study, we investigated the importance of the cyclin-dependent kinase inhibitor p21/Waf-1, on viral replication and tumor growth. To our knowledge, this is the first report describing the importance of p21/Waf-1shRNA on the induction of an androgen responsive element (ARE) based promoter driving the E1A gene. As a proof of concept, the study emphasizes the use of RNA interference technology to overcome promoter weaknesses for tissue-specific oncolytic viruses, as well as the cellular inhibitor pathways on viral life cycle. Using RNA interference against p21/Waf-1, we were able to show an increase in viral replication and viral oncolysis of prostate cancer cells. Similarly, CRAd viruses that carry p21/Waf-1 shRNA (Ad5-RV004.21) were able to prevent tumor outgrowth that resulted in a marked increase in the mean survival time of tumor-bearing mice compared with CRAd without p21/Waf-1 shRNA (Ad5-RV004). In studies combining Ad5-RV004.21 with Adriamycin, a suprar-additive effect was observed only in CRAds that harbor shRNA against p21/Waf-1. Taken together, these findings of enhanced viral replication in prostate cancer cells by using RNA interference against the cdk inhibitor p21/Waf-1 have significant implications in the development of prostate-specific CRAd therapies.
Höti
N
N
Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287-2101, USA.
Chowdhury
W H
WH
Mustafa
S
S
Ribas
J
J
Castanares
M
M
Johnson
T
T
Liu
M
M
Lupold
S E
SE
Rodriguez
R
R
D000256:Adenoviridae / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics*; D015536:Down-Regulation; D004317:Doxorubicin / Q000494:pharmacology; D055785:Gene Knockdown Techniques; D020868:Gene Silencing; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050504:Oncolytic Viruses / Q000235:genetics* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics*; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication / Q000235:genetics / Q000502:physiology
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D004317:Doxorubicin
J Urol. 2008 Jul;180(1):352-60
18499163
Science. 2008 Aug 22;321(5892):1084-5
18719283
Nucleic Acids Res. 2003 Aug 1;31(15):4481-9
12888508
Cancer Res. 2001 Oct 15;61(20):7464-72
11606381
Cochrane Database Syst Rev. 2006 Oct 18;(4):CD005247
17054249
Cancer Gene Ther. 2005 Aug;12(8):715-22
15832172
Oncogene. 1998 Jan 22;16(3):311-20
9467956
EMBO J. 2004 May 5;23(9):1949-56
15071503
Nucleic Acids Res. 2007;35(20):e138
17965092
Gene Ther. 2008 May;15(9):635-51
18273054
Urology. 2007 Dec;70(6):1243-8
18158069
J Virol. 2004 Dec;78(23):12868-76
15542639
Proc Natl Acad Sci U S A. 1997 Dec 23;94(26):14590-5
9405657
Mol Biol Cell. 1999 Jul;10(7):2119-29
10397753
Cancer Res. 1999 Sep 1;59(17):4200-3
10485454
Mol Cell Biol. 1998 Jan;18(1):629-43
9418909
Clin Cancer Res. 2009 Mar 1;15(5):1730-40
19223497
Am J Physiol Lung Cell Mol Physiol. 2009 Mar;296(3):L361-71
19112102
Biochem Biophys Res Commun. 1996 Aug 23;225(3):759-63
8780686
Cancer Gene Ther. 2009 Nov;16(11):810-9
19407849
Gene Ther. 2003 Nov;10(23):1982-91
14528322
Kidney Int. 1998 Feb;53(2):264-72
9461084
Mol Ther. 2007 Aug;15(8):1495-503
17565351
Cancer Res. 2002 Aug 15;62(16):4663-70
12183423
Science. 1996 Oct 18;274(5286):373-6
8832876
Science. 2008 Aug 22;321(5892):1086-8
18719284
Genome Biol. 2007;8(4):R58
17430596
Cell. 1993 Nov 5;75(3):477-86
8221887
Nat Med. 2005 Jan;11(1):77-84
15619633
Front Biosci. 2002 May 01;7:d1369-95
11991831
Hum Gene Ther. 2005 May;16(5):618-26
15916486
EMBO J. 1994 Nov 1;13(21):5075-85
7957073
Mol Ther. 2006 Jul;14(1):107-17
16690359
Mol Cell Biol. 1998 May;18(5):2845-54
9566903
Cancer Res. 1997 Jul 1;57(13):2559-63
9205053
Br J Cancer. 2006 Jun 19;94(12):1837-44
16736005
J Virol. 1991 Nov;65(11):5657-62
1920611
Proc Natl Acad Sci U S A. 1998 Mar 3;95(5):2509-14
9482916
Am J Physiol Lung Cell Mol Physiol. 2007 Mar;292(3):L716-24
17085526
Cell Death Differ. 2000 Aug;7(8):721-8
10918446
Proc Natl Acad Sci U S A. 1979 Aug;76(8):3665-9
291030
Gene Ther. 2008 Apr;15(7):484-94
18239605
J Virol. 2001 Oct;75(20):9844-56
11559818
Cancer Res. 2001 Oct 15;61(20):7544-51
11606392
Gene Ther. 2005 Jun;12(11):902-10
15690062
Cancer Res. 2002 May 1;62(9):2576-82
11980652
Mol Ther. 2006 Dec;14(6):768-78
16990052
Cancer Gene Ther. 2004 Jul;11(7):477-86
15118762