TY - JOUR
T1 - Small molecule, oligonucleotide-based telomerase template inhibition in combination with cytolytic therapy in an in vitro androgen-independent prostate cancer model
AU - Canales, Benjamin K.
AU - Li, Yingming
AU - Thompson, Melissa G.
AU - Gleason, Joseph M.
AU - Chen, Zhi
AU - Malaeb, Bahaa
AU - Corey, David R.
AU - Herbert, Brittney Shea
AU - Shay, Jerry W.
AU - Koeneman, Kenneth S.
N1 - Funding Information:
This work was supported by a New Award Idea, Department of Defense, CDMRP, DAMD 17-01-1-0107 “Targeting Osteoblastic Bone Metastasis with a Novel Site Restricted Gene Therapy” and Department of Defense, CDMRP, DAMD17-02-1-0148 “Targeting Orthotopic and Osseous Prostate Cancer Xenografts with Selective, Systemic Telomerase Inhibition” (K.S.K.), and a subcontract to DOD Consortium Award, DAMD17-03-2-0033 to Emory University (P.I. Jonathan Simmons).
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2006
Y1 - 2006
N2 - Purpose: Determine the efficacy and timing of small molecule oligonucleotide-based inhibitors to the enzyme telomerase in an in vitro model of androgen-independent, osseous prostate cancer. Materials and Methods: Telomerase was inhibited in prostate cancer cell lines C4-2/C4-2B and in controls by using small molecule antisense oligonucleotide-based inhibitors alone or in various combinations of small-dose Taxotere® (sanofi-aventis, Bridgewater, NJ) and/or conditionally replication competent adenovirus (AD-BSP-E1a). After transfection and proliferation, telomerase telomeric repeat amplification protocol and telomere restriction fragment assays were performed, with specific times for evaluating telomere length. Specimens were stained for analysis with hematoxylin and eosin (H&E), terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL), and prostate-specific antigen (PSA). Results: C4-2/C4-2B cell lines had the shortest initial mean telomere length (approximately 2.5 kilobase [kb]) compared to PC-3 (approximately 5.5 kb). Dose-dependent inhibition of telomerase activity was seen using match oligonucleotide-based inhibitors to telomerase (50% inhibitory concentration 3-5 nm), whereas mismatch compound showed no telomerase inhibition. Significant growth delay and apoptosis in cell lines occurred after >50 days of treatment. Cells treated with combination "triple therapy" (i.e., telomerase inhibitors, adenovirus, and Taxotere®) had the highest amount of apoptosis. Compared to controls, all combination treatment groups had statistically significant reductions in prostate-specific antigen in the conditioned media. Conclusions: Combining cytotoxic regimens with small molecule inhibitors to telomerase with oligonucleotide-based agents could be beneficial in controlling osseous hormone refractory prostate cancer, as evidenced by these in vitro, preclinical investigations. Telomerase inhibition needs to move into in vivo models and human studies.
AB - Purpose: Determine the efficacy and timing of small molecule oligonucleotide-based inhibitors to the enzyme telomerase in an in vitro model of androgen-independent, osseous prostate cancer. Materials and Methods: Telomerase was inhibited in prostate cancer cell lines C4-2/C4-2B and in controls by using small molecule antisense oligonucleotide-based inhibitors alone or in various combinations of small-dose Taxotere® (sanofi-aventis, Bridgewater, NJ) and/or conditionally replication competent adenovirus (AD-BSP-E1a). After transfection and proliferation, telomerase telomeric repeat amplification protocol and telomere restriction fragment assays were performed, with specific times for evaluating telomere length. Specimens were stained for analysis with hematoxylin and eosin (H&E), terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL), and prostate-specific antigen (PSA). Results: C4-2/C4-2B cell lines had the shortest initial mean telomere length (approximately 2.5 kilobase [kb]) compared to PC-3 (approximately 5.5 kb). Dose-dependent inhibition of telomerase activity was seen using match oligonucleotide-based inhibitors to telomerase (50% inhibitory concentration 3-5 nm), whereas mismatch compound showed no telomerase inhibition. Significant growth delay and apoptosis in cell lines occurred after >50 days of treatment. Cells treated with combination "triple therapy" (i.e., telomerase inhibitors, adenovirus, and Taxotere®) had the highest amount of apoptosis. Compared to controls, all combination treatment groups had statistically significant reductions in prostate-specific antigen in the conditioned media. Conclusions: Combining cytotoxic regimens with small molecule inhibitors to telomerase with oligonucleotide-based agents could be beneficial in controlling osseous hormone refractory prostate cancer, as evidenced by these in vitro, preclinical investigations. Telomerase inhibition needs to move into in vivo models and human studies.
KW - Docetaxel
KW - Gene therapy
KW - Oligonucleotide
KW - Prostate cancer
KW - Telomerase
KW - Telomerase inhibition
UR - http://www.scopus.com/inward/record.url?scp=33644762771&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33644762771&partnerID=8YFLogxK
U2 - 10.1016/j.urolonc.2005.11.003
DO - 10.1016/j.urolonc.2005.11.003
M3 - Article
C2 - 16520278
AN - SCOPUS:33644762771
SN - 1078-1439
VL - 24
SP - 141
EP - 151
JO - Urologic Oncology: Seminars and Original Investigations
JF - Urologic Oncology: Seminars and Original Investigations
IS - 2 SPEC. ISS.
ER -