dc.contributor.author |
Harikumar, KB |
en |
dc.contributor.author |
Kunnumakkara, AB |
en |
dc.contributor.author |
Ochi, N |
en |
dc.contributor.author |
Tong, Z |
en |
dc.contributor.author |
Deorukhkar, A |
en |
dc.contributor.author |
Sung, B |
en |
dc.contributor.author |
Kelland, L |
en |
dc.contributor.author |
Jamieson, Stephen |
en |
dc.contributor.author |
Sutherland, R |
en |
dc.contributor.author |
Raynham, T |
en |
dc.contributor.author |
Charles, M |
en |
dc.contributor.author |
Bagherzadeh, A |
en |
dc.contributor.author |
Foxton, C |
en |
dc.contributor.author |
Boakes, A |
en |
dc.contributor.author |
Farooq, M |
en |
dc.contributor.author |
Maru, D |
en |
dc.contributor.author |
Diagaradjane, P |
en |
dc.contributor.author |
Matsuo, Y |
en |
dc.contributor.author |
Sinnett-Smith, J |
en |
dc.contributor.author |
Gelovani, J |
en |
dc.contributor.author |
Krishnan, S |
en |
dc.contributor.author |
Aggarwal, BB |
en |
dc.contributor.author |
Rozengurt, E |
en |
dc.contributor.author |
Ireson, CR |
en |
dc.contributor.author |
Guha, S |
en |
dc.date.accessioned |
2012-06-12T21:28:42Z |
en |
dc.date.issued |
2010-05 |
en |
dc.identifier.citation |
Molecular Cancer Therapeutics 9(5):1136-1146 May 2010 |
en |
dc.identifier.issn |
1535-7163 |
en |
dc.identifier.uri |
http://hdl.handle.net/2292/18954 |
en |
dc.description.abstract |
Protein kinase D (PKD) family members are increasingly implicated in multiple normal and abnormal biological functions, including signaling pathways that promote mitogenesis in pancreatic cancer. However, nothing is known about the effects of targeting PKD in pancreatic cancer. Our PKD inhibitor discovery program identified CRT0066101 as a specific inhibitor of all PKD isoforms. The aim of our study was to determine the effects of CRT0066101 in pancreatic cancer. Initially, we showed that autophosphorylated PKD1 and PKD2 (activated PKD1/2) are significantly upregulated in pancreatic cancer and that PKD1/2 are expressed in multiple pancreatic cancer cell lines. Using Panc-1 as a model system, we showed that CRT0066101 reduced bromodeoxyuridine incorporation; increased apoptosis; blocked neurotensin-induced PKD1/2 activation; reduced neurotensin-induced, PKD-mediated Hsp27 phosphorylation; attenuated PKD1-mediated NF-kappaB activation; and abrogated the expression of NF-kappaB-dependent proliferative and prosurvival proteins. We showed that CRT0066101 given orally (80 mg/kg/d) for 24 days significantly abrogated pancreatic cancer growth in Panc-1 subcutaneous xenograft model. Activated PKD1/2 expression in the treated tumor explants was significantly inhibited with peak tumor concentration (12 micromol/L) of CRT0066101 achieved within 2 hours after oral administration. Further, we showed that CRT0066101 given orally (80 mg/kg/d) for 21 days in Panc-1 orthotopic model potently blocked tumor growth in vivo. CRT0066101 significantly reduced Ki-67-positive proliferation index (P < 0.01), increased terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling-positive apoptotic cells (P < 0.05), and abrogated the expression of NF-kappaB-dependent proteins including cyclin D1, survivin, and cIAP-1. Our results show for the first time that a PKD-specific small-molecule inhibitor CRT0066101 blocks pancreatic cancer growth in vivo and show that PKD is a novel therapeutic target in pancreatic cancer |
en |
dc.publisher |
American Association for Cancer Research |
en |
dc.relation.ispartofseries |
Molecular Cancer Therapeutics |
en |
dc.subject |
*Carcinoma,Pancreatic Ductal/pa [Pathology] |
en |
dc.subject |
*Cell Proliferation/de [Drug Effects] |
en |
dc.subject |
*Pancreatic Neoplasms/pa [Pathology] |
en |
dc.subject |
*Protein Kinase C/ai [Antagonists & Inhibitors] |
en |
dc.subject |
*Protein Kinase Inhibitors/pd [Pharmacology] |
en |
dc.subject |
a |
en |
dc.subject |
Abnormal |
en |
dc.subject |
ACTIVATION |
en |
dc.subject |
Administration |
en |
dc.subject |
Administration,Oral |
en |
dc.subject |
Animals |
en |
dc.subject |
Antineoplastic Agents/ad [Administration & Dosage] |
en |
dc.subject |
Antineoplastic Agents/ch [Chemistry] |
en |
dc.subject |
Antineoplastic Agents/pd [Pharmacology] |
en |
dc.subject |
Antineoplastic Agents/tu [Therapeutic Use] |
en |
dc.subject |
APOPTOSIS |
en |
dc.subject |
Apoptosis/de [Drug Effects] |
en |
dc.subject |
ARE |
en |
dc.subject |
as |
en |
dc.subject |
Biological |
en |
dc.subject |
Bromodeoxyuridine |
en |
dc.subject |
Cancer |
en |
dc.subject |
Cancer Cell |
en |
dc.subject |
Cancer Growth |
en |
dc.subject |
Carcinoma,Pancreatic Ductal/dt [Drug Therapy] |
en |
dc.subject |
CELL |
en |
dc.subject |
CELL LINE |
en |
dc.subject |
Cell Line,Tumor |
en |
dc.subject |
CELL-LINE |
en |
dc.subject |
CELL-LINES |
en |
dc.subject |
CELLS |
en |
dc.subject |
CONCENTRATION |
en |
dc.subject |
CYCLIN |
en |
dc.subject |
Cyclin D1 |
en |
dc.subject |
D |
en |
dc.subject |
DISCOVERY |
en |
dc.subject |
effects |
en |
dc.subject |
Experimental |
en |
dc.subject |
EXPRESSION |
en |
dc.subject |
Family |
en |
dc.subject |
GROWTH |
en |
dc.subject |
Humans |
en |
dc.subject |
in |
en |
dc.subject |
in vitro |
en |
dc.subject |
in vivo |
en |
dc.subject |
IN-VIVO |
en |
dc.subject |
INDEX |
en |
dc.subject |
Inhibitor |
en |
dc.subject |
KINASE |
en |
dc.subject |
LINES |
en |
dc.subject |
Male |
en |
dc.subject |
MICE |
en |
dc.subject |
Mice,Nude |
en |
dc.subject |
MODEL |
en |
dc.subject |
Molecular Weight |
en |
dc.subject |
Multiple |
en |
dc.subject |
Oral |
en |
dc.subject |
P |
en |
dc.subject |
Pancreatic |
en |
dc.subject |
pancreatic cancer |
en |
dc.subject |
Pancreatic Neoplasms/dt [Drug Therapy] |
en |
dc.subject |
PATHWAY |
en |
dc.subject |
Phosphorylation |
en |
dc.subject |
PROGRAM |
en |
dc.subject |
proliferation |
en |
dc.subject |
PROTEIN |
en |
dc.subject |
Protein Kinase Inhibitors/ad [Administration & Dosage] |
en |
dc.subject |
Protein Kinase Inhibitors/ch [Chemistry] |
en |
dc.subject |
Protein Kinase Inhibitors/tu [Therapeutic Use] |
en |
dc.subject |
PROTEIN-KINASE |
en |
dc.subject |
Proteins |
en |
dc.subject |
Pyrimidines/pd [Pharmacology] |
en |
dc.subject |
Pyrimidines/tu [Therapeutic Use] |
en |
dc.subject |
Targeting |
en |
dc.subject |
ther |
en |
dc.subject |
THERAPEUTICS |
en |
dc.subject |
Time |
en |
dc.subject |
TUMOR |
en |
dc.subject |
Tumor Growth |
en |
dc.subject |
XENOGRAFT |
en |
dc.subject |
Xenograft Model Antitumor Assays |
en |
dc.title |
A novel small-molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo. |
en |
dc.type |
Journal Article |
en |
dc.identifier.doi |
10.1158/1535-7163.MCT-09-1145 |
en |
pubs.issue |
5 |
en |
pubs.begin-page |
1136 |
en |
pubs.volume |
9 |
en |
dc.rights.holder |
Copyright: American Association for Cancer Research |
en |
dc.identifier.pmid |
20442301 |
en |
pubs.end-page |
1146 |
en |
dc.rights.accessrights |
http://purl.org/eprint/accessRights/RestrictedAccess |
en |
pubs.subtype |
Article |
en |
pubs.elements-id |
202013 |
en |
pubs.org-id |
Medical and Health Sciences |
en |
pubs.org-id |
Medical Sciences |
en |
pubs.org-id |
Pharmacology |
en |
pubs.org-id |
Science |
en |
pubs.org-id |
Science Research |
en |
pubs.org-id |
Maurice Wilkins Centre (2010-2014) |
en |
pubs.record-created-at-source-date |
2011-01-26 |
en |
pubs.dimensions-id |
20442301 |
en |