A novel small-molecule inhibitor of protein kinase D blocks pancreatic cancer growth in vitro and in vivo.

Show simple item record

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

Files in this item

There are no files associated with this item.

Find Full text

This item appears in the following Collection(s)

Show simple item record


Search ResearchSpace