A Novel Small-Molecule Inhibitor of Protein Kinase D Blocks Pancreatic Cancer Growth In vitro and In vivo

被引：141

作者：

Harikumar, Kuzhuvelil B. ^{[2
]}

Kunnumakkara, Ajaikumar B. ^{[2
]}

Ochi, Nobuo

Tong, Zhimin

Deorukhkar, Amit ^{[3
]}

Sung, Bokyung ^{[2
]}

Kelland, Lloyd ^{[7
]}

Jamieson, Stephen ^{[7
]}

Sutherland, Rachel ^{[7
]}

Raynham, Tony ^{[7
]}

Charles, Mark ^{[7
]}

Bagherzadeh, Azadeh ^{[7
]}

Foxton, Caroline ^{[7
]}

Boakes, Alexandra ^{[7
]}

Farooq, Muddasar ^{[7
]}

Maru, Dipen ^{[4
]}

Diagaradjane, Parmeswaran ^{[3
]}

Matsuo, Yoichi

Sinnett-Smith, James ^{[6
]}

Gelovani, Juri ^{[5
]}

Krishnan, Sunil ^{[3
]}

Aggarwal, Bharat B. ^{[2
]}

Rozengurt, Enrique ^{[6
]}

Ireson, Christopher R. ^{[7
]}

Guha, Sushovan ^{[1
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Gastroenterol Hepatol & Nutr, Unit 436, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Expt Therapeut, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Radiat Oncol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Expt Diagnost Imaging, Houston, TX 77030 USA

[6] Univ Calif Los Angeles, David Geffen Sch Med, Dept Med, Div Digest Dis, Los Angeles, CA 90095 USA

[7] Wolfson Inst Biomed Res, Canc Res Technol Discovery Labs, London WC1E 6BT, England

来源：

MOLECULAR CANCER THERAPEUTICS | 2010年 / 9卷 / 05期

关键词：

NF-KAPPA-B; CELL-LINE PANC-1; G(Q)-COUPLED RECEPTORS; TRANSCRIPTION FACTOR; DNA-SYNTHESIS; D ACTIVATION; P38; MAPK; CARCINOMA; PHOSPHORYLATION; PROLIFERATION;

D O I：

10.1158/1535-7163.MCT-09-1145

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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-.B activation; and abrogated the expression of NF-.B-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 mu mol/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 Ki67 -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-.B -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. Mol Cancer Ther; 9(5); 1136 -46. c 2010 AACR.

引用

页码：1136 / 1146

页数：11

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