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Broad-Spectrum G Protein–Coupled Receptor Antagonist, [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP: A Dual Inhibitor of Growth and Angiogenesis in Pancreatic Cancer

¹ Department of Medicine, Division of Digestive Diseases, and Molecular Biology Institute; ² Center for Ulcer Research and Education: Digestive Diseases Research Center, ³ Department of Medicine, Division of Pulmonary and Critical Care Medicine, and ⁴ Department of Surgery, Section of Gastrointestinal Surgery, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California

Requests for reprints: Enrique Rozengurt, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, 900 Veteran Avenue, Warren Hall Room 11-124, Los Angeles, CA 90095-1786. Phone: 310-794-6610; Fax: 310-267-2399; E-mail: erozengurt{at}mednet.ucla.edu.

Substance P analogues, including [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP (SPA) are broad-spectrum G protein–coupled receptor (GPCR) antagonists that have potential antitumorigenic activities, although the mechanism(s) are not completely understood. Here, we examined the effects of SPA in ductal pancreatic cancers that express multiple GPCRs for mitogenic agonists and also produce proangiogenic chemokines. Using HPAF-II, a well-differentiated pancreatic cancer cell line as our model system, we showed that SPA inhibited multiple neuropeptide-induced Ca²⁺ mobilization, DNA synthesis, and anchorage-independent growth in vitro. SPA also significantly attenuated the growth of HPAF-II tumor xenografts in nude mice beyond the treatment period. Interestingly, SPA markedly increased apoptosis but moderately decreased proliferation marker, Ki-67 in the tumor xenografts implying additional mechanism(s) for the significant growth inhibitory effect observed in vivo. HPAF-II cells express ELR⁺ CXC chemokines, including IL-8/CXCL8, which bind to CXCR2 (a member of GPCR superfamily) and promote angiogenesis in multiple cancers, including pancreatic cancer. SPA inhibited CXCR2-mediated Ca²⁺ mobilization and blocked specifically IL-8/CXCL8-induced angiogenesis in rat corneal micropocket assay in vivo. A salient feature of the results presented here is that SPA markedly reduced tumor-associated angiogenesis in the HPAF-II xenografts in vivo. Our results show that SPA, a broad-spectrum GPCR antagonist attenuates tumor growth in pancreatic cancer via a dual mechanism involving both the antiproliferative and antiangiogenic properties. We conclude that this novel dual-inhibitory property of SPA could be of significant therapeutic value in pancreatic cancer, when used in combination with other antiproliferative and/or antiangiogenic agents.

Key Words: [D-Arg¹,D-Trp^5,7,9,Leu¹¹]SP • Pancreatic cancer xenograft model • DNA synthesis • Anchorage-independent growth • Microvessel density • TUNEL assay

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