Gemcitabine is currently the best treatment available for pancreatic cancer, but the disease develops resistance to the drug over time. Agents that can either enhance the effects of gemcitabine or overcome chemoresistance to the drug are needed for the treatment of pancreatic cancer. Curcumin, a component of turmeric (Curcuma longa), is one such agent that has been shown to suppress the transcription factor nuclear factor-KB (NF-KB), which is implicated in proliferation, survival, angiogenesis, and chemoresistance. In this study, we investigated whether curcumin can sensitize pancreatic cancer to gemcitabine in vitro and in vivo. In vitro, curcumin inhibited the proliferation of various pancreatic cancer cell lines, potentiated the apoptosis induced by gemcitabine, and inhibited constitutive NF-KB activation in the cells. In vivo, tumors from nude mice injected with pancreatic cancer cells and treated with a combination of curcumin and gemcitabine showed significant reductions in volume (P = 0.008 versus control; P = 0.036 versus gemcitabine alone), Ki-67 proliferation index (P = 0.030 versus control), NF-KB activation, and expression of NF-KB-regulated gene products (cyclin D1, c-myc, Bcl-2, Bcl-xL, cellular inhibitor of apoptosis protein-1, cyclooxygenase-2, matrix metalloproteinase, and vascular endothelial growth factor) compared with tumors from control mice treated with olive oil only. The combination treatment was also highly effective in suppressing angiogenesis as indicated by a decrease in CD31 + microvessel density (P = 0.018 versus control). Overall, our results suggest that curcumin potentiates the antitumor effects of gemcitabine in pancreatic cancer by suppressing prolifera-

A small rise in tumor temperature (hyperthermia) makes cancer cells more susceptible to radiation and chemotherapy. The means of achieving this is not trivial, and traditional methods have certain drawbacks. Loading tumors with systematically asministered energy-transducing nanoparticles can circumvent several of the obstacles to achieve tumor hyperthermia. However, nanoparticles also face unique challenges prior to clinical implementation. This article summarizes the state-of-the-art current technology and discusses the advantages and challenges of the three major nanoparticle formulations in focus: gold nanoshells and nanorods, superparamagnetic iron oxide particles and carbon nanotubes.

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-κB activation; and abrogated the expression of NF-κB-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 μmol/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-κB-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. ©2010 AACR.

Neutrophil gelatinase-associated lipocalin (NGAL) is a 25-kDa secreted acute phase protein, which is also up-regulated in multiple cancers, including breast, lung, and pancreas. Recently, NGAL has been proposed as an early biomarker in pancreatic cancer (PaCa). However, its biological role in PaCa is unknown. In this study, we examined in vitro and in vivo the functional role of NGAL in PaCa. Well-to moderately differentiated PaCa cells (AsPC-1, BxPC-3, and Capan-2) expressed high levels of NGAL but moderately to poorly differentiated PaCa cells (PANC-1 and MIAPaCa-2) expressed undetectable NGAL levels. Immunohistochemistry of untreated tissue microarray showed specific NGAL staining in resected PaCa specimens (P = 0.0167). Stable NGAL overexpression (MIAPaCa-2 and PANC-1) significantly blocked PaCa cell adhesion and invasion in vitro and vice versa with stable PaCa clones (BxPC-3 and AsPC-1). Moreover, NGAL overexpression reduced focal adhesion kinase (FAK) tyrosine-397 phosphorylation in PaCa cells. Furthermore, NGAL overexpression potently decreased angiogenesis in vitro partly through reduced vascular endothelial growth factor (VEGF) production and vice versa. Stable NGAL overexpression or underexpression had no effect on PaCa cell survival, viability, and response to chemotherapeutic drugs. Finally, MIAPaCa-2 cells overexpressing NGAL reduced tumor volume (P = 0.012), local and distant metastasis (P = 0.002), and angiogenesis (P = 0.05) with no effect on K-67 proliferation index (P > 0.1) in an orthotopic nude mouse PaCa model. Collectively, our results suggest that NGAL reduces adhesion/invasion partly by suppressing FAK activation and inhibits angiogenesis partly by blocking VEGF production in PaCa cells. Thus, NGAL is a potential suppressor of invasion and angiogenesis in advanced PaCa. [Cancer Res 2008;68(15):6100-8]

We report noninvasive modulation of in vivo tumor radiation response using gold nanoshells. Mild-temperature hyperthermia generated by near-infrared illumination of gold nanoshell-laden tumors, noninvasively quantified by magnetic resonance temperature imaging, causes an early increase in tumor perfusion that reduces the hypoxic fraction of tumors. A subsequent radiation dose induces vascular disruption with extensive tumor necrosis. Gold nanoshells sequestered in the perivascular space mediate these two tumor vasculature-focused effects to improve radiation response of tumors. This novel integrated antihypoxic and localized vascular disrupting therapy can potentially be combined with other conventional antitumor therapies.