Abstract 3676: Attenuation of pancreatic cancer stemness and growth by a novel magnetic nanoparticle formulation

Abstract

Abstract Background: Pancreatic cancer (PanCa) is one of the deadliest cancers accounting for high mortality rates due to high desmoplasia and the development of chemo-resistance to chemotherapeutic drugs, such as gemcitabine (GEM). Curcumin (CUR) has showed potent anticancer, chemopreventive, chemo-sensitization properties and has entered phase II clinical trials in pancreatic adenocarcinoma patients. However, the clinical translation of CUR has been significantly hampered due to its low solubility, high rate of metabolism, poor bioavailability and pharmacokinetics. To address these clinically relevant issues, we have successfully engineered a magnetic nanoparticle formulation of curcumin (MNP-CUR) using a multi-layer approach, for its efficient and tumor targeted delivery. Methods: Western blotting and qPCR were used to investigate the effects of MNP-CUR, GEM and their combination on Hh signaling pathway and related proteins involved in PanCa. The antitumor effects were studied using PanCa xenograft mice. Tumor tissue sections were stained for SHH (sonic hedgehog) and its effector (Gli-1), cygb/STAP (stellate cell selective markers) α-SMA (PSC activation), F4/80 (macrophage) for imunohistochemistry/immunofluorescence and microRNAs through in situ hybridization. Results: MNP-CUR alone or in combination with GEM inhibits pluripotency maintaining factors (Nanog, Sox-2, c-Myc and Oct-4) in human pancreatic cancer stem cells thereby, restricts the formation of secondary mamospheres. Further investigations reveal that MNP-CUR inhibits Panca proliferation, migration, invasion and tumor growth in xenograft mouse model by suppression of the sonic hedgehog (SHH) signaling pathway and CXCR4/CXCL12 signaling axis that inhibit bidirectional tumor-stromal cells interaction. MNP-CUR treatment alone or in combination with CXCR4 antagonist (amd3100) inhibits CXCL12 induced up regulation of CXCR4, SHH and NFĸB-65 in cells. Further, qRT-PCR results showed that MNP-CUR treatment increases GEM sensitivity by up regulating the human nucleoside transporter genes (hENT, hCNT) and blocking ribonucletide reductase subunits (RRM1/RRM2) which further supports the use of MNP-CUR for suppression of PanCa growth. Immunostaining of tumor sections from treated pancreatic xenograft mice revealed that MNP-CUR treatment efficiently inhibits key proteins of SHH signaling such as SHH and Gli-1. MNP-CUR also disrupts the stroma of fibrotic pancreatic tumors by inhibiting proliferating stellate and myeloid cells. This was indicated by the decreased staining of αSMA, macrophages and cygb/STAP in tumor tissues. Additionally, the tumor tissues from MNP-CUR treated mice showed extensive downregulation of oncogenic miR-21 expression which has been associated with cancer progression and drug resistance. Conclusion: These data suggest that MNP-CUR possesses great promise as a treatment of choice for PanCa. Citation Format: Sheema Khan, Murali M. Yallapu, Sonam Kumari, Aditya Ganju, Swathi Balakrishna, Stephen W. Behrman, Nadeem Zafar, Meena Jaggi, Subhash C. Chauhan. Attenuation of pancreatic cancer stemness and growth by a novel magnetic nanoparticle formulation. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3676. doi:10.1158/1538-7445.AM2015-3676