Abstract
Abstract Brain tumors are highly aggressive and often afflict younger patients. In 2011 there were 22,340 estimated new cases of brain tumors in the United States with 40% arising from metastatic lesions originating mostly from lung, breast, and melanoma tumors. Treatment options remain limited and include steroids, whole brain radiation, and surgery. Because of difficulty penetrating the blood-brain barrier (BBB), chemotherapy is usually not a viable option. Therefore, any intervention that can block the malignant colonization of the brain and/or eliminate symptomatic and occult brain lesions will significantly improve both quality of life and survival. To target brain tumors, a successful therapy has to meet the following criteria: 1) penetrate the BBB; 2) exhibit specificity for the tumor cells; and 3) have minimal off-target effects. Here we investigate a Periwinkle minor derived natural product, eburnamonine (EBN), and its structural analog, 15-methylene-(-)-eburnamonine (15-M-EBN), as therapeutic agents against brain lesions from glioblastoma multiforme and metastatic breast cancer. The two common subtypes of breast tumors giving rise to brain metastases are triple negative and Her2 positive primary tumors. Potency of EBN and 15-M-EBN was evaluated in cultures of chemosensitive (U87) and chemoresistant (SF767) glioma cell lines and ‘brain-seeking’ metastatic breast cancer cells, MDA-MB-231BR (triple negative) and MDA-MB-231BR-Her2 (Her2 positive). To test whether our compounds can overcome the environment-mediated drug resistance (EM-DR) cells were treated in the context of extracellular matrix (ECM) (hyaluronic acid, collagen IV/laminin, and collagens I and IV/laminin/fibronectin to reconstruct the brain, mammary gland, and bone marrow microenvironments respectively). The off-target toxicity of EBN and 15-M-EBN was tested on normal neuronal cells, bone marrow stromal cells, and non-malignant mammary epithelial cells. To evaluate the capacity of EBN and 15-M-EBN to penetrate the BBB, we utilized a transwell model with hCMEC/D3 cell monolayer mimicking the BBB. We demonstrate that EBN and 15-M-EBN are cytotoxic against glioma and ‘brain-seeking’ metastatic breast cancer cells (LC50=42 micromolar and 14 micromolar respectively) with minimal toxicity against non-malignant cells. Moreover, 15-M-EBN is active in the tumor environment and predicted to cross the BBB and have anti-cancer stem cell activity. Our preclinical data establish that 15-M-EBN meets the major criteria for a successful therapeutic agent to target brain lesions, both primary and metastatic, due to its ability to: 1) exhibit specificity for the tumor cells; 2) have minimal neurotoxicity and off-target effects; and 3) penetrate the BBB. In vivo studies are in progress to establish a pro-drug strategy to increase water solubility and bioavailability of 15-M-EBN for further clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1984. doi:1538-7445.AM2012-1984
Published Version
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