EF24, a Curcumin Analogue Inhibits the Migration and Invasion of Highly Metastatic Breast Cancer Cells

In 2011, American Cancer Society reported that about 230,000 women were diagnosed with breast cancer in the US, and among them 40,000 died. This disease targets women of all ages and races, and although survival rates have increased recently, it is still a huge problem that influences the lives of millions of people. In case of non-metastatic breast cancers, patients are usually responsive to various treatments, but in patients with metastatic breast cancer the current medications are not fully effective. The goal of the current study is to evaluate the efficacy of a newly synthesized anti-cancer agent, EF-24, on metastatic breast cancer cells. To accomplish this, we have selected two breast cancer cell lines e.g., MDA-MB-231 and LM 2-4. While MDA-MB-231 cells were derived from patient with highly metastatic breast cancer, LM 2-4 cells were lung cancer cells metastasized by MDA-MB-231. The effectiveness of EF 24 was compared with various anti-carcinogens such as eicosapantaenoic acid (EPA found in fish oil), cisplatin (a common chemotherapeutic drug), ICI (fulvestrant, an estrogen receptor antagonist) MBCD (methyl-b-cyclodestrin, an inhibitor that binds to cholesterol), AACOCF3 (arachidonoyl-trifluoroketone, a cytoplasmic phospholipase A2 inhibitor) and NS-398 (anti-inflammatory drug). It was observed that among all the inhibitors, EF24 was most effective in arresting the migration and invasion of MDA-MB-231 and LM 2-4 with an inhibition of about ~65% for MDA-MB-231 and ~85% for LM 2-4. These results suggest that EF-24 should be considered as a new potential drug to treat patients with aggressive breast cancers

Evaluating Ceramide Analogs, 5-lipoxygenase expression, and lipid raft Biology in Breast Cancer

To investigate the role of lipid rafts in the biology of breast cancer cells, we designed a human breast cancer cell line panel (using MCF-7, MDA-MB-231, and HCC1419 cells) to test the anti-tumor impact of new ceramide analogs. Our aim is to use such a screening to ultimately develop a project to investigate the role of 5-lipoxygenase enzyme on the behavior of breast cancer cells, including MDA-MB231 that express 5-lipoxygenase and MCF-7 which do not, and to ask whether ceramide analogs can have an impact on this behavior. To date, we have evaluated three ceramide analogs, termed C2, C6 and C8, on two of the cell lines in our panel, as part of our ongoing study. C2 and C8 were found to produce massive cell death in MDA-231 and in HCC1419 breast cancer cells when the drugs were administered for 4 days at a concentration of 50 micromolar. C6 was found to be even more potent, producing massive cell death at 25 micromolar in the same assay. Our results show that ceramide analogs have potent cytotoxic effect on breast cancer cells. We will present the results of our ongoing studies, as well as an outline of our overall project to incorporate modulation of 5-lipoxygenase on the ability of breast cancer cells to migrate and to invade. The possible link between 5-lipoxygenase expression and ceramide analog treatment as a possible chemotherapeutic agent against breast cancer cell will be discussed

Glucosylceramide Transferase Activity is Critical for Encystation and Viable Cyst Production by an Intestinal Protozoan, Giardia lamblia

The production of viable cysts by Giardia is essential for its survival in the environment and spreading the infection via contaminated food and water. The hallmark of cyst production (also known as encystation) is the biogenesis of encystation-specific vesicles (ESVs) that transport cyst-wall proteins to trophozoite’s plasma membrane before laying down the protective cyst wall. However, the molecules that regulate ESV biogenesis and maintain cyst viability have never before been identified. Here, we report that giardial glucosylceramide transferase-1 (gGlcT1), an enzyme of sphingolipid biosynthesis, plays a key role in ESV biogenesis and maintaining cyst viability. We find that overexpression of this enzyme induced the formation of aggregated/enlarged ESVs and generated clustered cysts with reduced viability. The silencing of gGlcT1 synthesis by anti-sense morpholino oligonucleotide abolished ESV production and generated mostly non-viable cysts. Interestingly, when gGlcT1-overexpressed Giardia was transfected with anti-gGlcT1 morpholino, the enzyme activity, vesicle biogenesis, and cyst viability returned to normal, suggesting that the regulated expression of gGlcT1 is important for encystation and viable cyst production. Furthermore, the overexpression of gGlcT1 increased the influx of membrane lipids and fatty acids without altering the fluidity of plasma membranes, indicating that the expression of gGlcT1 activity is linked to lipid internalization and maintaining the overall lipid balance in this parasite. Taken together, our results suggest that gGlcT1 is a key player of ESV biogenesis and cyst viability and therefore could be targeted for developing new anti-giardial therapie