Lysosomotropic cholesterol transport inhibitors as potential chemotherapeutic agents
Başlık çevirisi mevcut değil.
- Tez No: 402309
- Danışmanlar: Belirtilmemiş.
- Tez Türü: Doktora
- Konular: Radyasyon Onkolojisi, Radyoloji ve Nükleer Tıp, Radiation Oncology, Radiology and Nuclear Medicine
- Anahtar Kelimeler: Belirtilmemiş.
- Yıl: 2014
- Dil: İngilizce
- Üniversite: The Pennsylvania State University
- Enstitü: Yurtdışı Enstitü
- Ana Bilim Dalı: Tıp Bilimleri Ana Bilim Dalı
- Bilim Dalı: Belirtilmemiş.
- Sayfa Sayısı: 176
Özet
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Özet (Çeviri)
According to American Cancer Society's 2014 Cancer Facts report, cancer is the second leading cause of death in United States and over half million people are expected to die from this deadly disease. Until 2030, it is forecasted to be the primary cause of death with a 45 % increase in new cancer cases. Skin cancer is the most common form of cancer in the United States with more than 3 million cases is diagnosed, annually. Most skin cancers can be surgically removed when detected early. However, melanoma, the malignancy of pigment producing skin cells, is the most aggressive and dangerous of all skin cancers. It accounts for approximately 80% of skin cancer associated deaths. Until 2013, dacarbazine (DTIC), an alkylating chemotherapeutic agent that was approved by U.S. Food and Drug Administration (FDA) in 1975, was the most common drug used for the treatment of melanoma. Recently, targeted agents such as those targeting the MAP kinase pathway have been approved by the FDA for the treatment of melanoma. However, in nearly all cases, development of drug resistance limits the efficacy of these agents to only few months. Therefore, there is need for development of new melanoma therapeutics that have long term efficacy. Recently, we have identified Leelamine, a small natural compound as a potential chemotherapeutic agent against melanoma. Leelamine was 3 to 5 fold more effective at inhibiting viability of malignant melanoma cell lines compared to other skin cells. More importantly, leelamine showed efficacy in-vivo leading to ~60% decrease in the growth of xenografted melanoma tumors. However, very few reports were available regarding the mechanism of action of this agent. Therefore, the primary objective of my dissertation is to identify the molecular mechanisms leading to leelamine-mediated cancer cell death. Our studies suggested that as a weakly basic amine, leelamine displayed lysosomotropism that lead to its accumulation inside the acidic organelles and consequently disrupted cholesterol egress from lysosomes. Inhibition of intracellular cholesterol transport by leelamine was the leading cause of cell death. These findings led to the development of our secondary objective, which was to explore the chemotherapeutic efficacy of other potential cholesterol transport inhibitors. A class of weakly basic lysosomotropic compounds called Functional Inhibitors of Acid Sphingomyelinases (FIASMA) were identified as potential cholesterol transport inhibitors and shown to be effective against melanoma cells as well as xenografted melanoma tumors. In this dissertation, we show that as a cholesterol transport inhibitor, leelamine and several FIASMA compounds disrupt autophagic flux and inhibit receptor-mediated endocytosis resulting in the shutdown of key pathways to which melanoma cells are addicted. Inhibition of lysosomotropic accumulation of compounds by Bafilomycin-A1 co-treatment or depletion of cellular cholesterol with β-cyclodextrin co-treatment was able to attenuate the cell death mediated by these agents. This study is unique in terms of identification of FIASMA compounds as potential chemotherapeutic agents showing efficacy through inhibiting intracellular cholesterol transport. In fact, two FIASMA compounds, Perphenazine and Fluphenazine, that are generic antipsychotic drugs, led to 50 to 60% inhibition of xenografted melanoma tumor development. Since most of the FIASMA compounds were generic tricyclic antidepressants or antipsychotics with well-known toxicity profiles, the findings of this study could open new perspectives for repurposing these drugs for the treatment of advanced-stage cancers.
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