INVESTIGATION OF THE EFFECTS OF MITOTAN AND STREPTOZOTOCIN USED IN ADRENOCORTICAL CARCINOMA ON MODEL MEMBRANES AT THE MOLECULAR LEVEL USING BIOPHYSICAL TECHNIQUES

Project no. 23979 · Status: Kapanmış (Yayın bekleniyor) · 2022

Summary

In this study, it was planned to study the molecular-level effects of mitotane (O,P'DDD) and streptozocin, cancer drugs used in adrenocortical carcinoma, using DPPC (Dipalmitoyl phosphatidylcholine) model membranes, one of the most abundant lipids in biological membranes, using spectroscopic and calorimetric methods.Cancer ranks second in the ranking of fatal diseases worldwide. Therefore, cancer is a serious problem that affects the health of all human societies. (Hassanpour and Dehghani, 2017). The best way to fight cancer is to prevent cancer before it occurs by controlling known risk factors (Erdem et al., 2013). The metabolism of cancer cells is different from most normal cells, but it is not fully understood how to use this difference for patient benefit. Cancer cells need altered metabolism to efficiently incorporate nutrients into biomass and support abnormal proliferation. Cells have developed complex regulatory mechanisms to adapt metabolism to suit physiological situations (Heiden, 2013). In order to better understand the effects of cancer and to advance studies in this field, it is very important to analyze and understand biological membranes well.Biological membranes, along with protecting the cell, also play an important role in the control and transportation of nutrients. Many mechanisms such as molecular recognition, enzymatic catalysis, cellular adhesion and membrane fusion are involved in biological membranes (Eeman and Deleu, 2010). Although biomembranes are usually impervious to large or highly charged molecules, cell-penetrating peptides have shown the capacity to mediate the intracellular transmission of a wide variety of exogenously charged molecules, especially peptides and proteins (Cardoso et al., 2011). Biological membranes are complex systems containing lipids, proteins and carbohydrates (Ergun et al. 2014). The lip Decit content differs between tissues and depends on the physiological function of the cell. For example, mobile lymphocytes are characterized by a low cholesterol level and a high unsaturated lipid content (Szlasa and Zendran,2020). Cell or plasma membranes are the first cellular barriers faced by extracellular ions, molecules, lipid vesicles and globules, viruses and other cells. Cell membrane interactions with extracellular molecules determine how individual cells process nutrients, initiate cellular signaling, and respond to and maintain normal cellular physiology (Nicolson and Mattos, 2021).Mitotane (O, P'DDD) is an adrenolytic drug recommended for the treatment of primary and recurrent adrenocortical carcinoma (ACC). Although it has had limited success, pharmacological options for better efficacy are not yet available. In 2002, the European Commission granted the drug orphan designation under the trade name Lysodrene, based on the low prevalence of the disease. The question remains whether the continued use of mitotane helps disease-free and overall survival in patients with low grade and radically operated. Mitotane sensitivity varies greatly between species, but there is a relationship between morphological and functional toxic effects (Waszut Dec Dec et al. ,2017). Mitotane is the only approved drug for the treatment of adrenocortical carcinoma and is used for both adjuvant therapy and advanced disease, although its effectiveness has never been demonstrated in a randomized trial (Fassnacht et al. 2012).About 40% of mitotan is absorbed by the gastrointestinal tract, and a significant amount of it is distributed to fat. After a normal daily dose of 5 to 15 g / d, plasma levels range from 0 to 90mg / L. Regular doses of more than 20 g cause neurological side effects, which can be repeated with the normalization of the level in the blood plasma. Some studies have evaluated the effectiveness of mitota as an adjuvant therapy or as a single treatment for advanced ACC or in combination with chemotherapy (Else et al., 2014).Streptozotocin (Streptozocin, STZ, CAS No.18883-66-4) is a monofunctional nitroside derivative isolated from Streptomyces achromogenes. It has also been synthesized by three different procedures (tetra-O-acetyl glucosamine hydrochloride, d-glucosamine + N-nitrosomethyl carbamoyl-azide, d-glucosamine N-methylurea). Streptozocin is a member of a group of alkylating antineo plastic drugs known as alkylnitrosoureas, which contain 1,3-bis (2-chloroethyl)-1-N. It is clinically active against a wide range of tumor types, including small cell lung cancer, lymphomas, mycosis fungoides, multiple myeloma, glioma, and malignant melanoma and adrenocortical carcinoma. However, these agents are not considered curative therapy (Bolzán and Bianchi, 2002).Adrenocortical carcinoma is a rare type of cancer that is malignant. The 5-year survival rate of patients with metastatic disorders is less than 15%. These tumors lead to gynecomastia and testicular atrophy. Non-specific symptoms such as fever, weight loss and loss of appetite are less typical in patients with ACC.In fact, patients can carry a large tumor burden without signs and symptoms of hormone excess, as well as evidence of systemic disease (Fassnacht and Allolio, 2009).Although mitotane and streptozotocin are clinically effective in adenocortical carcinoma, their effects at the molecular level are not yet known. For this reason, in this study, it was planned to study the changes in the effects of these agents used in adrenocortical carcinoma in terms of membrane layout and fluidity, structure and phase transitions depending on concentration and temperature.All these examinations will be carried out using Differential Scanning Calorimeter (DSC) and Fourier Transform Infrared (FTIR) techniques.DSC is the experimental technique of choice for systematically characterizing the thermodynamics of phase transitions and conformational changes of biological macromolecules and supramolecular structures (Giatrellis and Nounesis, 2022). Fourier transform infrared (FTIR) spectroscopy is a powerful technique for investigating the structure of such systems. This technique has proven to be useful in characterizing SC phase transitions. Stratum corneum (SC), the upper part of the epidermis layer, is a biomaterial with vital functions. (Corbe et al., 2007).

View details