![]() These conjugates have a longer plasma half-life and a higher bioavailability (Engelbrecht 2011). 2009).Ĭonjugation of drug with fatty acids increases its lipid solubility what facilitates permeation into the cell membrane. It is known that they inhibit the formation of the tumor growth promotor 13-hydroxy-octadecadienoic acid (13-HODE) and they have a cardioprotective effect, which can reduce the cardiotoxicity of DOX (Sauer et al. They can play an important role in delay of the cancer progression by modulating hormone receptors, Akt kinase, and nuclear factors к B as well as being the target for ROS (Das 2004 Narayanan et al. ω-3 fatty acids (e.g., DHA) can bind to cognate receptors on cancer cells and then exert a targeting effect (Sauer et al. The most important ω-3 PUFAs are: α-linolenic ( cis-9,12,15-octadecatrienoic, LNA) and cis-7,7,10,13,16,19-docosahexaenoic (DHA). In addition, compared with normal cells, PUFAs are more avidly taken up by tumor cells (Sauer et al. One of the most important compounds that affect cell metabolism are polyunsaturated fatty acids (PUFAs). They display uncontrolled growth and usually require a large amount of various nutrients (Jaracz et al. It is well known that cancer cells differ from normal cells. ![]() To design a tumor-targeting drug, it is crucial to understand the tumor cell microenvironment. The improvement in the effectiveness of anticancer properties of DOX though conjugation or derivatization could be an alternative option to reduce time and costs required to develop a new anticancer agent (Hidayat et al. The use of DOX is associated with very high risks, such as cardiomyopathy and congestive heart failure (Lenaz and 6 Weiss 1992 Johnson et al. 2003) and binding to lipids in cell membrane resulting in the changes of its permeability (Pessah et al. The anticancer action of DOX is also mediated by chelating of iron, zinc and copper ions, formation of reactive oxygen species (ROS) (Minotti et al. 1975), or topoisomerase II (Binaschi et al. 1981), inhibition of RNA and DNA polymerases (Zunina et al. These compounds can act independently or in combination with other medicines (combined therapy) and can be used in treatment of cancer diseases (Xu and Mao 2016 Narang and Desai 2009).ĭoxorubicin (DOX) is a multidirectional chemotherapy agent (Gewirtz 1999), which mechanism of action includes intercalation and alkylation of DNA (Young et al. Availability of new technologies related to research on tumor pathogenesis designated new strategies of searching active compounds, which can be used as medications. ![]() Nowadays many different active substances are used to inhibit the proliferation of cancer cells, but still there is a need to find substances, which act specifically as anticancer factors. They show high cytotoxicity toward the tumor cell lines and moderate cytotoxicity towards the normal cell line.Īpplication of chemotherapy seems to be crucial in the fight against cancer diseases. Among the all derivatives, the conjugates formed by the amide and ester linkages ( 4, 5) were found to be more promising compared with conjugates ( 2, 3) formed only by the amide linkage. We found that all studied conjugates exhibit lower cytotoxicity but higher selectivity than DOX. To explain the basic mechanism of cell death induction the Annexin V-FITC/IP flow cytometry analysis was investigated. Lactate dehydrogenase (LDH) assay was performed for all compounds to assess the level of cell damage. In addition, a cytotoxic capacity against tumor cells for tested compounds was expressed as a selectivity factor (selectivity index, SI). The cytotoxic activity was established by calculation of the inhibitory concentration IC 50. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effect on human cancer cell lines (SW480, SW620, and PC3) and Chinese hamster lung fibroblasts (V79) that were used as a control. The structures of the compounds were confirmed by Proton Nuclear Magnetic Resonance (1H NMR), Carbon-13 Nuclear Magnetic Resonance (13C NMR), and High Resolution Mass Spectrometry (HRMS) analyses. In our work, we obtained amide derivatives of DOX by reaction of the amino group with α-linolenic (LNA) and docosahexaenoic (DHA) acids ( 2, 3), as well as double-substituted derivatives via amide and ester linkages ( 4, 5). We are still looking for methods that will allow us to preserve the therapeutic effect against the tumor cells and reduce the toxicity to the normal cells. Doxorubicin (DOX) is a leading cytostatic drug with many adverse effects in use.
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