Synthesis and anticancer effects of conjugates of doxorubicin and unsaturated fatty acids (LNA and DHA)

Abstract

Doxorubicin (DOX) is a leading cytostatic drug with many adverse effects in use. 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. 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). 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. For all compounds 3-(4,5-dimethylthiazolyl-2)-2,5diphenyltetrazolium 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 cytotoxic activity was established by calculation of the inhibitory concentration IC 50. In addition, a cytotoxic capacity against tumor cells for tested compounds was expressed as a selectivity factor (selectivity index, SI). Lactate dehydrogenase (LDH) assay was performed for all compounds to assess the level of cell damage. To explain the basic mechanism of cell death induction the Annexin V-FITC/IP flow cytometry analysis was investigated. We found that all studied conjugates exhibit lower cytotoxicity but higher selectivity than DOX. 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. They show high cytotoxicity toward the tumor cell lines and moderate cytotoxicity towards the normal cell line. Keywords Doxorubicin derivatives • Unsaturated fatty acids • Cytotoxicity • Apoptosis

Anti-Proliferative Effect of Doxorubicin-Loaded AS1411 Aptamer on Colorectal Cancer Cell

“…Moreover, cytotoxicity level of Dox reported in this work was in the same order of magnitude as the results from other research groups. For instance, after treating the cells with Dox for 24, 48, and 72 hours, the IC 50 values were 65.25 µM (Xu et al, 2003), 0.35 µM (Zhang et al, 2020b) and 0.29 µM (Mielczarek-Puta et al, 2019), respectively. This might indicate that cytotoxicity of Dox increased with the longer treatment durations.…”

An Insight into the Mechanism of Holamine- and Funtumine-Induced Cell Death in Cancer Cells

“…A high selectivity index towards cancer cells is an important consideration when assessing the medicinal and therapeutic attributes of bioactive moieties from natural sources. Compounds with high selectivity indices impart lower toxicities to the sensitive and regulated normal proliferative cell compartments in the tissue microenvironment and afford a cost-effective way to rationalize a minimum level of tumor resistance and side effects in response to chemotherapy [15]. Mitochondria play diverse and crucial roles in cell survival and death and are also critical for oncogenesis and the sustained progression of malignant cells.…”

Anti-Tumor Effects of Queen Bee Acid (10-Hydroxy-2-Decenoic Acid) Alone and in Combination with Cyclophosphamide and Its Cellular Mechanisms against Ehrlich Solid Tumor in Mice

“…[25]. Today, studies showed that adjustment of current anticancer drugs by combining these agents with some bioactive compounds can increase the tissue selectivity and may make chemotherapy considerably more effective with lower toxicity [26,27]. In this regard, a number of studies have reported the in vitro and in vivo promising effects of fatty acids which improved the efficacy of the antitumor drugs which enhance the tumor cell targeting selectivity and reduce the cytotoxic effects [25,28].…”