Effects of Isoprenoid Analogues of SDB-Ethylenediamine on Multidrug Resistant Tumor Cells Alone and in Combination with Chemotherapeutic Drugs

Abstract

Multidrug resistance (MDR) mediated by P-glycoprotein (Pgp) remains the major obstacle for successful treatment of cancer. Inhibition of Pgp transport is important for higher efficacy of anticancer drugs. Lipophilic cationogenic amines with at least one tertiary N atom, such as verapamil, are classical PgP-blocking agents. In a search for novel accessible compounds potent against MDR tumor cells, we synthesized a series of arylalkylamines that contain isoprenoid side chains of different length. Two out of seven new analogues of the known N,N'-bis(3,4-dimethoxybenzyl)-N-solanesylethylenediamine (SDB-ethylenediamine), namely, compounds with C10 and C15 side chains, at low micromolar concentrations were preferentially toxic for several mammalian tumor cell lines that acquired MDR during prolonged drug selection. Moreover, at noncytotoxic concentrations, these compounds potently sensitized MDR cells to Pgp substrates vinblastine and adriamycin. We conclude that these analogues of SDB-ethylenediamine may have dual therapeutic advantage because (i) they are preferentially toxic for MDR cells when administered alone and (ii) they potentiate the cytotoxicity of Pgp-transported anticancer drugs.

Solanesol: a review of its resources, derivatives, bioactivities, medicinal applications, and biosynthesis

“…Moreover, solanesol possesses antibacterial, antifungal, antiviral, anticancer, antiinflammatory, and anti-ulcer activities (Serebryakov Fig. 1 The chemical structures of solanesol and solanesol-like substances (SLSs) Phytochem Rev and Nigmatov 1990; Khidyrova and Shakhidoyatov 2002;Guo et al 2008;Li and Chase 2010), and solanesol derivatives have anti-oxidant and antitumour activities, as well as other bioactivities (Enokida et al 2002;Sidorova et al 2002;Zhao et al 2006a;Wang et al 2007;Abdin and Homouda 2008;Srivastava et al 2009;Bentinger et al 2010;Qin et al 2014). Solanesol derivatives can be used for the treatment of cardiovascular disease, osteoporosis, acquired immune deficiency syndrome (AIDS), and wound healing (Srivastava et al 2009;Hu and Wang 2011;Wang et al 2013a, b).…”

Novel Antitumor L‐Arabinose Derivative of Indolocarbazole with High Affinity to DNA

“…All chemicals were purchased from Sigma-Aldrich unless specified otherwise. The protocols of the assays of cell survival, [29] flow cytometry, DNA replication, b-galactosidase reporter activity and topo I uncoiling are presented in the Supporting Information. In all experiments each drug concentration was tested in three independent trials.…”

Olivomycin Induces Tumor Cell Apoptosis and Suppresses p53-Induced Transcription

“…The range of cytotoxic concentrations for OM and olivin was evaluated by cell capacity to reduce 3-(4,5-dimethylthiasol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2P-tetrazolium salt to formazan (MTT test) [8]. The cells were incubated with OM or olivin in 96-well plates (5×10 4 cells/well) for 72 h at 37 o C and 5% CO 2 .…”