Enhancement of doxorubicin cytotoxicity by polyunsaturated fatty acids in the human breast tumor cell line MBA-MB-231: Relationship to lipid peroxidation

Exogenous polyunsaturated fatty acids modulate the cytotoxic activity of anti-cancer drugs. In this study, we examined whether lipid peroxidation is a potential mechanism through which fatty acids enhance drug cytotoxicity. We measured cell viability in the human breast cancer cell line MDA-MB-231 exposed to doxorubicin in the presence of non-cytotoxic concentrations of various polyunsaturated fatty acids for 6 days. To determine the role of lipid peroxidation, the hydroperoxide level was measured in cell extracts. Among all polyunsaturated fatty acids tested, docosahexaenoic acid (DHA, 22:6n-3) was the most potent in increasing doxorubicin cytotoxicity: cell viability decreased from 54% in the presence of 10⁻⁷ M doxorubicin alone to 21% when cells were incubated with doxorubicin and DHA. After addition of an oxidant system (sodium ascorbate/2-methyl-1,4-naphthoquinone) to cells incubated with doxorubicin and DHA, cell viability further decreased to 12%. Cell hydroperoxides increased commensurately. The effect of DHA on doxorubicin activity and lipid hydroperoxide formation was abolished by a lipid peroxidation inhibitor (dl-α-tocopherol) or when oleic acid (a non-peroxidizable fatty acid) was used in place of DHA. No effect was observed with mitoxantrone, a drug with a low peroxidation-generating potential. Thus, DHA may increase the efficacy of oxyradical-producing drugs through a mechanism involving a generation of lipoperoxides. This may lead in vivo to a modulation of tumor cell chemosensitivity by DHA and oxidant agents. Int. J. Cancer 75:578–583, 1998. © 1998 Wiley-Liss, Inc.     

Standard Operating Procedures for Anesthesia Management in Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy Improve Patient Outcomes: A Patient Cohort Analysis

Annals of Surgical Oncology - Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) offer survival benefits in well-selected patients with peritoneal tumors. The...     

The SK3/K(Ca)2.3 potassium channel is a new cellular target for edelfosine

BACKGROUND AND PURPOSE

The 1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine (edelfosine) is an ether-linked phospholipid with promising anti-cancer properties but some side effects that preclude its full clinical therapeutic exploitation. We hypothesized that this lipid could interact with plasma membrane ion channels and modulate their function.

EXPERIMENTAL APPROACH

Using cell migration-proliferation assays, patch clamp, spectrofluorimetry and ¹²⁵I-Apamin binding experiments, we studied the effects of edelfosine on the migration of breast cancer MDA-MB-435s cells, mediated by the small conductance Ca²⁺-activated K⁺ channel, SK3/K_Ca2.3.

KEY RESULTS

Edelfosine (1 µM) caused plasma membrane depolarization by substantially inhibiting activity of SK3/K_Ca2.3 channels, which we had previously demonstrated to play an important role in cancer cell migration. Edelfosine did not inhibit ¹²⁵I-Apamin binding to this SK_Ca channel; rather, it reduced the calcium sensitivity of SK3/K_Ca2.3 channel and dramatically decreased intracellular Ca²⁺ concentration, probably by insertion in the plasma membrane, as suggested by proteinase K experiments. Edelfosine reduced cell migration to the same extent as known SK_Ca channel blockers. In contrast, K+ channel openers prevented edelfosine-induced anti-migratory effects. SK3 protein knockdown decreased cell migration and totally abolished the effect of edelfosine on MDA-MB-435s cell migration. In contrast, transient expression of SK3/K_Ca2.3 protein in a SK3/K_Ca2.3-deficient cell line increased cell migration and made these cells responsive to edelfosine.

CONCLUSIONS AND IMPLICATIONS

Our data clearly establish edelfosine as an inhibitor of cancer cell migration by acting on SK3/K_Ca2.3 channels and provide insights into the future development of a new class of migration-targeted, anti-cancer agents.     

Azole resistant Aspergillus fumigatus: An emerging problem

Azole resistance has appeared recently in Aspergillus fumigatus and increased dangerously in the last decade. The main resistance mechanism is a point mutation of CYP51A, the gene encoding 14α-sterol demethylase, the target enzyme of azole antifungal drugs. This mutation can induce resistance to itraconazole alone or multi-azole resistance. CYP51A mutation can occur in two cases. The first usually concerns patients receiving long-term azole therapy, most of the time for chronic aspergillosis, and involves a wide range of mutations. The second is due to the use of azole fungicides in agriculture. The latter favors a single mutagenesis event: a substitution of leucine for histidine at codon 98 and the tandem repeat of a 34-base pair tandem sequence in the CYP51A gene promoter region. This confers cross-resistance to all azole antifungal drugs. This emerging and environmentally linked issue is of growing concern for the management of antifungal therapy. This mechanism of resistance was first described in the Netherlands and is now reported worldwide. It may have become the leading mechanism of azole resistance in A. fumigatus. Azoles are major agents for the treatment of aspergillosis, and the only oral antifungals. Infection with antifungal-resistant strains is correlated with treatment failure. This emerging phenomenon stresses the urgent need for new preventive strategies (controlled use of antifungals and azole prophylaxis), new diagnostic strategies (early detection of resistance), and new therapeutic strategies in the management of A. fumigatus infections.