title: Purine nucleoside analog--sulfinosine modulates diverse mechanisms of cancer progression in multi-drug resistant cancer cell lines.
abstract: Achieving an effective treatment of cancer is difficult, particularly when resistance to conventional chemotherapy is developed. P-glycoprotein (P-gp) activity governs multi-drug resistance (MDR) development in different cancer cell types. Identification of anti-cancer agents with the potential to kill cancer cells and at the same time inhibit MDR is important to intensify the search for novel therapeutic approaches. We examined the effects of sulfinosine (SF), a quite unexplored purine nucleoside analog, in MDR (P-gp over-expressing) non-small cell lung carcinoma (NSCLC) and glioblastoma cell lines (NCI-H460/R and U87-TxR, respectively). SF showed the same efficacy against MDR cancer cell lines and their sensitive counterparts. However, it was non-toxic for normal human keratinocytes (HaCaT). SF induced caspase-dependent apoptotic cell death and autophagy in MDR cancer cells. After SF application, reactive oxygen species (ROS) were generated and glutathione (GSH) concentration was decreased. The expression of key enzyme for GSH synthesis, gamma Glutamyl-cysteine-synthetase (γGCS) was decreased as well as the expression of gst-π mRNA. Consequently, SF significantly decreased the expression of hif-1α, mdr1 and vegf mRNAs even in hypoxic conditions. SF caused the inhibition of P-gp (coded by mdr1) expression and activity. The accumulation of standard chemotherapeutic agent--doxorubicin (DOX) was induced by SF in concentration- and time-dependent manner. The best effect of SF was obtained after 72 h when it attained the effect of known P-gp inhibitors (Dex-verapamil and tariquidar). Accordingly, SF sensitized the resistant cancer cells to DOX in subsequent treatment. Furthermore, SF decreased the experssion of vascular endothelial growth factor (VEGF) on mRNA and protein level and modulated its secretion. In conclusion, the effects on P-gp (implicated in pharmacokinetics and MDR), GSH (implicated in detoxification) and VEGF (implicated in tumor-angiogenesis and progression) qualify SF as multi-potent anti-cancer agent, which use must be considered, in particular for resistant malignancies.
authors: Faculty of Medicine, University of Belgrade, Doktora Subotića 8, Belgrade, Serbia.
authors: Mirjana
authors: M
authors: Dačević
authors: Aleksandra
authors: A
authors: Isaković
authors: Ana
authors: A
authors: Podolski-Renić
authors: Andelka M
authors: AM
authors: Isaković
authors: Tijana
authors: T
authors: Stanković
authors: Zorica
authors: Z
authors: Milošević
authors: Ljubisav
authors: L
authors: Rakić
authors: Sabera
authors: S
authors: Ruždijić
authors: Milica
authors: M
authors: Pešić
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004317:Doxorubicin / Q000008:administration & dosage; D018432:Drug Resistance, Multiple / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005909:Glioblastoma / Q000188:drug therapy*; D005721:Glutamate-Cysteine Ligase / Q000378:metabolism; D005978:Glutathione / Q000096:biosynthesis; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D011684:Purine Nucleosides / Q000008:administration & dosage*; D017382:Reactive Oxygen Species / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011684:Purine Nucleosides; D017382:Reactive Oxygen Species; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C063871:sulfinosine; D004317:Doxorubicin; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione