title: Pyrazolotriazolopyrimidine derivatives sensitize melanoma cells to the chemotherapic drugs: taxol and vindesine.
abstract: In this study, we have evaluated the "in vitro" modulatory activity of a series of pyrazolotriazolopyrimidine derivatives (PTP-d) in sensitizing malignant melanoma cells to the chemotherapic drugs: taxol and vindesine. To that end, we have described the impact of chemotherapeutic agents on the cell cycle and on the induction of apoptosis when used alone or in combination with PTP-d. We have demonstrated that four PTP-d reduced chemotherapic drugs EC(50) doses of the G(2)/M accumulation with an average of 1.7-fold for taxol and 9.5-fold for vindesine when challenged on A375 human melanoma cell line. This sensitization activity was also confirmed by analyzing the apoptosis degree induced by the chemotherapic drugs. Interestingly, PTP-d had no effects on the response to cytotoxic agents by skin-derived human keratinocyte cells, NCTC 2544. Therefore, we have investigated the signaling pathway sustaining the sensitizing effect of PTP-d, providing functional evidence that active compounds are able to inhibit multidrug resistance-associated ATP-binding cassette drug transporter. These results suggested that PTP-d hold great promise for the treatment of multidrug resistance in cancers, leading to potential new therapies for melanoma.
authors.affiliation: Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, 44100 Ferrara, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Merighi
authors.forename: Prisco
authors.initials: P
authors.lastname: Mirandola
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Stefania
authors.initials: S
authors.lastname: Gessi
authors.forename: Silvano
authors.initials: S
authors.lastname: Capitani
authors.forename: Edward
authors.initials: E
authors.lastname: Leung
authors.forename: Pier Giovanni
authors.initials: PG
authors.lastname: Baraldi
authors.forename: Mojgan Aghazadeh
authors.initials: MA
authors.lastname: Tabrizi
authors.forename: Pier Andrea
authors.initials: PA
authors.lastname: Borea
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects / Q000473:pathology; D008545:Melanoma / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D058915:Purinergic P1 Receptor Antagonists; D011743:Pyrimidines / Q000494:pharmacology*; D043684:Receptor, Adenosine A3; D014230:Triazoles / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014751:Vindesine / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D058915:Purinergic P1 Receptor Antagonists; C477655:Pyrazolotriazolopyrimidine; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles; D017239:Paclitaxel; D014751:Vindesine