Pyrazolotriazolopyrimidine derivatives sensitize melanoma cells to the chemotherapic drugs: taxol and vindesine.
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.
Merighi
Stefania
S
Department of Clinical and Experimental Medicine, Pharmacology Unit, University of Ferrara, 44100 Ferrara, Italy.
Mirandola
Prisco
P
Varani
Katia
K
Gessi
Stefania
S
Capitani
Silvano
S
Leung
Edward
E
Baraldi
Pier Giovanni
PG
Tabrizi
Mojgan Aghazadeh
MA
Borea
Pier Andrea
PA
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*
D000970:Antineoplastic Agents; D058915:Purinergic P1 Receptor Antagonists; C477655:Pyrazolotriazolopyrimidine; D011743:Pyrimidines; D043684:Receptor, Adenosine A3; D014230:Triazoles; D017239:Paclitaxel; D014751:Vindesine