New pyrazolo[3,4-d]pyrimidine derivatives reverse multidrug resistance in cancer cells by inhibiting P-glycoprotein activity
2020
Аутори:
Podolski-Renić, AnaDinić, Jelena
Stanković, Tijana
Dragoj, Miodrag
Jovanović, Mirna
Jovanović Stojanov, Sofija
Pešić, Milica
Тип документа:
Конференцијски прилог (Објављена верзија)
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© 2020 by the COST Action CA17104
Метаподаци
Приказ свих података о документуАпстракт:
Multidrug resistance (MDR) represents the leading cause of cancer treatment failure. One of the main causes of MDR is overexpression of P-glycoprotein (P-gp). As a member of the ATP-binding cassette (ABC) transporter family, P-gp is responsible for reduced intracellular accumulation of both targeted therapies and classic chemotherapeutics. Tyrosine kinase inhibitors (TKIs) have been reported to interact with ABC transporters either as their substrates or inhibitors depending on the concentration range applied. We have investigated the anticancer potential of novel TKIs pyrazolo[3,4- d]pyrimidines and their prodrugs against two pairs of sensitive and MDR cancer cell lines with P-gp overexpression: nonsmall cell lung carcinoma (NCI-H460 and NCI-H460/R) and colorectal carcinoma (DLD1 and DLD1-TxR). The tested
compounds displayed significant cell growth inhibition that was not compromised by the MDR phenotype. Treatment with the compounds inhibited P-gp activity in concentration- and time-dependent manneras revealed by the increase in accumulation of the P-gp substrate rhodamine 123. TKIs directly interacted with P-gp and inhibited its ATPase activity. The investigated pyrazolo[3,4-d]pyrimidines enhanced the efficacy of doxorubicin and paclitaxel in MDR cancer cells. The potential for reversing P-gp-mediated MDR makes investigated TKIs prospective candidates for further development regarding the treatment of resistant cancers.
У:
- Abstract book: STRATAGEM CA17104: New diagnostic and therapeutic tools against multidrug resistant tumours: Annual conference 3rd MC meeting and 4th WGs meeting; 2020 Feb 27-28; Belgrade, Serbia. COST Action CA17104; 2020. p. 50.