Novel pyrazolo[3,4-d]pyrimidine derivatives supress P-glycoprotein activity and reverse multidrug resistance in cancer cells
2019
Аутори:
Dinić, JelenaPodolski-Renić, Ana
Stanković, Tijana
Botta, Maurizio
Pešić, Milica
Остала ауторства
Saksida, TamaraSuzana, Stanisavljević
Đorđe, Miljković
Тип документа:
Конференцијски прилог (Објављена верзија)
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© 2019 Institute for Biological Research "Siniša Stanković" – National Institute of Republic of Serbia, University of Belgrade
Метаподаци
Приказ свих података о документуАпстракт:
P-glycoprotein (P-gp) is an ATP-binding cassette (ABC) transporter whose
overexpression in cancer cells is one of the main causes of multidrug resistance (MDR).
P-gp overexpression is responsible for reduced intracellular accumulation and efficacy
of both targeted therapies and classic chemotherapeutics. Therefore, P-gp has an
important role in "absorption, distribution, metabolism, and excretion" – ADME
studies. It is also considered as the first cellular defense line and a part of so-called
“cellular immunity’. Tyrosine kinase inhibitors (TKIs) have been reported to interact
with ABC transporters, and in some cases increase the susceptibility of cancer cells to
chemotherapy. We have investigated the anticancer potential of novel tyrosine kinase
inhibitors pyrazolo[3,4-d] pyrimidines and their prodrugs against two pairs of sensitive
and MDR cancer cell lines with P-gp overexpression: non-small cell lung carcinoma
(NCI-H460 and NCI-H460/R) and colorectal carcinoma (DLD1 and DLD1-TxR). The
tested compounds displayed significant cell growth inhibition and enhanced the
efficacy of doxorubicin and paclitaxel in MDR cancer cells. Some of the TKIs directly
interacted with P-gp and inhibited its ATPase activity. A kinetics study showed that the
compounds increased the intracellular accumulation of the P-gp substrate rhodamine
123 in a time-dependent manner. Treatment with the compounds did not increase the
mRNA expression level of P-gp in resistant cancer cells. The investigated pyrazolo[3,4-
d] pyrimidines showed significant potential for reversing P-gp-mediated MDR even in
prolonged treatment, making them good candidates for further development regarding
treatment of resistant cancers.
У:
- Saksida T, Stanisavljević S, Miljković Đ, editors. Immunology at the Confluence of Multidisciplinary Approaches : abstract book: 2019 Dec 6-8; Belgrade, Serbia. Belgrade: Institute for Biological Research "Siniša Stanković", University of Belgrade; Immunological Society of Serbia; 2019. p. 122.