Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing
Само за регистроване кориснике
2013
Аутори
Podolski-Renic, Ana
Jadranin, Milka
Stanković, Tijana

Bankovic, Jasna
Stojkovic, Sonja
Chiourea, Maria
Aljancic, Ivana S.
Vajs, Vlatka
Tešević, Vele

Ruzdijic, Sabera
Gagos, Sarantis
Tanic, Nikola
Pesic, Milica

Чланак у часопису (Објављена верзија)

Метаподаци
Приказ свих података о документуАпстракт
Multi-drug resistance (MDR) is a major obstacle to successful cancer treatment. Therefore, in vitro models are necessary for the investigation of the phenotypic changes provoked by cytotoxic agents and more importantly for preclinical testing of new anticancer drugs. We analyzed chromosomal, numerical, and structural changes after development of MDR, alterations in p53 and PTEN, single nucleotide polymorphisms (SNPs) in the mdr1 gene and corresponding protein expression of P-glycoprotein (P-gp) in three human MDR cancer cell lines: non-small cell lung carcinoma NCI-H460/R, colorectal carcinoma DLD1-TxR, and glioma U87-TxR. In addition, we explored how these molecular and phenotypic alterations influence the anticancer effect of new drugs. Cytogenetic analysis showed polyploidy reduction after development of MDR in U87-TxR. Losses of 6q in all resistant cancer cell lines and inactivation of p53 in U87-TxR and PTEN in DLD1-TxR were also revealed. Overexpression of P-gp was observed in al...l MDR cancer cell lines. We evaluated the anticancer activities and MDR reversal potential of Akt inhibitor GSK690693, Ras inhibitor Tipifarnib, and two P-gp inhibitors (jatrophane diterpenoids). Their effects vary due to the cell-type differences, existence of MDR phenotype, presence of mdr1 SNP, and tumor suppressors' alterations. Tipifarnib and jatrophane diterpenoids significantly sensitized MDR cancer cells to paclitaxel. In conclusion, investigated MDR cancer cells obtained new molecular and cytogenetic characteristics that may serve as potential clinical prognostic markers. In addition, these MDR cancer cell lines present a valuable model for preclinical evaluation of new anticancer agents.
Кључне речи:
Multi-drug resistance / Cytogenetics / Loss of heterozygosity / P-glycoprotein / Anticancer agentsИзвор:
Cancer Chemotherapy and Pharmacology, 2013, 72, 3, 683-697Издавач:
- Springer, New York
Пројекти:
- Идентификација молекуларних маркера за предикцију прогресије тумора, одговора на терапију и исхода болести (RS-41031)
- Биоактивни природни производи самониклих, гајених и јестивих биљака: одређивање структура и активности (RS-172053)
- Cancer and Control of Genomic Integrity (CANGENIN) COST Action [BM0703]
DOI: 10.1007/s00280-013-2247-1
ISSN: 0344-5704
PubMed: 23934261