Molecular and cytogenetic changes in multi-drug resistant cancer cells and their influence on new compounds testing

• Published in: Cancer chemotherapy and pharmacology 2013-09, Vol.72 (3), p.683-697
• Main Authors: Podolski-Renić, Ana, Jadranin, Milka, Stanković, Tijana, Banković, Jasna, Stojković, Sonja, Chiourea, Maria, Aljančić, Ivana, Vajs, Vlatka, Tešević, Vele, Ruždijić, Sabera, Gagos, Sarantis, Tanić, Nikola, Pešić, Milica
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - pharmacology; ATP Binding Cassette Transporter, Sub-Family B; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; Biological and medical sciences; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Cytogenetic Analysis; Drug Resistance, Multiple - drug effects; Drug Resistance, Neoplasm - drug effects; Gene Expression Regulation, Neoplastic; Glioma - drug therapy; Glioma - genetics; Humans; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medical sciences; Medicine; Medicine & Public Health; Oncology; Original Article; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Pharmacology/Toxicology; Phenotype; Polymorphism, Single Nucleotide; Prognosis; PTEN Phosphohydrolase - genetics; Tumor Suppressor Protein p53 - genetics
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2247-1

Purpose 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. Methods 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. Results 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 all 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. Conclusion 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.