Antiproliferative effects of imatinib mesylate on ZR‑75‑1 and MDA‑MB‑231 cell lines via PDGFR‑β, PDGF‑BB, c‑Kit and
Ali Kadivar1, Mohamed Ibrahim Noordin1, Arya Aditya2
1Department of Pharmacy, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia.
Abstract:
Imatinib mesylate is an anti‑neoplastic targeted chemotherapeutic agent, which can inhibit tyrosine kinase receptors, including BCR‑ABL, platelet‑derived growth factor receptors (PDGFRs) and c‑Kit. Cellular processes, including differentiation, proliferation and survival are regulated by these receptors. The present study aimed to evaluate the antiproliferative effects of imatinib mesylate, and its effects on apoptotic induction and cell cycle arrest in breast cancer cell lines. In addition, the study aimed to determine whether the effects of this drug were associated with the mRNA and protein expression levels of PDGFR‑β, c‑Kit, and their corresponding ligands PDGF‑BB and stem cell factor (SCF), which may potentially modulate cell survival and proliferation. To assess the antiproliferative effects of imatinib mesylate, an MTS assay was conducted following treatment of cells with 2‑10 µM imatinib mesylate for 96, 120 and 144 h; accordingly the half maximal inhibitory concentration of imatinib mesylate was calculated for each cell line. In addition, the proapoptotic effects and cytostatic activity of imatinib mesylate were investigated. To evaluate the expression of imatinib‑targeted genes, PDGFR‑β, c‑Kit, PDGF‑BB and SCF, under imatinib mesylate treatment, mRNA expression was detected using semi‑quantitative polymerase chain reaction and protein expression was detected by western blot analysis in ZR‑75‑1 and MDA‑MB‑231 breast carcinoma cell lines. Treatment with imatinib mesylate suppressed cell proliferation, which was accompanied by apoptotic induction and cell cycle arrest in the investigated cell lines. In addition, PDGFR‑β, PDGF‑BB, c‑Kit and SCF were expressed in both breast carcinoma cell lines; PDGFR‑β and c‑Kit, as imatinib targets, were downregulated in response to imatinib mesylate treatment. The present results revealed that at least two potential targets of imatinib mesylate were expressed in the two breast carcinoma cell lines studied. In conclusion, the antiproliferative, cytostatic and proapoptotic effects of imatinib mesylate may be the result of a reduction in the expression of c‑Kit and PDGFR tyrosine kinase receptors, thus resulting in suppression of the corresponding ligand PDGF‑BB. Therefore, imatinib mesylate may be considered a promising target therapy for the future treatment of breast cancer.
Insights
Imatinib mesylate demonstrated antiproliferative effects in breast cancer cells by inducing apoptosis and cell cycle arrest. This targeted therapy downregulates platelet-derived growth factor receptor-beta (PDGFR-β) and c-Kit, suggesting potential for breast cancer treatment.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Imatinib mesylate is a targeted chemotherapeutic agent inhibiting tyrosine kinase receptors like PDGFRs and c-Kit.
- These receptors regulate critical cellular processes including proliferation, differentiation, and survival.
Purpose of the Study:
- To evaluate the antiproliferative, apoptotic, and cell cycle arrest effects of imatinib mesylate in breast cancer cell lines.
- To investigate the association between imatinib's effects and the expression of PDGFR-β, c-Kit, PDGF-BB, and SCF.
Main Methods:
- MTS assay to determine half maximal inhibitory concentration (IC50) of imatinib mesylate.
- Semi-quantitative PCR and Western blot analysis to assess mRNA and protein expression of target genes.
- Treatment of ZR-75-1 and MDA-MB-231 breast carcinoma cell lines with imatinib mesylate.
Main Results:
- Imatinib mesylate suppressed breast cancer cell proliferation, induced apoptosis, and caused cell cycle arrest.
- PDGFR-β, c-Kit, PDGF-BB, and SCF were expressed in both cell lines.
- Imatinib mesylate treatment led to downregulation of PDGFR-β and c-Kit expression.
Conclusions:
- Imatinib mesylate exhibits antiproliferative, cytostatic, and proapoptotic effects on breast cancer cells.
- These effects are potentially mediated by the downregulation of c-Kit and PDGFR tyrosine kinase receptors.
- Imatinib mesylate shows promise as a targeted therapy for breast cancer treatment.
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