Rilmenidine suppresses proliferation and promotes apoptosis via the mitochondrial pathway in human leukemic K562 cells
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Published on: November 10, 2017
Tatjana Srdic-Rajic1, Katarina Nikolic2, Milena Cavic1
1Department of Experimental Oncology, Institute for Oncology and Radiology of Serbia, Pasterova 14, 11000, Belgrade, Serbia.
Abstract:
Imidazoline I1 receptor signaling is associated with pathways that regulate cell viability leading to varied cell-type specific phenotypes. We demonstrated that the antihypertensive drug rilmenidine, a selective imidazoline I1 receptor agonist, modulates proliferation and stimulates the proapoptotic protein Bax thus inducing the perturbation of the mitochondrial pathway and apoptosis in human leukemic K562 cells. Rilmenidine acts through a mechanism which involves deactivation of Ras/MAP kinases ERK, p38 and JNK. Moreover, rilmenidine renders K562 cells, which are particularly resistant to chemotherapeutic agents, susceptible to the DNA damaging drug doxorubicin. The rilmenidine co-treatment with doxorubicin reverses G2/M arrest and triggers apoptotic response to DNA damage. Our data offer new insights into the pathways associated with imidazoline I1 receptor activation in K562 cells suggesting rilmenidine as a valuable tool to deepen our understanding of imidazoline I1 receptor signaling in hematologic malignancies and to search for medicinally active agents.
Insights
The antihypertensive drug rilmenidine induces apoptosis in human leukemia K562 cells by targeting imidazoline I1 receptor signaling. It also enhances susceptibility to doxorubicin, offering potential for hematologic malignancy treatments.
Area of Science:
- Pharmacology
- Molecular Biology
- Cancer Research
Background:
- Imidazoline I1 receptor signaling influences cell viability and phenotypes.
- Leukemic K562 cells exhibit resistance to conventional chemotherapeutic agents.
Purpose of the Study:
- To investigate the effects of rilmenidine, an imidazoline I1 receptor agonist, on human leukemic K562 cells.
- To explore rilmenidine's mechanism of action and its potential to overcome chemotherapy resistance.
Main Methods:
- Treatment of K562 cells with rilmenidine and doxorubicin.
- Analysis of cell proliferation, apoptosis markers (Bax), and signaling pathways (Ras/MAP kinases ERK, p38, JNK).
- Assessment of cell cycle progression (G2/M arrest) and apoptotic response to DNA damage.
Main Results:
- Rilmenidine modulated proliferation and stimulated Bax, inducing mitochondrial pathway-mediated apoptosis in K562 cells.
- Rilmenidine deactivated Ras/MAP kinases ERK, p38, and JNK.
- Rilmenidine sensitized resistant K562 cells to doxorubicin, reversing G2/M arrest and triggering apoptosis.
Conclusions:
- Imidazoline I1 receptor activation by rilmenidine induces apoptosis and overcomes chemotherapy resistance in K562 cells.
- Rilmenidine offers a potential therapeutic strategy for hematologic malignancies and aids in understanding I1 receptor signaling.
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