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. 2024 Jul 22;51(1):832.
doi: 10.1007/s11033-024-09764-3.

Ruxolitinib-loaded poly-ɛ-caprolactone (PCL) nanoparticles inhibit JAK2/STAT5 signaling in BT474 breast cancer cells by downregulating Bcl-2 and Mcl-1

Esin Guvenir Celik  1   2 , Onur Eroglu  3
Affiliations

Ruxolitinib-loaded poly-ɛ-caprolactone (PCL) nanoparticles inhibit JAK2/STAT5 signaling in BT474 breast cancer cells by downregulating Bcl-2 and Mcl-1

Esin Guvenir Celik et al. Mol Biol Rep. .

Abstract

Background: JAK/STAT signaling plays an important role in regulating cell proliferation. Reducing proliferation and inducing cell death with gene-specific inhibitors such as ruxolitinib, Receptor tyrosine kinases (RTK) inhibitor targeting JAK1/2, are therapeutic approaches. The use of nanoparticles can reduce the toxicity and side effects of drugs, as they act directly on cancer cells and can selectively increase drug accumulation in tumor cells. Poly-ɛ-caprolactone (PCL) is a polymer that is frequently used in drug development. In this study, Rux-PCL-NPs were synthesized to increase the effectiveness of ruxolitinib. In addition, this study aimed to determine the effect of Rux-PCL-NPs on JAK/STAT signaling and apoptotic cell death.

Methods and results: Rux-PCL-NPs were synthesized by nanoprecipitation. The Rux-PCL-NPs had a spherical and mean particle size of 219 ± 88.66 nm and a zeta potential of 0.471 ± 0.453 mV. In vitro cytotoxicity and antiproliferative effects were determined by MTT and soft agar colony formation assays, respectively. The effects of ruxolitinib, PCL-NPs, and Rux-PCL-NPs on apoptosis and the JAK/STAT pathway in cells were examined by western blot analysis. PCL-NPs did not have a toxic effect on the cells. The IC50 value of Rux-PCL-NPs was decreased 50-fold compared to that of ruxolitinib. Rux-PCL-NPs promoted cell death by downregulating JAK2 and STAT5, thereby inhibiting the JAK/STAT pathway.

Conclusions: Our results revealed that Rux-PCL-NPs, which increased the efficacy of ruxolitinib, regulated apoptosis and the JAK2/STAT5 pathway.

Keywords: BT474; JAK/STAT; Poly-ɛ-caprolactone; Ruxolitinib; Ruxolitinib-loaded poly-ɛ-caprolactone nanoparticles.

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