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c-Jun N-Terminal Kinase (JNK) Inhibitor IQ-1S as a Suppressor of Tumor Spheroid Growth
Elena Afrimzon1,2, Mordechai Deutsch1, Maria Sobolev1
1The Biophysical Interdisciplinary Jerome Schottenstein Center for the Research and Technology of the Cellome, Physics Department, Bar Ilan University, Ramat Gan 5290002, Israel.
Abstract:
c-Jun N-terminal kinase (JNK) activation has been shown to play a crucial role in the development of various types of cancer. IQ-1S is a JNK inhibitor based on the 11H-indeno[1,2-b]quinoxalin-11-one scaffold. The aim of this study was to investigate the antiproliferative effect of IQ-1S on MCF7 breast cancer cells in both two-dimensional (2D) monolayer and 3D multicellular spheroid test-systems. Non-adherent, non-tethered 3D objects were generated from single MCF7 breast cancer cells in a hydrogel array. IQ-1S was added directly to the cells seeded in the hydrogel array. MCF7 spheroids were grown for 7 days. Spheroid size, growth rate, and morphology were assessed at single-object resolution. The study revealed significant differences in the size, morphology and some vital characteristics of breast cancer 3D objects when treated with the JNK inhibitor compared to vehicle (dimethyl sulfoxide)-treated controls. Spheroids treated with IQ-1S (20 μM) after 7 days are significantly smaller than the control objects. This difference was not attributable to variations in the initial number of cells seeding for the spheroid formation. Morphological examinations showed that 3D multicellular objects grown from IQ-1S-treated cells lose their regular, round morphology, in contrast to control spheroids. Furthermore, cell proliferation measured using a label-free impedance monitoring platform was reduced in monolayer (2D) culture of MCF7 cells in the presence of 10 and 20 μM IQ-1S. MCF7 cells in 2D culture treated with IQ-1S (20 μM) for 72 and 153 h showed a significant increase in apoptosis as assessed by flow cytometry with annexin V/propidium iodide staining. An in silico evaluation showed that compound IQ-1S has generally satisfactory ADME (absorption, distribution, metabolism, and excretion) properties and high bioavailability. We conclude that IQ-1S effectively inhibits the growth of 3D spheroids and MCF7 cells in 2D culture and has a high potential for use in preclinical tumor growth models.
Insights
IQ-1S, a c-Jun N-terminal kinase (JNK) inhibitor, effectively reduced breast cancer cell proliferation in both 2D cultures and 3D spheroids. This JNK inhibitor demonstrated significant antiproliferative effects and induced apoptosis in MCF7 cells, showing potential for preclinical cancer models.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- c-Jun N-terminal kinase (JNK) activation is implicated in cancer development.
- IQ-1S is a novel JNK inhibitor derived from the 11H-indeno[1,2-b]quinoxalin-11-one scaffold.
Purpose of the Study:
- To evaluate the antiproliferative effects of IQ-1S on MCF7 breast cancer cells.
- To assess IQ-1S efficacy in both 2D monolayer and 3D multicellular spheroid models.
Main Methods:
- MCF7 cells were cultured in 2D monolayers and 3D hydrogel arrays to form multicellular spheroids.
- IQ-1S was administered to cells, and spheroid growth, morphology, and cell proliferation were monitored.
- Apoptosis was assessed via flow cytometry, and in silico ADME properties were evaluated.
Main Results:
- IQ-1S treatment significantly reduced the size and altered the morphology of 3D MCF7 spheroids.
- Cell proliferation was inhibited in 2D MCF7 cultures treated with IQ-1S.
- IQ-1S treatment led to increased apoptosis in MCF7 cells and demonstrated favorable in silico ADME properties.
Conclusions:
- IQ-1S effectively inhibits the growth of breast cancer cells in both 2D and 3D culture systems.
- The JNK inhibitor IQ-1S shows significant potential for preclinical evaluation in tumor growth models.
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