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Combination Treatment of a Phytochemical and a Histone Demethylase Inhibitor-A Novel Approach towards Targeting

Nidhi Dalpatraj1, Ankit Naik1, Noopur Thakur1

  • 1Department of Biological and Life Sciences, School of Arts and Sciences, Ahmedabad University, Ahmedabad 380009, India.

International Journal of Molecular Sciences
|February 11, 2023
PubMed

Insights

This study explores combining hesperetin, a phytochemical, with a demethylase inhibitor (GSK-J4) to combat prostate cancer. This novel approach targets epigenetic changes and inhibits cancer cell migration and invasion.

Area of Science:

  • Oncology
  • Epigenetics
  • Pharmacology

Background:

  • Phytochemicals like hesperetin show promise in cancer therapy with fewer side effects.
  • Cancer drug resistance, metastasis, and side effects are key challenges in current treatments.
  • Epigenetic modifications, such as reduced H3K27me3 in prostate cancer, offer reversible therapeutic targets.

Purpose of the Study:

  • To investigate the effects of an H3K27 demethylase inhibitor (GSK-J4) on TGFβ-induced epithelial-to-mesenchymal transition (EMT) in prostate cancer cells.
  • To evaluate the combined therapeutic potential of hesperetin and GSK-J4 in prostate cancer.
  • To explore the impact of GSK-J4 on epigenetic modifications (H3K27me3, H3K4me3, H3K9me3) and cancer hallmarks.

Main Methods:

  • Treatment of PC-3 and LNCaP prostate cancer cells with GSK-J4 and/or hesperetin.
  • Assessment of cytotoxicity, migration, and invasion inhibition.
  • Analysis of epigenetic modifications including H3K27me3, H3K4me3, and H3K9me3 levels.

Main Results:

  • GSK-J4 demonstrated dose-dependent cytotoxicity and inhibited TGFβ-induced migration and invasion.
  • GSK-J4 treatment led to increased H3K27me3 and H3K4me3, with a surprising decrease in H3K9me3.
  • Both GSK-J4 alone and the combination therapy significantly inhibited cancer cell proliferation, migration, and invasion by altering the epigenetic landscape.

Conclusions:

  • Combining hesperetin with the H3K27 demethylase inhibitor GSK-J4 is a promising strategy against prostate cancer.
  • This combination therapy effectively targets key cancer hallmarks by modulating epigenetic modifications.
  • The findings suggest a novel therapeutic approach to overcome cancer drug resistance and reduce metastasis.
Keywords:
GSK-J4combinatorial treatmentdrug synergismepigeneticsepithelial-to-mesenchymal transition

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