Stylosin and some of its synthetic derivatives induce apoptosis in prostate cancer cells as 15-lipoxygenase enzyme inhibitors

Abstract

Overexpression of 15-lipoxygenase-1 (15-LOX-1) enzyme has been reported in prostate tumors, and its expression levels are associated with the degree of cancer malignancy. The aim of this study was to investigate inhibitory effects of stylosin and some similar synthetic monoterpenoids on 15-LOX and also their cytotoxic and anti-cancer activities on prostate cancer cells. Cytotoxicity of compounds was evaluated on prostate cancer cell line “PC-3” and normal human fibroblast “HFF3” cells using AlamarBlue reduction test. The inhibitory effects of the compounds against soybean 15-LOX, a commercially available enzyme, were also assessed. Finally, mechanism of cell death was investigated by flow cytometry. Some of these terpenoids had cytotoxic effects on PC-3 cells, and strong positive correlation was observed between the 15-LOX-1 inhibition potential and the cytotoxicity of the compounds. Moreover, flow cytometry results indicated that apoptosis was the predominant mechanism of induced cell death, which emphasizes the potential of these compounds in prostate cancer therapy. Among studied terpenoids, “fenchyl ferulate” exhibited about three times more cytotoxicity than cisplatin. Strong positive correlation observed between 15-LOX inhibition potential and cytotoxicity of the compounds indicates selective anti-cancer properties of the compounds might be exerted via inhibition of 15-LOX-1 in PC-3 cells. Furthermore, observed cytotoxicity is mediated through apoptosis, which is probably triggered via 15-LOX-1 inhibition.

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Acknowledgments

The authors are grateful to Prof. K. Abnous and Dr. P. Lavaee from Mashhad University of Medical Sciences, and Dr. R. Jalal from Ferdowsi University of Mashhad (FUM) for their kind technical support. We would like to thank M. Mirahmadi for his technical assistance on flow cytometry.

Funding

This study was funded by FUM under grant no. 31788.

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SNG conducted the methodology and inferences, carried out the statistical analyses, and wrote the manuscript. HS carried out the chemicals synthesis and had discussions about the content. ARB designed the study and had discussions about the content. FM had technical assistance. MMM conceived the original idea and designed the study, analyzed the results, and wrote the manuscript.

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Correspondence to Maryam M. Matin.

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Goftari, S.N., Sadeghian, H., Bahrami, A.R. et al. Stylosin and some of its synthetic derivatives induce apoptosis in prostate cancer cells as 15-lipoxygenase enzyme inhibitors. Naunyn-Schmiedeberg's Arch Pharmacol 392, 1491–1502 (2019). https://doi.org/10.1007/s00210-019-01689-0

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Keywords

  • Prostate cancer
  • Stylosin
  • 15-LOX-1
  • Monoterpenoids
  • Cytotoxicity