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Naringenin enhances anti-proliferation effect of 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one on two different cells via targeting calmodulin signaling pathway

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Abstract

Background

FMSP is a synthesized ferrocene derivative with anti-cancer characteristics on tumor cells. Naringenin is a polyphenolic flavonoid with anti-tumor ability.

Methods

Cell viability and proliferation of two cancer cells and a normal cell line after treatment with these agents were determined with MTT assay. To predict the possible interaction between calmodulin (CaM) and FMSP and naringenin, docking studies were performed. By using fluorescence emission spectra, the effects of FMSP and naringenin on CaM structure and activity were studied. CaM-dependent activation of phosphodiesterase 1 (PDE1) by FMSP in relation to naringenin and their combination were compared. Effects of these compounds on PDE1 inhibition, cAMP accumulation, and cAMP-dependent protein kinase A (PKA) activation were assayed.

Results

The combination of FMSP and naringenin had more inhibitory effects on CaM structure than FMSP and naringenin alone. Results of docking analyses also confirmed efficient interaction of the two compounds with a hydrophobic pocket of calmodulin active site. Kinetic analyses of these agents’ interaction with CaM showed FMSP and naringenin both competitively inhibited PDE1 activation without changing the Vmax parameter. FMSP and naringenin synergistically increased Km values at a higher level compared to FMSP or naringenin alone. The combination of these two agents also had more cytotoxic effects on cancer cells than FMSP alone.

Conclusions

It was shown that mechanism of proliferation inhibition in both cancer cells by these compounds is based on CaM and consequent PDE inhibition followed by intracellular cAMP level elevation and increased PKA activity in a dose-dependent manner.

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Data availability

Our data is available upon any request from the corresponding author.

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Acknowledgements

The authors thank the Vice Chancellor for Research of Shahid Beheshti University of Medical Sciences.

Funding

No funding resources were received.

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Authors and Affiliations

  1. Traditional Medicine and Materia Medica Research Center (TMRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Sadegh Rajabi

  2. Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Shokoofe Noori

  3. Department of Biochemistry, Afzalipoor Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran

    Mohammad Reza Ashrafi

  4. Department of Pharmaceutical Chemistry, School of Pharmacy, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mahsa Azami Movahed, Shabnam Farzaneh & Afshin Zarghi

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  1. Sadegh Rajabi
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  4. Mahsa Azami Movahed
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  5. Shabnam Farzaneh
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Contributions

SN and AZ designed the experiment and research methodology. MAM and SF performed the experiments, while SR and MRA were involved in the data analysis and manuscript write-up.

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Correspondence to Shokoofe Noori or Afshin Zarghi.

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Rajabi, S., Noori, S., Ashrafi, M.R. et al. Naringenin enhances anti-proliferation effect of 1-ferrocenyl-3-(4-methylsulfonylphenyl) propen-1-one on two different cells via targeting calmodulin signaling pathway. Mol Biol Rep 49, 1027–1036 (2022). https://doi.org/10.1007/s11033-021-06923-8

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