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Phytochemical analysis of Daphne pontica L. stems with their pro-apoptotic properties against DU-145 and LNCaP prostate cancer cells

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Abstract

Background

Daphne pontica is an endemic plant grown wild in the North part of Iran, with anticancer activities.

Objectives

This study aims to analyze the phytochemistry and screen the cytotoxic activity of new bioactive compounds against a panel of cancer cells, in addition to proapototic properties against prostate cancer cells.

Method

Purification procedure was done using repeated column chromatographies by MPLC and HPLC systems. The structures were elucidated by the NMR and exact mass spectroscopy, stereochemistry by NOESY, and absolute configuration by electronic circular dichroism (ECD) spectra. Cytotoxicity was done against DU 145, LNCaP, HeLa, MCF-7, and MDA-MB 231 cells by standard MTT assay. An annexin V/PI assay was performed to measure the type of death following treatment with these compounds for 48 h, followed by the caspase-3 activity test.

Results

In this study, one new dilignan named lignopontin A (9), in addition to 13 known compounds including two phenolic acids (3, 5), one flavanone (6), one bis flavonoid (1), one cumarin glycoside (2), one mono (4) and two dicumarins (10, 11), two lignans (7, 8), and three daphnane diterpenoids (12-14) were isolated for the first time from D. pontica stems. Complete spectral data of compound 12, named as 6,7α-epoxy-5β-hydroxy-9,13,14-ortho-(4,2E)-pentadeca-2,4-diene-1-yl)-resiniferonol, and compound 14, named as 6,7α-epoxy-5β-hydroxy-9,3,14-ortho-(2,4E)-pentadeca-2,4-di-1-yl)-resiniferonol-12β-yl-acetate are reported for the first time. In the MTT assay of newly described compounds against a panel of cancer cells, compounds 9, 12, and 14 possessed moderate to potent cytotoxicity against prostate, breast, and cervical cancer cells in a dose-dependent manner. Flow cytometry analysis against prostate cancer cells indicated that the cytotoxicity of compounds 12 and 14 was due to their ability to induce apoptosis. In the case of compound 9, in Du 145 cells, cell death was mainly through apoptosis. In contrast, LNCaP cells showed both apoptosis and necrotic cell death, predominated by necrosis at the higher concentrations. Caspase-3 activity confirmed apoptosis observed in these compounds through the caspase pathway in prostate cancer cells.

Conclusion

D. pontica is a new source of dimeric phenolic compounds, including bisflavonoids, phenylpropanoid-cumarin adduct, and dilignans, as well as daphnane diterpenoids with resiniferonol core with long-chain orthoester moieties. In cytotoxicity screening, compounds 9, 12, and 14 inhibited the growth of DU-145 and LNCaP cells in a dose-dependent manner with IC50 varied from 0.9 – 27.3 and 25.2 - 87.4 μM, respectively. Among them, 9 exhibited selective growth inhibition against DU 145 treated cells. LNCaP cells demonstrated the highest sensitivity to treatment with compound 12.

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Data availability

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

The research leading to these results received funding from Vice-chancellery for Research and Technology, Isfahan University of Medical Sciences, Iran, under Grant number: 194247.

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Authors and Affiliations

  1. Department of Pharmacognosy, Isfahan Pharmaceutical Sciences Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Maryam Nikahd, Seyed Ebrahim Sajjadi & Mustafa Ghanadian

  2. Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran

    Mahmoud Aghaei

  3. National Center for Natural Products Research, University of Mississippi, University, Oxford, MS, 38677, USA

    Zulfiqar Ali & Ikhlas A. Khan

Authors
  1. Maryam Nikahd
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  2. Mahmoud Aghaei
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  3. Zulfiqar Ali
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  4. Seyed Ebrahim Sajjadi
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  5. Ikhlas A. Khan
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  6. Mustafa Ghanadian
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Contributions

All authors contributed to the study's conception and design. Material preparation, data collection, and analysis were performed by [Maryam Nikahd], [Mustafa Ghanadian], and [Mahmoud Aghaei]. Seyed Ebrahim Sajjadi did conceptualization. Zulfiqar Ali and Ikhlas A. Khan reviewed, edited, and analyzed the structure. The first draft of the manuscript was written by [Mustafa Ghanadian], and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Mustafa Ghanadian.

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This work has been approved by the Ethics Committee in the Isfahan University of Medical Science by ethical code: IR.MUI.REC.1394.247.

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Nikahd, M., Aghaei, M., Ali, Z. et al. Phytochemical analysis of Daphne pontica L. stems with their pro-apoptotic properties against DU-145 and LNCaP prostate cancer cells. DARU J Pharm Sci 30, 85–101 (2022). https://doi.org/10.1007/s40199-022-00434-y

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