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Biphasic effect of the dietary phytochemical linalool on angiogenesis and metastasis

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Abstract

Cytotoxic chemotherapy dominates the field of cancer treatment. Consequently, anticancer phytochemicals are largely screened on the basis of their cytotoxicity towards cancer cells which are achieved at higher doses, leading to various toxic side effects. Some phytochemicals also showed pro-carcinogenic effects at certain doses. The concept of hormesis has taught us to look into biphasic responses of phytochemicals in a more systematic way. Interestingly, the monoterpenoid alcohol, linalool, also has been reported to display both anti-oxidant and pro-oxidant properties, which prompted us to explore a probable biphasic effect on cancer cells. Cytotoxicity of various concentrations of linalool (0.1–4 mM) was tested on B16F10 murine melanoma cell line, and two sub-lethal concentrations (0.4 and 0.8 mM) were selected for further experiments. 0.4 mM linalool inhibited angiogenesis and metastasis, while 0.8 mM increased them. Similarly, B16F10 cell migration, invasion, and epithelial-mesenchymal transition markers also showed inhibition and induction with lower and higher linalool concentrations, respectively. Chorioallantoic membrane assay, scratch wound assay, and Boyden’s chamber were used to analyze angiogenesis and metastasis. Expression of molecular markers such as vascular endothelial growth factor (VEGF) and its receptor phosphorylated VEGF receptor II (p-VEGFRII or p-Flk-1), Hypoxia-inducible factor-1 α (HIF-1α), E-cadherin, and vimentin were detected using Western blot, ELISA, PCR, qPCR, and immunofluorescence. Finally, ChIP assay was performed to evaluate HIF-1α association with VEGF promoter. Interestingly, measurement of intracellular reactive oxygen species at the selected concentrations of linalool using DCFDA in a flow cytometer showed that the phytochemical induced significant amount of ROS at 0.8 mM. This work sheds light on bimodal dose–response relationship exhibited by dietary phytochemicals like linalool, and it should be taken into consideration to elicit a desirable therapeutic effect.

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Data availability

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

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Acknowledgements

This work was funded by Department of Biotechnology (DBT), Govt of India, under the scheme “Pilot Grant for Young Investigators.” We thank DST-FIST, New Delhi, Govt. of India (SR/FST/LSI-585/2014) and DBT-BOOST (49(11)/BT(Estt)/IP-4/2013) for instrumental support. We also express our gratitude towards Bose Institute, Kolkata, West Bengal, India, for kindly allowing us to use the Confocal Microscope.

Funding

The research leading to these results received funding from Department of Biotechnology (DBT), Govt of India, under the scheme “Pilot Grant for Young Investigators” (No. 6242-P3/RGCB/PMD/DBT/SHMB/2015).

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Author notes

  1. Priyanka Pal and Samarjit Jana have contributed equally to this work.

Authors and Affiliations

  1. Department of Zoology, West Bengal State University, Berunanpukuria, Malikapur, North-24 Parganas, Barasat, Kolkata, West Bengal, 700126, India

    Priyanka Pal, Samarjit Jana, Ipsita Biswas, Deba Prasad Mandal & Shamee Bhattacharjee

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  1. Priyanka Pal
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  2. Samarjit Jana
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  4. Deba Prasad Mandal
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Contributions

Grant acquisition: SB & DPM, project administration: SB & DPM, conceptualization: SB, DPM, and SJ, methodology and experimentation: PP, SJ and IB, data analysis: PP, SJ, IB, SB, and DPM, figures: PP, SJ, IB, and DPM, writing the original draft: SB, manuscript editing: SB and DPM.

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Correspondence to Deba Prasad Mandal or Shamee Bhattacharjee.

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The author declare no competing interests.

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The experiments in this study used commercial cell lines with no permanent transfections. The study does not involve any human participation or animal experimentation. All the experiments were performed without violation of any ethical norms.

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Pal, P., Jana, S., Biswas, I. et al. Biphasic effect of the dietary phytochemical linalool on angiogenesis and metastasis. Mol Cell Biochem 477, 1041–1052 (2022). https://doi.org/10.1007/s11010-021-04341-9

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  • DOI: https://doi.org/10.1007/s11010-021-04341-9

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