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Combinations of Indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of Nasopharyngeal carcinoma cell lines

Gregory Domnic, Nelson Jeng-Yeou Chear, Siti Fairus Abdul Rahman, Surash Ramanathan, Kwok-Wai Lo, Darshan Singh, View ORCID ProfileNethia Mohana-Kumaran
doi: https://doi.org/10.1101/2020.12.18.423377
Gregory Domnic
1School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
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Nelson Jeng-Yeou Chear
2Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia
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Siti Fairus Abdul Rahman
1School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
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Surash Ramanathan
2Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia
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Kwok-Wai Lo
3Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong, China
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Darshan Singh
2Centre for Drug Research, Universiti Sains Malaysia, 11800 Penang, Malaysia
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Nethia Mohana-Kumaran
1School of Biological Sciences, Universiti Sains Malaysia, 11800 Penang, Malaysia
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  • ORCID record for Nethia Mohana-Kumaran
  • For correspondence: nethiakumaran@usm.my
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Abstract

Ethnopharmacological relevance Mitragyna speciosa (Korth.) or kratom is a medicinal plant indigenous to Southeast Asia. The leaves of M. speciosa is used as a medication in pain management including cancer related pain, in a similar way as opioids and cannabis. Despite its well-known analgesic effect, there is a scarce of information on the cancer-suppressing potential of M. speciosa and its active constituents.

Aim of the study To assess the potential applicability of M. speciosa alkaloids (mitragynine, speciociliatine or paynantheine) as chemosensitizers for cisplatin in Nasopharyngeal carcinoma (NPC) cell lines.

Materials and Methods The cytotoxic effects of the extracts, fractions and compounds were determined by conducting in vitro cytotoxicity assays. Based on the cytotoxic screening, the alkaloid extract of M. speciosa exhibited potent inhibitory effect on the NPC cell line HK-1, and therefore, was chosen for further fractionation and purification. NPC cell lines HK-1 and C666-1 were treated with combinations of cisplatin and M. speciosa alkaloids in 2D monolayer culture. The effect of the drug combination on cell migration was tested using in vitro wound healing and spheroid invasion assays.

Results In our bioassay guided isolation, both methanolic and alkaloid extracts showed mild to moderate cytotoxic effect against the HK-1 cell line. Both NPC cell lines were insensitive to single agent and combination treatments of the M. speciosa alkaloids. However, mitragynine and speciociliatine sensitised the HK-1 and C666-1 to cisplatin ~4- and >5-fold, respectively in 2D monolayer culture. The combination of mitragynine and cisplatin also significantly inhibited cell migration of the NPC cell lines. Similarly, combination of mitragynine and cisplatin inhibited growth and invasion of HK-1 spheroids in a dose-dependent manner. Moreover, the spheroids did not rapidly develop resistance to the drug combinations at high concentrations over 10 days.

Conclusion Collectively, data shows that both mitragynine and speciociliatine could be potential chemosensitizers for cisplatin. Further extensive drug mechanistic studies and investigations in animal models are necessary to delineate the applicability of M. speciosa alkaloids for NPC therapy.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • Email addresses of all authors: Gregory Domnic: gregoryunited{at}yahoo.com, Siti Fairus Abdul Rahman: fairus_rahman90{at}yahoo.com, Nelson Jeng Yeou Chear: jychear{at}gmail.com, Surash Ramanathan: srama{at}usm.my, Kwok-Wai Lo: kwlo{at}cuhk.edu.hk, Darshan Singh: darshan{at}usm.my, Nethia Mohana-Kumaran: nethiakumaran{at}usm.my; nethia82{at}gmail.com

  • Title revised Abstract revised Introduction revised Some results sections were revised and some were newly added. Discussion revised New images and supplementary images added.

  • Abbreviations

    NPC
    Nasopharyngeal carcinoma
    2D
    2-dimensional
    FBS
    Foetal Bovine Serum
    PBS
    Phosphate Buffer Saline
    NMR
    Nuclear Magnetic Resonance
    GC-MS
    Gas Chromatography-Mass Spectrometry
    HPLC-PDA
    High-Performance Liquid Chromatography–Photodiode Array
  • Copyright 
    The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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    Posted April 05, 2021.
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    Combinations of Indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of Nasopharyngeal carcinoma cell lines
    Gregory Domnic, Nelson Jeng-Yeou Chear, Siti Fairus Abdul Rahman, Surash Ramanathan, Kwok-Wai Lo, Darshan Singh, Nethia Mohana-Kumaran
    bioRxiv 2020.12.18.423377; doi: https://doi.org/10.1101/2020.12.18.423377
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    Combinations of Indole based alkaloids from Mitragyna speciosa (Kratom) and cisplatin inhibit cell proliferation and migration of Nasopharyngeal carcinoma cell lines
    Gregory Domnic, Nelson Jeng-Yeou Chear, Siti Fairus Abdul Rahman, Surash Ramanathan, Kwok-Wai Lo, Darshan Singh, Nethia Mohana-Kumaran
    bioRxiv 2020.12.18.423377; doi: https://doi.org/10.1101/2020.12.18.423377

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