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Planta Med 2019; 85(01): 14-23
DOI: 10.1055/a-0660-0236
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Network Pharmacology Uncovers Anticancer Activity of Mammea-Type Coumarins from Calophyllum brasiliense

Juan Carlos Gómez-Verjan   *
1   División de Investigación Básica, Instituto Nacional de Geriatría (InGer), Mexico City, Mexico
,
Nadia Alejandra Rivero-Segura   *
2   Unidad de Investigación en Reproducción Humana, Instituto de Perinatología/Lab. Biología Celular, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
,
Edgar Estrella-Parra
3   Laboratorio de Fitoquímica, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico
,
Ruth Rincón-Heredia
4   División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico
,
Abraham Madariaga-Mazón
5   Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
,
Edgar Flores-Soto
6   Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
,
Mario González-Meljem
1   División de Investigación Básica, Instituto Nacional de Geriatría (InGer), Mexico City, Mexico
,
Marco Cerbón
2   Unidad de Investigación en Reproducción Humana, Instituto de Perinatología/Lab. Biología Celular, Facultad de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
,
Ricardo Reyes-Chilpa
5   Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico
› Author Affiliations
Further Information

Publication History

received 13 April 2018
revised 02 July 2018

accepted 10 July 2018

Publication Date:
23 July 2018 (online)

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Abstract

Mammea-type coumarins are a particular type of secondary metabolites biosynthesized by the tropical rainforest tree Calophyllum Brasiliense, which is distributed from South America to Mexico. Particularly, mammea A/BA and A/BB (alone or as a mixture) possess biological properties such as cytotoxic and antitumoral activities, however, most of its molecular targets remain unknown. In this context, novel bioinformatic approaches, such as network pharmacology analysis, have been successfully used in herbal medicine to accelerate research in this field, and the support of experimental validations has been shown to be quite robust. In the present study, we performed a network pharmacology analysis to assess the possible molecular biological networks that interact with mammea A/BA and A/BB. Moreover, we validated the most relevant networks experimentally in vitro on K562 cancer cells. The results of the network pharmacology analysis indicate that mammea A/BA and A/BB interacts with cell death, PI3K/AKT, MAPK, Ras, and cancer pathways. The in vitro model shows that mammea A/BA and A/BB induce apoptosis through the overexpression of the proapoptotic proteins Bax and Bak, disrupt the autophagic flux as seen by the cytosolic accumulation of LC3-II and p62, disrupting the mitochondria ultrastructure and concomitantly increase the intracellular calcium concentration. Additionally, docking analysis predicted a possible interaction with a rapamycin-binding domain of mTOR. In conclusion, we validated network pharmacology analysis and report, for the first time, that mammea A/BA and A/BB coumarins induce apoptosis through the inhibition of the autophagic flux, possibly interacting with mTOR.

Key words

network pharmacology - anticancer - mammea-type coumarins - Calophyllum brasiliense - cell death - autophagy - Clusiaceae

* These two authors contributed equally to this work.


Supporting Information

    A detailed scheme of NPr methodology (Fig. 1S), complete image for the Western blot of LC3 and P62 proteins (Fig. 2S), a complete list of the potential targets of MABB obtained by the NPr analysis (Table 1S), and the results for the validation of the docking protocol, which include resulting conformations of the validation protocol images (Fig. 3S A, B) and docking scores for MABB and ligands of co-crystallization for each mTOR studied (Table 2S), are available as Supporting Information.

  • Supporting Information
 

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