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

Juan Carlos Gómez-Verjan; Nadia Alejandra Rivero-Segura; Edgar Estrella-Parra; Ruth Rincón-Heredia; Abraham Madariaga-Mazón; Edgar Flores-Soto; Mario González-Meljem; Marco Cerbón; Ricardo Reyes-Chilpa

doi:10.1055/a-0660-0236

Planta Medica, Table of Contents

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^*

¹División de Investigación Básica, Instituto Nacional de Geriatría (InGer), Mexico City, Mexico

,

Nadia Alejandra Rivero-Segura^*

²Unidad 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

³Laboratorio de Fitoquímica, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México, Tlalnepantla, Mexico

,

Ruth Rincón-Heredia

⁴División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Mexico City, Mexico

,

Abraham Madariaga-Mazón

⁵Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico

,

Edgar Flores-Soto

⁶Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico

,

Mario González-Meljem

¹División de Investigación Básica, Instituto Nacional de Geriatría (InGer), Mexico City, Mexico

,

Marco Cerbón

²Unidad 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

⁵Instituto de Química, Universidad Nacional Autónoma de México, Mexico City, Mexico

› Author Affiliations

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

Full Text

References

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