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

Abstract

Mammea-type coumarins are a particular type of secondary metabolites biosynthesized by the tropical rainforest tree , 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 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 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.

Mammea B/BA Isolated From the Seeds of Mammea americana L. (Calophyllaceae) is a Potent Inhibitor of Methicillin-Resistant Staphylococcus aureus

“…Based on the substituent at C-4, there are so far five designated series: mammea A (4-fenil), B (4-propil), C (4-pentil), D [4-(1-metilpropil)], and E (1-acetoxipropil) ( Crombie et al, 1987 ). These types of coumarins are biologically active with antiprotozoal activity against Leishmania amazonensis ( Brenzan et al, 2007 , 2012 ), L. brasiliensis ( Honda et al, 2010 ) and Trypanosoma cruzi ( Reyes-Chilpa et al, 2008 ); cytotoxic activity ( Reyes-Chilpa et al, 2004 ; Ito et al, 2006 ; Du et al, 2010 ; Gómez-Verjan et al, 2019 ), and others have shown good activity against dengue and chikungunya viruses ( Gómez-Calderón et al, 2017 ).…”

Schizandrin A induces non‐small cell lung cancer apoptosis by suppressing the epidermal growth factor receptor activation

“…Network pharmacology is an emerging discipline of “drug‐target‐disease” relationship network based on systems biology and multidirectional pharmacology, which is used to systematically and comprehensively observe the impact of drugs on disease networks 10 . Accumulating researches have proved that network pharmacology is a feasible systematic approach to uncovering the molecular mechanisms by which drugs exert physiological effects or to searching for small molecule drugs that may have therapeutic effects 11,12 . In this study, we used network pharmacology combined with laboratory methods to explore the possible molecular mechanism of the anti‐tumor effect of SchA.…”

“… 10 Accumulating researches have proved that network pharmacology is a feasible systematic approach to uncovering the molecular mechanisms by which drugs exert physiological effects or to searching for small molecule drugs that may have therapeutic effects. 11 , 12 In this study, we used network pharmacology combined with laboratory methods to explore the possible molecular mechanism of the anti‐tumor effect of SchA.…”

Systems biology and network pharmacology of frailty reveal novel epigenetic targets and mechanisms

“…These approaches are often used to discover new mechanisms of action and possible adverse effects of drugs 8 . Several research groups have used network pharmacology for different application, for instance, to explore bioactive ethnobotanical compounds with known use and to repurpose them for other pharmacological use 11,12 . Other example is metformin that has been repurposed as a chemo-preventive drug and is already on clinical trials 13 .…”