Identification of the Marine Alkaloid Lepadin A as Potential Inducer of Immunogenic Cell Death.

Genoveffa Nuzzo,Mario Dell’Isola,Lucia Romano,Giuliana D’Ippolito,Giusi Barra,Guido Villani,Carmela Gallo,Giuseppina Senese,Valentina Tanduo,Federica Albiani,Fabio Crocetta,Dalila Carbone,Emiliano Manzo,Angelo Fontana

doi:10.3390/biom12020246

Abstract

Natural products and their synthetic analogs and derivatives are a traditional source of bioactive molecules with potential development as drug candidates. In this context, Marine Natural Products (MNPs) represent a rich reservoir of diverse molecular skeletons with potential pharmacological activity that, so far, has been mostly explored in cancer and infectious diseases. Starting from the development of a novel bioassay-guided screening platform for immunomodulatory compounds from an in-house MNPs library, we report the identification of the alkaloid lepadin A as a new model compound for immune-based anticancer activity with characteristics that suggest a possible mechanism as Immunogenic Cell Death inducer. The work describes the molecular-based bioprospecting in the Gulf of Naples together with the bioassay-guided fractionation, the chemical characterization of the alkaloid, and the biological activity in mouse dendritic cells (D1).

Highlights

The marine environment with its boundless chemodiversity represents a huge source of molecules with relevant potential in several pharmacological fields [1,2]
A single sequence was deposited in GenBank (OM278387). It showed a 98.10–100% similarity with 19 sequences deposited as C. lepadiformis, and a 95.08–95.90% similarity with eight additional sequences deposited under the same binomial name (Table S1)
Chemotherapy agents can have a profound impact on the host immune system and to our knowledge, no systematic analysis of the immune-based effects of chemotherapeutic agents has been carried out so far, it is becoming evident that these mechanisms can represent a key therapeutic aspect to the successful development of new drugs to fight cancer

Summary

Introduction

The marine environment with its boundless chemodiversity represents a huge source of molecules with relevant potential in several pharmacological fields [1,2]. Among approved drugs based on compounds of marine origin, six are used in cancer therapy: cytarabine (Ara-C), eribulin mesylate (E7389), trabectedin (ET-743), brentuximab vedotin (SGN-35), polatuzamab vedotin and aplidin [3]. Many other compounds are currently under clinical investigations with promising anticancer activities [4]. Conventional anticancer drugs are cytotoxic substances having severe deleterious effects on tumor cells and on normal cells, especially if they are in rapid replication. The resulting anticancer activity avoids side effects on physiological functions, which rapidly made training of the immune system to fight cancer a new therapeutic approach. Research has increased the number of patients

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