Bioactivity Screening of Antarctic Sponges Reveals Anticancer Activity and Potential Cell Death via Ferroptosis by Mycalols.

Gennaro Riccio,Daniela Coppola,Genoveffa Nuzzo,Gianluca Zazo,Daniela Giordano,Cinzia Verde,Giuseppina Senese,Adrianna Ianora,Chiara Lauritano,Marco Bertolino,Nadia Ruocco,Lucia Romano,Angelo Fontana,Maria Costantini

doi:10.3390/md19080459

Abstract

Sponges are known to produce a series of compounds with bioactivities useful for human health. This study was conducted on four sponges collected in the framework of the XXXIV Italian National Antarctic Research Program (PNRA) in November-December 2018, i.e., Mycale (Oxymycale) acerata, Haliclona (Rhizoniera) dancoi, Hemimycale topsenti, and Hemigellius pilosus. Sponge extracts were fractioned and tested against hepatocellular carcinoma (HepG2), lung carcinoma (A549), and melanoma cells (A2058), in order to screen for antiproliferative or cytotoxic activity. Two different chemical classes of compounds, belonging to mycalols and suberitenones, were identified in the active fractions. Mycalols were the most active compounds, and their mechanism of action was also investigated at the gene and protein levels in HepG2 cells. Of the differentially expressed genes, ULK1 and GALNT5 were the most down-regulated genes, while MAPK8 was one of the most up-regulated genes. These genes were previously associated with ferroptosis, a programmed cell death triggered by iron-dependent lipid peroxidation, confirmed at the protein level by the down-regulation of GPX4, a key regulator of ferroptosis, and the up-regulation of NCOA4, involved in iron homeostasis. These data suggest, for the first time, that mycalols act by triggering ferroptosis in HepG2 cells.

Highlights

IntroductionMarine organisms represent an excellent source of natural products with bioactivities useful for the treatment and prevention of human pathologies, such as cancer, inflammation, and infections
The C7 specimen belongs to the species
We further investigated the cell death pathway triggered by the pool of mycalols in hepatocellular carcinoma cells

Summary

Introduction

Marine organisms represent an excellent source of natural products with bioactivities useful for the treatment and prevention of human pathologies, such as cancer, inflammation, and infections. The chemistry of natural products derived from marine organisms has received growing interest in the scientific community. There are fourteen approved pharmaceutical products in clinical use and more than 20 marine natural products in various stages of clinical development (i.e., four compounds in Phase III, twelve in Phase II, and seven in Phase I clinical trials), especially in the field of oncology These compounds have been identified mainly from invertebrates, such as sponges, mollusks, bryozoans, and ascidians. The last two drugs approved in 2020 are Belantamabmafodotinblmf (BlenrepTM ) from a mollusk/cyanobacterium for the treatment of relapsed/refractory multiple myeloma and Lurbinectedin (ZepzelcaTM ) from a tunicate for metastatic small cell lung cancer treatment

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