Biomedicine & Pharmacotherapy (Jun 2023)

Exploiting bioactive natural products of marine origin: Evaluation of the meroterpenoid metachromin V as a novel potential therapeutic drug for colorectal cancer

  • Donatella Lucchetti,
  • Francesca Luongo,
  • Filomena Colella,
  • Enrico Gurreri,
  • Giulia Artemi,
  • Claudia Desiderio,
  • Stefano Serra,
  • Felice Giuliante,
  • Ruggero De Maria,
  • Alessandro Sgambato,
  • Alberto Vitali,
  • Micol Eleonora Fiori

Journal volume & issue
Vol. 162
p. 114679

Abstract

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Colorectal cancer (CRC) is the second most common cause of cancer death, leading to almost 1 million deaths per year. Despite constant progress in surgical and therapeutic protocols, the 5-year survival rate of advanced CRC patients remains extremely poor. Colorectal Cancer Stem Cells (CRC-CSCs) are endowed with unique stemness-related properties responsible for resistance, relapse and metastasis. The development of novel therapeutics able to tackle CSCs while avoiding undesired toxicity is a major need for cancer treatment. Natural products are a large reservoir of unexplored compounds with possible anticancer bioactivity, sustainability, and safety. The family of meroterpenoids derived from sponges share interesting bioactive properties. Bioassay-guided fractionation of a meroterpenoids extract led to the isolation of three compounds, all cytotoxic against several cancer cell lines: Metachromins U, V and W. In this study, we evaluated the anticancer potential of the most active one, Metachromins V (MV), on patient-derived CRC-CSCs. MV strongly impairs CSCs-viability regardless their mutational background and the cytotoxic effect is maintained on therapy-resistant metastatic CSCs. MV affects cell cycle progression, inducing a block in G2 phase in all the cell lines tested and more pronouncedly in CRC-CSCs. Moreover, MV triggers an important reorganization of the cytoskeleton and a strong reduction of Rho GTPases expression, impairing CRC-CSCs motility and invasion ability. By Proteomic analysis identified a potential molecular target of MV: CCAR1, that regulates apoptosis under chemotherapy treatments and affect β-catenin pathway. Further studies will be needed to confirm and validate these data in in vivo experimental models

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