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The marine natural product Scalarin inhibits the receptor for advanced glycation end products (RAGE) and autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines

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Summary

Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Although combination therapies are showing improvements in treatment, the survival rate for pancreatic cancer five years post diagnosis is only 8%, stressing the need for new treatments. The receptor for advanced glycation end products (RAGE) has recently emerged as a chemotherapeutic target in KRAS driven pancreatic cancers both for treatment and in chemoprevention. RAGE appears to be an important regulator of inflammatory, stress and survival pathways that lead to carcinogenesis, resistance to chemotherapy, enhanced proliferation and the high metastatic potential of pancreatic cancer. RAGE expression has been demonstrated in pancreatic cancer tumors but not in adjacent epithelial tissues. Its presence is associated with increased proliferation and metastasis. In an effort to identify novel inhibitors of RAGE among our collection of marine-derived secondary metabolites, a cell-based screening assay utilizing flow cytometry was developed. This effort led to the identification of scalarin as the active compound in a marine sponge identified as Euryspongia cf. rosea. Scalarin is a sesterterpene natural product isolated previously from a different marine sponge. Scalarin reduces the levels of RAGE and inhibits autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. Its IC50 for cytotoxicity ranges between 20 and 30 μM in the AsPC-1, PANC-1, MIA PaCa-2 and BxPC-3 pancreatic cancer cell lines. Inhibition of autophagy limits tumor growth and tumorigenesis in pancreatic cancer, making scalarin an interesting compound that may merit further study.

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Acknowledgements

Funding for this project was provided by the National Institutes of Health R21CA176222 awarded to Dr. Guzmán. Research Excellence funds from the Harbor Branch Oceanographic Institute Foundation (HBOIF) awarded to Dr. Guzmán and Dr. Wright contributed to finalizing this publication. We thank Dr. Peter McCarthy for proofreading the article. This is HBOI contribution number 2167.

Funding

This study was funded by the National Institutes of Health R21CA176222.

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Authors and Affiliations

  1. Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute at Florida Atlantic University, 5600 US 1 North, Fort Pierce, FL, 34946, USA

    Esther Amalia Guzmán, Tara Peterson Pitts, Maria Cristina Diaz & Amy Elizabeth Wright

Authors
  1. Esther Amalia Guzmán
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  2. Tara Peterson Pitts
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  3. Maria Cristina Diaz
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  4. Amy Elizabeth Wright
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Corresponding author

Correspondence to Esther Amalia Guzmán.

Ethics declarations

Only invertebrate not-sentient marine sponges were used in this study. Projects using invertebrates are not subject to review by the Institutional Animal Care and Use Committee of Florida Atlantic University. This article does not contain studies with human participants or vertebrate animals performed by any of the authors.

Conflict of interest

All authors—Guzmán, Pitts, Diaz and Wright—declare that they have no conflicts of interest.

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Guzmán, E.A., Pitts, T.P., Diaz, M.C. et al. The marine natural product Scalarin inhibits the receptor for advanced glycation end products (RAGE) and autophagy in the PANC-1 and MIA PaCa-2 pancreatic cancer cell lines. Invest New Drugs 37, 262–270 (2019). https://doi.org/10.1007/s10637-018-0635-4

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  • DOI: https://doi.org/10.1007/s10637-018-0635-4

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