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Proc Natl Acad Sci U S A. 2014 Oct 14;111(41):14687-92. doi: 10.1073/pnas.1410932111. Epub 2014 Sep 30.

Seriniquinone, a selective anticancer agent, induces cell death by autophagocytosis, targeting the cancer-protective protein dermcidin.

Author information

1
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093;
2
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093; Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brazil, 60430-270; jlaclair@ucsd.edu costalotufo@gmail.com wfenical@ucsd.edu.
3
Departamento de Fisiologia e Farmacologia, Universidade Federal do Ceará, Fortaleza, CE, Brazil, 60430-270;
4
Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA 92093; and jlaclair@ucsd.edu costalotufo@gmail.com wfenical@ucsd.edu.
5
Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California at San Diego, La Jolla, CA 92093; Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093 jlaclair@ucsd.edu costalotufo@gmail.com wfenical@ucsd.edu.

Abstract

Natural products continue to provide vital treatment options for cancer. Although their translation into chemotherapeutics is complex, collaborative programs continue to deliver productive pipelines for cancer chemotherapy. A new natural product, seriniquinone, isolated from a marine bacterium of the genus Serinicoccus, demonstrated potent activity over a select set of tumor cell lines with particular selectivity toward melanoma cell lines. Upon entering the cell, its journey began by localization into the endoplasmic reticulum. Within 3 h, cells treated with seriniquinone underwent cell death marked by activation of autophagocytosis and gradually terminated through a caspase-9 apoptotic pathway. Using an immunoaffinity approach followed by multipoint validation, we identified the target of seriniquinone as the small protein, dermcidin. Combined, these findings revealed a small molecule motif in parallel with its therapeutic target, whose potential in cancer therapy may be significant. This discovery defines a new pharmacophore that displayed selective activity toward a distinct set of cell lines, predominantly melanoma, within the NCI 60 panel. This selectivity, along with the ease in medicinal chemical modification, provides a key opportunity to design and evaluate new treatments for those cancers that rely on dermcidin activity. Further, the use of dermcidin as a patient preselection biomarker may accelerate the development of more effective personalized treatments.

KEYWORDS:

cancer; chemical biology; drug discovery; marine natural products; mode of action

PMID:
25271322
PMCID:
PMC4205641
DOI:
10.1073/pnas.1410932111
[Indexed for MEDLINE]
Free PMC Article

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