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

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.

• Authors: Lynnie Trzoss, Takashi Fukuda, Letícia V Costa-Lotufo, Paula Jimenez, James J La Clair, William Fenical
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 111 Issue 41 Pg. 14687-92 (Oct 14 2014) ISSN: 1091-6490 [Electronic] United States
• PMID: 25271322 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Dermcidins
• Quinones

Topics

• Amino Acid Sequence
• Antineoplastic Agents (chemical synthesis, chemistry, isolation & purification, pharmacology)
• Autophagy (drug effects)
• Cell Cycle (drug effects)
• Dermcidins (antagonists & inhibitors, metabolism)
• Electrophoresis, Polyacrylamide Gel
• HCT116 Cells
• Humans
• Magnetic Resonance Spectroscopy
• Microscopy, Fluorescence
• Molecular Sequence Data
• Molecular Targeted Therapy
• Phagocytosis (drug effects)
• Quinones (chemical synthesis, chemistry, isolation & purification, pharmacology)
• Subcellular Fractions (drug effects, metabolism)