The Zinc-Schiff Base-Novicidin Complex as a Potential Prostate Cancer Therapy

Vedran Milosavljevic; Yazan Haddad; Miguel Angel Merlos Rodrigo; Amitava Moulick; Hana Polanska; David Hynek; Zbynek Heger; Pavel Kopel; Vojtech Adam

doi:10.1371/journal.pone.0163983

The Zinc-Schiff Base-Novicidin Complex as a Potential Prostate Cancer Therapy

PLoS One. 2016 Oct 11;11(10):e0163983. doi: 10.1371/journal.pone.0163983. eCollection 2016.

Authors

Vedran Milosavljevic¹, Yazan Haddad¹, Miguel Angel Merlos Rodrigo^{1

2}, Amitava Moulick², Hana Polanska³, David Hynek^{1

2}, Zbynek Heger^{1

2}, Pavel Kopel^{1

2}, Vojtech Adam^{1

2}

Affiliations

¹ Department of Chemistry and Biochemistry, Mendel University in Brno, Zemedelska 1, CZ-613 00, Brno, Czech Republic, European Union.
² Central European Institute of Technology, Brno University of Technology, Purkynova 123, CZ-612 00, Brno, Czech Republic, European Union.
³ Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, CZ-625 00, Brno, Czech Republic, European Union.

Abstract

Prostate cancer cells control energy metabolism by chelating intracellular zinc. Thus, zinc delivery has been a popular therapeutic approach for prostate cancer. Here, we propose the use of the membrane-penetrating peptide Novicidin connected to zinc-Schiff base as a carrier vehicle for the delivery of zinc to prostate cells. Mass spectrometry, electrochemistry and spectrophotometry confirmed the formation/stability of this complex and provided insight regarding the availability of zinc for complex interactions. This delivery system showed minor toxicity in normal PNT1A cells and high potency towards PC3 tumor cells. The complex preferentially penetrated PC3 tumor cells in contrast to confinement to the membranes of PNT1A. Furthermore, zinc uptake was confirmed in both cell lines. Molecular analysis was used to confirm the activation of zinc stress (e.g., ZnT-1) and apoptosis (e.g., CASP-1). Our results strongly suggest that the zinc-Schiff base-Novicidin complex has great potential as a novel anticancer drug.

MeSH terms

Antimicrobial Cationic Peptides / chemistry*
Antineoplastic Agents / chemistry*
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Apoptosis / drug effects
Caspase 1 / metabolism
Cation Transport Proteins / metabolism
Cell Line, Tumor
Coordination Complexes / chemistry*
Coordination Complexes / pharmacology
Coordination Complexes / therapeutic use
Gene Expression / drug effects
Humans
Male
Microscopy, Fluorescence
Molecular Conformation
Prostatic Neoplasms / drug therapy
Schiff Bases / chemistry*
Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
Zinc / chemistry*
Zinc / metabolism

Substances

Antimicrobial Cationic Peptides
Antineoplastic Agents
Cation Transport Proteins
Coordination Complexes
SLC30A1 protein, human
Schiff Bases
novicidin
Caspase 1
Zinc

Grants and funding

This research was carried out under the project CEITEC 2020 (LQ1601) with financial support from the Ministry of Education, Youth and Sports of the Czech Republic under the National Sustainability Programme II and GACR 16-18917S.