The cytotoxic and pro-apoptotic activities of the novel fluoropyrimidine F10 towards prostate cancer cells are enhanced by Zn(2+) -chelation and inhibiting the serine protease Omi/HtrA2.

Abstract

BACKGROUND:

Intracellular Zn(2+) levels decrease during prostate cancer progression and agents that modulate intracellular Zn(2+) are cytotoxic to prostate cancer cells by an incompletely described mechanism. F10 is a new polymeric fluoropyrimidine drug-candidate that displays strong activity with minimal systemic toxicity in pre-clinical models of prostate cancer and other malignancies. The effects of exogenous Zn(2+) or Zn(2+) chelation for enhancing F10 cytotoxicity are investigated as is the role of Omi/HtrA2, a serine protease that promotes apoptosis in response to cellular stress.

METHODS:

To test the hypothesis that the pro-apoptotic effects of F10 could be enhanced by modulating intracellular Zn(2+) we investigated cell-permeable and cell-impermeable Zn(2+) chelators and exogenous Zn(2+) and evaluated cell viability and apoptosis in cellular models of castration-resistant prostate cancer (CRPC; PC3, C4-2). The role of Omi/HtrA2 for modulating apoptosis was evaluated by pharmacological inhibition and Western blotting.

RESULTS:

Exogenous Zn(2+) initially reduced prostate cancer cell viability but these effects were transitory and were ineffective at enhancing F10 cytotoxicity. The cell-permeable Zn(2+) -chelator tetrakis-(2-pyridylmethl) ethylenediamine (TPEN) induced apoptosis in prostate cancer cells and enhanced the pro-apoptotic effects of F10. The pro-apoptotic effects of Zn(2+) -chelation in combination with F10 treatment were enhanced by inhibiting Omi/HtrA2 implicating this serine protease as a novel target for prostate cancer treatment.

CONCLUSIONS:

Zn(2+) -chelation enhances the pro-apoptotic effects of F10 and may be useful for enhancing the effectiveness of F10 for treatment of advanced prostate cancer. The serine protease Omi/HtrA2 modulates Zn(2+) -dependent apoptosis in prostate cancer cells and represents a new target for treatment of CRPC. Prostate 75:360-369, 2015. © 2014 Wiley Periodicals, Inc.

• Authors: William H Gmeiner, Olcay Boyacioglu, Christopher H Stuart, Jamie Jennings-Gee, K C Balaji
• Journal: The Prostate (Prostate) Vol. 75 Issue 4 Pg. 360-9 (Mar 01 2015) ISSN: 1097-0045 [Electronic] United States
• PMID: 25408502 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Wiley Periodicals, Inc.

Chemical References

• Chelating Agents
• Ethylenediamines
• FdUMP(10)
• Mitochondrial Proteins
• Fluorodeoxyuridylate
• Serine Endopeptidases
• HTRA2 protein, human
• High-Temperature Requirement A Serine Peptidase 2
• Zinc
• N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine

Topics

• Apoptosis (drug effects)
• Chelating Agents (pharmacology)
• Ethylenediamines (pharmacology)
• Fluorodeoxyuridylate (analogs & derivatives, pharmacology, therapeutic use)
• High-Temperature Requirement A Serine Peptidase 2
• Humans
• Male
• Mitochondrial Proteins (antagonists & inhibitors)
• Prostatic Neoplasms (drug therapy, metabolism, pathology)
• Serine Endopeptidases
• Zinc (metabolism)