PARP inhibitor PJ34 protects mitochondria and induces DNA-damage mediated apoptosis in combination with cisplatin or temozolomide in B16F10 melanoma cells

Anna Maria Cseh, Zsolt Fabian, Ruben Quintana-Cabrera, A. Szabó, Krisztian Eros, Maria Eugenia Soriano, F. Gallyas, Luca Scorrano, B. Sümegi

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.

Original languageEnglish
Article number538
JournalFrontiers in Physiology
Volume10
Issue numberMAY
DOIs
Publication statusPublished - Jan 1 2019

Fingerprint

temozolomide
Cisplatin
DNA Damage
Melanoma
Mitochondria
Apoptosis
Cell Survival
Mitochondrial Dynamics
Mitochondrial Membrane Potential
Alkylating Agents
Cytostatic Agents
Antineoplastic Agents
Therapeutics
DNA
Poly(ADP-ribose) Polymerase Inhibitors
N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride
Neoplasms

Keywords

  • Cancer
  • Cell death
  • Melanoma
  • Mitochondria
  • PARP

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

PARP inhibitor PJ34 protects mitochondria and induces DNA-damage mediated apoptosis in combination with cisplatin or temozolomide in B16F10 melanoma cells. / Cseh, Anna Maria; Fabian, Zsolt; Quintana-Cabrera, Ruben; Szabó, A.; Eros, Krisztian; Soriano, Maria Eugenia; Gallyas, F.; Scorrano, Luca; Sümegi, B.

In: Frontiers in Physiology, Vol. 10, No. MAY, 538, 01.01.2019.

Research output: Contribution to journalArticle

Cseh, Anna Maria ; Fabian, Zsolt ; Quintana-Cabrera, Ruben ; Szabó, A. ; Eros, Krisztian ; Soriano, Maria Eugenia ; Gallyas, F. ; Scorrano, Luca ; Sümegi, B. / PARP inhibitor PJ34 protects mitochondria and induces DNA-damage mediated apoptosis in combination with cisplatin or temozolomide in B16F10 melanoma cells. In: Frontiers in Physiology. 2019 ; Vol. 10, No. MAY.
@article{dbf82ac947574c1193287c047b0dad6a,
title = "PARP inhibitor PJ34 protects mitochondria and induces DNA-damage mediated apoptosis in combination with cisplatin or temozolomide in B16F10 melanoma cells",
abstract = "PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.",
keywords = "Cancer, Cell death, Melanoma, Mitochondria, PARP",
author = "Cseh, {Anna Maria} and Zsolt Fabian and Ruben Quintana-Cabrera and A. Szab{\'o} and Krisztian Eros and Soriano, {Maria Eugenia} and F. Gallyas and Luca Scorrano and B. S{\"u}megi",
year = "2019",
month = "1",
day = "1",
doi = "10.3389/fphys.2019.00538",
language = "English",
volume = "10",
journal = "Frontiers in Physiology",
issn = "1664-042X",
publisher = "Frontiers Research Foundation",
number = "MAY",

}

TY - JOUR

T1 - PARP inhibitor PJ34 protects mitochondria and induces DNA-damage mediated apoptosis in combination with cisplatin or temozolomide in B16F10 melanoma cells

AU - Cseh, Anna Maria

AU - Fabian, Zsolt

AU - Quintana-Cabrera, Ruben

AU - Szabó, A.

AU - Eros, Krisztian

AU - Soriano, Maria Eugenia

AU - Gallyas, F.

AU - Scorrano, Luca

AU - Sümegi, B.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.

AB - PARP-1 inhibition has recently been employed in both mono- and combination therapies in various malignancies including melanoma with both promising and contradicting results reported. Although deeper understanding of the underlying molecular mechanisms may help improving clinical modalities, the complex cellular effects of PARP inhibitors make disentangling of the mechanisms involved in combination therapies difficult. Here, we used two cytostatic agents used in melanoma therapies in combination with PARP inhibition to have an insight into cellular events using the B16F10 melanoma model. We found that, when used in combination with cisplatin or temozolomide, pharmacologic blockade of PARP-1 by PJ34 augmented the DNA-damaging and cytotoxic effects of both alkylating compounds. Interestingly, however, this synergism unfolds relatively slowly and is preceded by molecular events that are traditionally believed to support cell survival including the stabilization of mitochondrial membrane potential and morphology. Our data indicate that the PARP inhibitor PJ34 has, apparently, opposing effects on the mitochondrial structure and cell survival. While, initially, it stimulates mitochondrial fusion and hyperpolarization, hallmarks of mitochondrial protection, it enhances the cytotoxic effects of alkylating agents at later stages. These findings may contribute to the optimization of PARP inhibitor-based antineoplastic modalities.

KW - Cancer

KW - Cell death

KW - Melanoma

KW - Mitochondria

KW - PARP

UR - http://www.scopus.com/inward/record.url?scp=85068218276&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85068218276&partnerID=8YFLogxK

U2 - 10.3389/fphys.2019.00538

DO - 10.3389/fphys.2019.00538

M3 - Article

AN - SCOPUS:85068218276

VL - 10

JO - Frontiers in Physiology

JF - Frontiers in Physiology

SN - 1664-042X

IS - MAY

M1 - 538

ER -