PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells.

08:00 EDT 7th May 2019 | BioPortfolio

Summary of "PARP Inhibitor PJ34 Protects Mitochondria and Induces DNA-Damage Mediated Apoptosis in Combination With Cisplatin or Temozolomide in B16F10 Melanoma Cells."

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.


Journal Details

This article was published in the following journal.

Name: Frontiers in physiology
ISSN: 1664-042X
Pages: 538


DeepDyve research library

PubMed Articles [14478 Associated PubMed Articles listed on BioPortfolio]

Doxorubicin-induced testicular damage is related to PARP-1 signaling molecules in mice.

Doxorubicin (DOX), is a chemotherapeutic agent, which evokes oxidative stress and cell apoptosis in testicular tissue. It is known that the activation of the nuclear enzyme poly (ADP-ribose) polymeras...

PJ34, a PARP1 inhibitor, promotes endothelial repair in a rabbit model of high fat diet-induced atherosclerosis.

: Atherosclerosis involves endothelial injury caused by oxidative stress. Endothelial progenitor cells (EPCs) play important roles in preventing the early stages of atherosclerosis. Meanwhile, poly (A...

An alternative mitophagy pathway mediated by Rab9 protects the heart against ischemia.

Energy stress, such as ischemia, induces mitochondrial damage and death in the heart. Degradation of damaged mitochondria by mitophagy is essential for the maintenance of healthy mitochondria and surv...

Acquired Resistance of EGFR-Mutated Lung Cancer to Tyrosine Kinase Inhibitor Treatment Promotes PARP Inhibitor Sensitivity.

Lung cancers with oncogenic mutations in the epidermal growth factor receptor (EGFR) invariably acquire resistance to tyrosine kinase inhibitor (TKI) treatment. Vulnerabilities of EGFR TKI-resistant c...

Combination of PARP inhibitor and temozolomide to suppress chordoma progression.

Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we ...

Clinical Trials [5772 Associated Clinical Trials listed on BioPortfolio]

Investigation of Anti-tumour Effect and Tolerability of the PARP Inhibitor 2X-121 in Patients With Metastatic Breast Cancer Selected by the 2X-121 DRP

2X-121 is a small molecule targeted inhibitor of Poly ADP ribose polymerase (PARP), a key enzyme involved in DNA damage repair in cancer cells. The PARP inhibitor demonstrated clinical act...

Study to Assess the Safety and Tolerability of a PARP Inhibitor in Combination With Carboplatin and/or Paclitaxel

The purpose of this study is to identify a safe and tolerable dose of the drug KU-0059436 that can be given in combination with carboplatin and/or Paclitaxel chemotherapy

Study of the Poly (ADP-ribose) Polymerase-1 (PARP-1) Inhibitor BSI-201 in Patients With Newly Diagnosed Malignant Glioma

The phase I portion of study is designed to determine the Maximum Tolerated Dose (MTD) of BSI-201 with two clinically relevant dosing regimens of temozolomide (TMZ). Secondary objectives ...

Trial of MitoQ for Raised Liver Enzymes Due to Hepatitis C

A Phase 2, randomized, double-blind, parallel design trial of two doses of mitoquinone mesylate (MitoQ) and of placebo in patients with chronic Hepatitis C. MitoQ is a mitochondria-target...

MK4827 in Patients With Advanced Solid Tumors

This study will be a two part study. Part A will determine: 1) whether MK4827 is generally safe well-tolerated to warrant further studies; and 2) whether MK4827 causes at least 50% inhibi...

Medical and Biotech [MESH] Definitions

Mitochondria of skeletal and smooth muscle. It does not include myocardial mitochondria for which MITOCHONDRIA, HEART is available.

An inhibitor of apoptosis protein that is translated by a rare cap-independent mechanism. It blocks caspase-mediated cellular destruction by inhibiting CASPASE 3; CASPASE 7; and CASPASE 9.

Substances that influence the course of a chemical reaction by ready combination with free radicals. Among other effects, this combining activity protects pancreatic islets against damage by cytokines and prevents myocardial and pulmonary perfusion injuries.

A butyryl-beta-alanine that can also be viewed as pantoic acid complexed with BETA ALANINE. It is incorporated into COENZYME A and protects cells against peroxidative damage by increasing the level of GLUTATHIONE.

An intracellular cystatin subtype that is found in a broad variety of cell types. It is a cytosolic enzyme inhibitor that protects the cell against the proteolytic action of lysosomal enzymes such as CATHEPSINS.

Quick Search


DeepDyve research library

Relevant Topics

Bioinformatics is the application of computer software and hardware to the management of biological data to create useful information. Computers are used to gather, store, analyze and integrate biological and genetic information which can then be applied...

Melanoma is a highly malignant tumor of melanin-forming cells (melanocytes) There are most commonly found in the skin (resulting from sunlight exposure), but also in the eyes and mucous membranes. Metastasis to other regions of the body is also common....

Searches Linking to this Article