Features Partner Sites Information LinkXpress
Sign In
Advertise with Us
RANDOX LABORATORIES

Events

10 Oct 2016 - 12 Oct 2016
12 Nov 2016 - 16 Nov 2016

PARP Inhibitors Destroy Cisplatin-Resistant Lung Cancer Cells

By BiotechDaily International staff writers
Posted on 15 Apr 2013
Print article
After relapse from treatment with the chemotherapeutic drug cisplatin, some types of cancer cells become dependent on the activity of the enzyme PARP1 (poly (ADP-ribose) polymerase1), which renders them susceptible to attack by the new generation of PARP inhibitors.

PARP enzymes are essential in a number of cellular functions, including expression of inflammatory genes. This protein is found in the nucleus of cells where its primary function is to detect and signal single-strand DNA breaks (SSB) to the enzyme mechanisms involved in SSB repair. PARP activation is an immediate cellular response to metabolic, chemical, or radiation-induced DNA SSB damage. Once PARP detects a SSB, it binds to the DNA, and, after a structural change, begins the synthesis of a poly (ADP-ribose) (PAR) chain as a signal for the other DNA-repairing enzymes. After completing the repair, the PAR chains are degraded via poly (ADP-ribose) glycohydrolase (PARG).

Investigators at University Paris Descartes (Paris, France) used non-small-cell lung cancer (NSCLC) cells to study the role of PARP1 in the aftermath of cisplatin treatment. They chose this model system because NSCLC is the leading cause of cancer-related morbidity and mortality worldwide, and patients with NSCLC are frequently treated with cisplatin.

They reported in the April 1, 2013, issue of the journal Cancer Research that PARP1 was highly expressed and constitutively hyperactivated in a majority of human cisplatin-resistant cancer cells. Cells manifesting elevated intracellular levels of poly(ADP-ribosyl)ated (PAR) proteins responded to pharmacologic PARP inhibitors as well as to PARP1-targeting siRNAs (small interfering RNAs) initiating a DNA damage response that translated into cell death following the activation of the intrinsic pathway of apoptosis. Complementing the findings in NSCLC, hyperactivated PARP1 was detected in cisplatin-resistant mesothelioma, ovarian cancer, and cervical cancer cell lines.

PARP1-overexpressing NSCLC tumor cells and xenografts displayed elevated levels of PAR, which predicted the response to PARP inhibitors in vitro and in vivo more accurately than PARP1 expression itself.

"Cisplatin is one of the most widely used conventional, anticancer chemotherapy drugs," said senior author Dr. Guido Kroemer, professor of medicine at University Paris Descartes. "Unfortunately, most patients respond only transiently to cisplatin therapy because their cancer cells develop ways to resist the effects of the drug. Our data show that in most cases, cisplatin resistance is linked to stereotyped biochemical changes in cancer cells that render them vulnerable to PARP inhibitors. This has clear implications for new treatment regimens and for developing biomarkers of response to cisplatin. We are following up these exciting clinical possibilities in our laboratory."

Related Links:
University Paris Descartes



Print article

Channels

Drug Discovery

view channel
Image: Ginger is the source of a novel class of nanolipid transport vector (Photo courtesy of Georgia State University).

Ginger-Derived Doxorubicin-Loaded Nanovectors as Drug Delivery for Cancer Therapy

A novel type of nanoparticle drug transport system based on lipids isolated from ginger was used to deliver the toxic chemotherapeutic agent doxorubicin (Dox) to colon cancer cells with minimal damage... Read more

Biochemistry

view channel
Image: A space-filling model of the anticonvulsant drug carbamazepine (Photo courtesy of Wikimedia Commons).

Wastewater May Contaminate Crops with Potentially Dangerous Pharmaceuticals

Reclaimed wastewater used to irrigate crops is contaminated with pharmaceutical residues that can be detected in the urine of those who consumed such produce. Investigators at the Hebrew University... Read more

Business

view channel

Collaborative Agreement to Aid in Setting Guidelines for Evaluating Potential Ebola Therapy

Cooperation between an Israeli biopharmaceutical company and medical branches of the US government is designed to set ground rules for continued evaluation of an experimental therapy for Ebola virus disease. RedHill Biopharma Ltd. (Tel Aviv, Israel), a biopharmaceutical company primarily focused on development and c... Read more
Copyright © 2000-2016 Globetech Media. All rights reserved.