Drug repurposing screen identifies lestaurtinib amplifies the ability of the poly (ADP-ribose) polymerase 1 inhibitor AG14361 to kill breast cancer associated gene-1 mutant and wild type breast cancer cells.

Abstract

INTRODUCTION:

Breast cancer is a devastating disease that results in approximately 40,000 deaths each year in the USA. Current drug screening and chemopreventatitive methods are suboptimal, due in part to the poor specificity of compounds for cancer cells. Poly (ADP-ribose) polymerase 1 (PARP1) inhibitor (PARPi)-mediated therapy is a promising approach for familial breast cancers caused by mutations of breast cancer-associated gene-1 and -2 (BRCA1/2), yet drug resistance frequently occurs during the treatment. Moreover, PARPis exhibit very little effect on cancers that are proficient for DNA repair and clinical efficacy for PARPis as single-agent therapies has yet to be illustrated.

METHODS:

Using a quantitative high-throughput screening approach, we screened a library containing 2,816 drugs, most of which are approved for human or animal use by the Food and Drug Administration (FDA) or other countries, to identify compounds that sensitize breast cancer cells to PARPi. After initial screening, we performed further cellular and molecular analysis on lestaurtinib, which is an orally bioavailable multikinase inhibitor and has been used in clinical trials for myeloproliferative disorders and acute myelogenous leukemia.

RESULTS:

Our study indicated that lestaurtinib is highly potent against breast cancers as a mono-treatment agent. It also strongly enhanced the activity of the potent PARPi AG14361 on breast cancer cell growth both in vitro and in vivo conditions. The inhibition of cancer growth is measured by increased apoptosis and reduced cell proliferation. Consistent with this, the treatment results in activation of caspase 3/7, and accumulation of cells in the G2 phase of the cell cycle, irrespective of their BRCA1 status. Finally, we demonstrated that AG14361 inhibits NF-κB signaling, which is further enhanced by lestaurtinib treatment.

CONCLUSIONS:

Lestaurtinib amplifies the ability of the PARP1 inhibitor AG14361 to kill BRCA1 mutant and wild-type breast cancer cells, at least in part, by inhibiting NF-κB signaling. Each of these drugs has been approved for clinical trials for several different cancers, thus, their combination treatment should be applicable for a breast cancer trial in the future.

• Authors: Guelaguetza Vazquez-Ortiz, Cristine Chisholm, Xiaoling Xu, Tyler J Lahusen, Cuiling Li, Srilatha Sakamuru, Ruili Huang, Craig J Thomas, Menghang Xia, Chuxia Deng
• Journal: Breast cancer research : BCR (Breast Cancer Res) Vol. 16 Issue 3 Pg. R67 (Jun 24 2014) ISSN: 1465-542X [Electronic] England
• PMID: 24962108 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• 1-(4-dimethylaminomethylphenyl)-8,9-dihydro-7H-2,7,9a-benzo(cd)azulen-6-one
• Antineoplastic Agents
• Azulenes
• BRCA1 Protein
• BRCA1 protein, human
• Carbazoles
• Furans
• NF-kappa B
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA, Small Interfering
• Benzodiazepines
• lestaurtinib
• Parp1 protein, mouse
• Poly (ADP-Ribose) Polymerase-1
• Caspase 3
• Caspase 7

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Azulenes (pharmacology)
• BRCA1 Protein (genetics)
• Benzodiazepines (pharmacology)
• Breast Neoplasms (drug therapy, genetics)
• Carbazoles (pharmacology)
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Drug Repositioning
• Drug Resistance, Neoplasm
• Drug Synergism
• Female
• Furans
• G2 Phase Cell Cycle Checkpoints (drug effects)
• High-Throughput Screening Assays
• Humans
• Mice
• Mice, Nude
• NF-kappa B (antagonists & inhibitors)
• Neoplasm Transplantation
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerase Inhibitors
• RNA Interference
• RNA, Small Interfering