Synergistic anticancer effects of the 9.2.27PE immunotoxin and ABT-737 in melanoma

In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE)-based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination re...

Full description

Saved in:
Bibliographic Details
Published in:PloS one 2011-09, Vol.6 (9), p.e24012
Main Authors: Risberg, Karianne, Fodstad, Øystein, Andersson, Yvonne
Format: Article
Language:English
Subjects:
Adenosine diphosphate
Aging
Analysis
Animal models
Animals
Anticancer properties
Antigens
Antineoplastic Agents - pharmacology
Antineoplastic Agents - therapeutic use
Antineoplastic Combined Chemotherapy Protocols
Apoptosis
Biology
Biphenyl Compounds - pharmacology
Biphenyl Compounds - therapeutic use
Blotting, Western
Calcium
Calcium (intracellular)
Calcium - metabolism
Cancer
Cancer treatment
Caspase
Caspase-3
cathepsins
Cell death
Cell Line, Tumor
Cell Survival - drug effects
Clinical trials
Combination drug therapy
Cytotoxicity
Deactivation
Deoxyribonucleic acid
DNA
DNA fragmentation
DNA Fragmentation - drug effects
Drug delivery
Drug therapy
Drugs
Endoplasmic reticulum
Exotoxin A
Female
Hepatology
Humans
Immunotoxins
Immunotoxins - pharmacology
Immunotoxins - therapeutic use
Inactivation
Initiation factor eIF-2
Intracellular
Kinases
Lymphoma
Mcl-1 protein
Medical research
Medicine
Melanoma
Melanoma - drug therapy
Melanoma - metabolism
Membrane Potential, Mitochondrial - drug effects
Metastasis
Mice
Mice, Nude
Nitrophenols - pharmacology
Nitrophenols - therapeutic use
Piperazines - pharmacology
Piperazines - therapeutic use
Poly(ADP-ribose) polymerase
Protein synthesis
Proteins
Pseudomonas
Ribonucleic acid
Ribose
RNA
Rodents
Signal transduction
Sulfonamides - pharmacology
Sulfonamides - therapeutic use
Toxicity
Tumors
Xenograft Model Antitumor Assays
Xenografts
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:In cancer, combinations of drugs targeting different cellular functions is well accepted to improve tumor control. We studied the effects of a Pseudomonas exotoxin A (PE)-based immunotoxin, the 9.2.27PE, and the BH-3 mimetic compound ABT-737 in a panel of melanoma cell lines. The drug combination resulted in synergistic cytotoxicity, and the cell death observed was associated with apoptosis, as activation of caspase-3, inactivation of Poly (ADP-ribose) polymerase (PARP) and increased DNA fragmentation could be prevented by pre-treatment with caspase and cathepsin inhibitors. We further show that ABT-737 caused endoplasmic reticulum (ER) stress with increased GRP78 and phosphorylated eIF2α protein levels. Moreover, treatment with ABT-737 increased the intracellular calcium levels, an effect which was enhanced by 9.2.27PE, which as a single entity drug had minimal effect on calcium release from the ER. In addition, silencing of Mcl-1 by short hairpin RNA (shRNA) enhanced the intracellular calcium levels and cytotoxicity caused by ABT-737. Notably, the combination of 9.2.27PE and ABT-737 caused growth delay in a human melanoma xenograft mice model, supporting further investigations of this particular drug combination.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0024012