pgp - publications

Predict more pgp - ligand interactions now!


1. Proc Natl Acad Sci U S A. 2012 May 21. [Epub ahead of print]

Heat shock factor-1 knockout induces multidrug resistance gene, MDR1b, and
enhances P-glycoprotein (ABCB1)-based drug extrusion in the heart.

Krishnamurthy K, Vedam K, Kanagasabai R, Druhan LJ, Ilangovan G.

Departments of Internal Medicine and Anesthesiology, Division of Cardiovascular
Medicine, Davis Heart and Lung Research Institute, The Ohio State University,
Columbus, OH 43210.

Heat-shock factor 1 (HSF-1), a transcription factor for heat-shock proteins
(HSPs), is known to interfere with the transcriptional activity of many oncogenic
factors. In the present work, we have discovered that HSF-1 ablation induced the
multidrug resistance gene, MDR1b, in the heart and increased the expression of
P-glycoprotein (P-gp, ABCB1), an ATP binding cassette that is usually associated
with multidrug-resistant cancer cells. The increase in P-gp enhanced the
extrusion of doxorubicin (Dox) to alleviate Dox-induced heart failure and reduce
mortality in mice. Dox-induced left ventricular (LV) dysfunction was
significantly reduced in HSF-1(-/-) mice. DNA-binding activity of NF-κB was
higher in HSF-1(-/-) mice. IκB, the NF-κB inhibitor, was depleted due to enhanced
IκB kinase (IKK)-α activity. In parallel, MDR1b gene expression and a large
increase in P-gp and lowering Dox loading were observed in HSF-1(-/-) mouse
hearts. Moreover, application of the P-gp antagonist, verapamil, increased Dox
loading in HSF-1(-/-) cardiomyocytes, deteriorated cardiac function in HSF-1(-/-)
mice, and decreased survival. MDR1 promoter activity was higher in HSF-1(-/-)
cardiomyocytes, whereas a mutant MDR1 promoter with heat-shock element (HSE)
mutation showed increased activity only in HSF-1(+/+) cardiomyocytes. However,
deletion of HSE and NF-κB binding sites diminished luminescence in both
HSF-1(+/+) and HSF-1(-/-) cardiomyocytes, suggesting that HSF-1 inhibits MDR1
activity in the heart. Thus, because high levels of HSF-1 are attributed to poor
prognosis of cancer, systemic down-regulation of HSF-1 before chemotherapy is a
potential therapeutic approach to ameliorate the chemotherapy-induced
cardiotoxicity and enhance cancer prognosis.

PMID: 22615365 [PubMed - as supplied by publisher]