title: Genomic profiling reveals the potential role of TCL1A and MDR1 deficiency in chemotherapy-induced cardiotoxicity.
abstract: BACKGROUND
  Anthracyclines, such as doxorubicin (Adriamycin), are highly effective chemotherapeutic agents, but are well known to cause myocardial dysfunction and life-threatening congestive heart failure (CHF) in some patients.
  
  
  METHODS
  To generate new hypotheses about its etiology, genome-wide transcript analysis was performed on whole blood RNA from women that received doxorubicin-based chemotherapy and either did, or did not develop CHF, as defined by ejection fractions (EF)≤40%. Women with non-ischemic cardiomyopathy unrelated to chemotherapy were compared to breast cancer patients prior to chemo with normal EF to identify heart failure-related transcripts in women not receiving chemotherapy. Byproducts of oxidative stress in plasma were measured in a subset of patients.
  
  
  RESULTS
  The results indicate that patients treated with doxorubicin showed sustained elevations in oxidative byproducts in plasma. At the RNA level, women who exhibited low EFs after chemotherapy had 260 transcripts that differed >2-fold (p<0.05) compared to women who received chemo but maintained normal EFs. Most of these transcripts (201) were not altered in non-chemotherapy patients with low EFs. Pathway analysis of the differentially expressed genes indicated enrichment in apoptosis-related transcripts. Notably, women with chemo-induced low EFs had a 4.8-fold decrease in T-cell leukemia/lymphoma 1A (TCL1A) transcripts. TCL1A is expressed in both cardiac and skeletal muscle, and is a known co-activator for AKT, one of the major pro-survival factors for cardiomyocytes. Further, women who developed low EFs had a 2-fold lower level of ABCB1 transcript, encoding the multidrug resistance protein 1 (MDR1), which is an efflux pump for doxorubicin, potentially leading to higher cardiac levels of drug. In vitro studies confirmed that inhibition of MDR1 by verapamil in rat H9C2 cardiomyocytes increased their susceptibility to doxorubicin-induced toxicity.
  
  
  CONCLUSIONS
  It is proposed that chemo-induced cardiomyopathy may be due to a reduction in TCL1A levels, thereby causing increased apoptotic sensitivity, and leading to reduced cardiac MDR1 levels, causing higher cardiac levels of doxorubicin and intracellular free radicals. If so, screening for TCL1A and MDR1 SNPs or expression level in blood, might identify women at greatest risk of chemo-induced heart failure.
authors: Department of Medicine, Division of Genomic Medicine, George Washington University School of Medicine and Health Sciences, Washington DC, USA.
authors: Timothy A
authors: TA
authors: McCaffrey
authors: Constantine
authors: C
authors: Tziros
authors: Jannet
authors: J
authors: Lewis
authors: Richard
authors: R
authors: Katz
authors: Robert
authors: R
authors: Siegel
authors: William
authors: W
authors: Weglicki
authors: Jay
authors: J
authors: Kramer
authors: I Tong
authors: IT
authors: Mak
authors: Ian
authors: I
authors: Toma
authors: Liang
authors: L
authors: Chen
authors: Elizabeth
authors: E
authors: Benas
authors: Alexander
authors: A
authors: Lowitt
authors: Shruti
authors: S
authors: Rao
authors: Linda
authors: L
authors: Witkin
authors: Yi
authors: Y
authors: Lian
authors: Yinglei
authors: Y
authors: Lai
authors: Zhaoqing
authors: Z
authors: Yang
authors: Sidney W
authors: SW
authors: Fu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D018943:Anthracyclines / Q000009:adverse effects / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced / Q000378:metabolism; D002478:Cells, Cultured; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000378:metabolism; D051381:Rats
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018943:Anthracyclines; D000970:Antineoplastic Agents; D011518:Proto-Oncogene Proteins; C090851:TCL1A protein, human; D004317:Doxorubicin
keywords: MDR1; TCL1A.; adriamycin; cardiomyopathy; doxorubicin; expression profiling; free radicals; heart failure; microarray; multidrug resistance protein
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