PMID- 15876859
OWN - NLM
STAT- MEDLINE
DCOM- 20060321
LR  - 20200930
IS  - 1538-4047 (Print)
IS  - 1538-4047 (Linking)
VI  - 4
IP  - 3
DP  - 2005 Mar
TI  - Inhibition of P-glycoprotein-mediated multidrug resistance by unfractionated 
      heparin: a new potential chemosensitizer for cancer therapy.
PG  - 313-7
AB  - Anticoagulant treatment with heparins is frequently used to prevent venous 
      thromboembolism in cancer patients. In the present study, we investigated the 
      ability of unfractionated heparin (UFH) to inhibit P-glycoprotein (Pgp)-mediated 
      multidrug resistance (MDR) on human breast cancer cell line (MDA-MB231) and its 
      doxo-resistant subline. Results were a compared to the classic reversing agent, 
      Verapamil (Ver), used, as reference at 50 microM concentration. We analysed the 
      Pgp function by calcein acetoxymethylester (calcein-AM) uptake, a fluorescent 
      marker substrate, before and after in vitro exposure to UFH at clinically 
      achievable dose of 20 U/ml. The mean percentage of calcein-AM retained into 
      cancer cells after 3 and 12 h were 32 +/- 10.9 and 45 +/- 12.3, respectively, for 
      UFH pretreated cells and 25.3 +/- 8.7 and 29.4 +/- 10.4, respectively, for Ver 
      pretreated cells when compared to control cells, receiving only medium. Pgp 
      activity was studied by measuring intracellular drug accumulation in 
      doxo-resistant subline, treated (2 h) with either UFH or Ver, prior exposure (2 
      h) at different doxo concentrations (2, 4 and 8 microM). The mean percentage of 
      remaining intracellular doxo were 55.4 +/- 4.5 , 51.4 +/- 3.9 and 50 +/- 1.8 
      percent, respectively for UFH treated cells, and 44.1 +/- 5.8, 39.3 +/- 4.4 and 
      19.4 +/- 8.6%, respectively, for Ver treated cells as compared with control 
      cells, receiving only doxo. These results were consistent with the increase of 
      sensitivity to doxo of the same doxo-resistant subline resulting in a 2.2, 2.6 
      and 2.2-fold increase, respectively, for UFH-doxo combination and 2.2, 2.5 and 
      2.0-fold respectively, for Ver-doxo combination respect to cells receiving doxo 
      alone, as assessed by MTT test. In conclusion, these findings demonstrate the 
      potentiating effect in vitro of UFH on doxo accumulation and cytotoxicity in the 
      MDA-231 cell line and its doxo-resistant subline and suggest that UFH could to be 
      used, as an potential chemosensitizer, in clinical chemotherapy for increasing in 
      vivo, the efficacy of the anticancer treatment.
FAU - Angelini, Antonio
AU  - Angelini A
AD  - Department of Medicine and Aging, Shool of Medicine and Aging Research Center, 
      Ce.S.I. Gabriele D'Annunzio, University Foundation, Chieti-Pescara, Italy. 
      aangelini@unich.it
FAU - Di Febbo, Concetta
AU  - Di Febbo C
FAU - Ciofani, Giuliano
AU  - Ciofani G
FAU - Di Nisio, Marcello
AU  - Di Nisio M
FAU - Baccante, Giovanna
AU  - Baccante G
FAU - Di Ilio, Carmine
AU  - Di Ilio C
FAU - Cuccurullo, Franco
AU  - Cuccurullo F
FAU - Porreca, Ettore
AU  - Porreca E
LA  - eng
PT  - Journal Article
DEP - 20050323
PL  - United States
TA  - Cancer Biol Ther
JT  - Cancer biology & therapy
JID - 101137842
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B, Member 1)
RN  - 0 (Fluoresceins)
RN  - 148504-34-1 (calcein AM)
RN  - 80168379AG (Doxorubicin)
RN  - 9005-49-6 (Heparin)
RN  - CJ0O37KU29 (Verapamil)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B, Member 1/*antagonists & inhibitors
MH  - Biological Transport
MH  - Breast Neoplasms/*drug therapy
MH  - Cell Line, Tumor
MH  - Doxorubicin/metabolism/therapeutic use
MH  - Drug Resistance, Multiple/*drug effects
MH  - Drug Resistance, Neoplasm/*drug effects
MH  - Female
MH  - Fluoresceins/metabolism
MH  - Heparin/*pharmacology
MH  - Humans
MH  - Verapamil/pharmacology
EDAT- 2005/05/07 09:00
MHDA- 2006/03/22 09:00
CRDT- 2005/05/07 09:00
PHST- 2005/05/07 09:00 [pubmed]
PHST- 2006/03/22 09:00 [medline]
PHST- 2005/05/07 09:00 [entrez]
AID - 1503 [pii]
AID - 10.4161/cbt.4.3.1503 [doi]
PST - ppublish
SO  - Cancer Biol Ther. 2005 Mar;4(3):313-7. doi: 10.4161/cbt.4.3.1503. Epub 2005 Mar 
      23.