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Int. J. Mol. Sci. 2012, 13(1), 369-382; doi:10.3390/ijms13010369

Potentiation of Anticancer Drugs: Effects of Pentoxifylline on Neoplastic Cells

1,* , 2
1 Institute for Heart Research, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava 840 05, Slovakia 2 Institute of Molecular Physiology and Genetics, Centre of Excellence of the Slovak Research and Development Agency “BIOMEMBRANES 2008” Slovak Academy of Sciences, Vlárska 5, Bratislava 83334, Slovakia 3 Cancer Research Institute, Slovak Academy of Sciences, Vlárska 7, Bratislava 833 91, Slovakia
* Authors to whom correspondence should be addressed.
Received: 8 November 2011 / Revised: 7 December 2011 / Accepted: 13 December 2011 / Published: 28 December 2011
(This article belongs to the Section Molecular Toxicology)
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The drug efflux activity of P-glycoprotein (P-gp, a product of the mdr1 gene, ABCB1 member of ABC transporter family) represents a mechanism by which tumor cells escape death induced by chemotherapeutics. In this study, we investigated the mechanisms involved in the effects of pentoxifylline (PTX) on P-gp-mediated multidrug resistance (MDR) in mouse leukemia L1210/VCR cells. Parental sensitive mouse leukemia cells L1210, and multidrug-resistant cells, L1210/VCR, which are characterized by the overexpression of P-gp, were used as experimental models. The cells were exposed to 100 μmol/L PTX in the presence or absence of 1.2 μmol/L vincristine (VCR). Western blot analysis indicated a downregulation of P-gp protein expression when multidrug-resistant L1210/VCR cells were exposed to PTX. The effects of PTX on the sensitization of L1210/VCR cells to VCR correlate with the stimulation of apoptosis detected by Annexin V/propidium iodide apoptosis necrosis kit and proteolytic activation of both caspase-3 and caspase-9 monitored by Western blot analysis. Higher release of matrix metalloproteinases (MMPs), especially MMP-2, which could be attenuated by PTX, was found in L1210/VCR than in L1210 cells by gelatin zymography in electrophoretic gel. Exposure of resistant cells to PTX increased the content of phosphorylated Akt kinase. In contrast, the presence of VCR eliminated the effects of PTX on Akt kinase phosphorylation. Taken together, we conclude that PTX induces the sensitization of multidrug-resistant cells to VCR via downregulation of P-gp, stimulation of apoptosis and reduction of MMPs released from drug-resistant L1210/VCR cells. These facts bring new insights into the mechanisms of PTX action on cancer cells.
Keywords: pentoxifylline; P-glycoprotein; multidrug resistance; apoptosis; matrix metalloproteinases; caspases pentoxifylline; P-glycoprotein; multidrug resistance; apoptosis; matrix metalloproteinases; caspases
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Barancik, M.; Bohacova, V.; Gibalova, L.; Sedlak, J.; Sulova, Z.; Breier, A. Potentiation of Anticancer Drugs: Effects of Pentoxifylline on Neoplastic Cells. Int. J. Mol. Sci. 2012, 13, 369-382.

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