Pentoxifylline enhances lung colonization and alters cell adhesion and glycosaminoglycan synthesis by metastatic B16 melanoma cells

Abstract

The effect of pentoxifylline on B16 melanoma cell lung colonization, synthesis and properties of glycosaminoglycans (GAGS), and adhesion to and degradation of subendothelial extracellular matrix was examined. Pentoxifylline inhibited cell growth, cell numbers being reduced by 50% following incubation for 4 days in the presence of 250 micrograms/ml pentoxifylline, while the treated cells appeared more flattened, possessed numerous but short dendritic processes, and exhibited greatly enhanced tyrosinase activity and melanin synthesis. Pentoxifylline treatment increased the cells' ability to colonize the lungs of syngeneic C57BL mice following tail-vein injection of 10(5) cells. The number of lung tumours increased from 16.7 +/- 6.1 to 52.2 +/- 17.8. In addition, pentoxifylline-treated cell GAG synthesis was reduced by 36%, and the charge density of chondroitin sulphate reduced, while tumour-cell aggregation and adhesion to subendothelial extracellular matrix was increased, as was the tumour-cell-mediated release of 35SO4 from radiolabelled subendothelial matrix. The observed changes in GAG synthesis may contribute toward the increased cell adhesiveness which, in addition to increased degradation of certain components of the subendothelial extracellular matrix, may account, at least in part, for the enhancement of lung colonization.

Studies on the Mechanisms Responsible for Inhibition of Experimental Metastasis of B16-F10 Murine Melanoma by Pentoxifylline

“…Nevertheless, lung nodules could not be evaluated macroscopically in an accurate way due to their very small size and high fluctuation in lung seeding in all groups (data not shown). Our results do not agree with those obtained before by others in B16F1M2, a tumor cell line related to the one used here [9]. The differences obtained could be a consequence of different experimental treatments used in both cases.…”

“…The 2 h incubation of cells with the drug did not show significantly inhibitory effect on B16-F10 cell proliferation in concentrations below 10 mM PTX, being IC 50 around 40 mM. Although other authors previously reported having obtained in vitro cell growth inhibition with much lower PTX concentrations, it must be considered that drug exposure times were considerably longer (48-96 h) than that used by us and that different cell lines were stud- ied [3,9]. Since plasma half lives of PTX and its metabolites are of 2 h or less [21], we decided to expose cells in vitro for not longer than 2 h. Our results can explain, at least in part, the nonsignificant effects of PTX in vivo treatment on B16-F10 primary tumor growth.…”

“…Due to some of its characteristics, such as inhibitor of platelet aggregation and thrombus formation [1], cytoskeleton depolymerizer [22], tumor necrosis factor (TNF) suppressor [17], and cell membrane fluidity modifier [19], among others, it has lately been the focus of some studies in experimental cancer. PTX has been reported to enhance chemo-and radiosensitivity in some cancer cells [7,10] and to affect tumor growth, angiogenesis and metastasis in certain models [2,3,9].…”

Pentoxifylline modulates cell surface integrin expression and integrin mediated adhesion of B16F10 cells to extracellular matrix components

“…11 Ambrus et al 27 has previously reported on the ability of PTX to reduce spontaneous metastasis and studies from Futakuchi et al has shown that PTX can strongly inhibit lung metastasis from rat HCCs in vivo. 28 This is in contrast with studies from Edward et al, 29 who has shown that PTX significantly increased the ability of B16F1M2 murine melanoma cells to form lung colonies. Further Lazarczyk et al showed that PTX facilitated the development of murine colon adenocarcinoma but not melanoma derived tumors in lungs suggesting that the tumor-promoting activity of PTX might be tissue dependent and might depend on the cancer cell line studied.…”

NF-κB c-Rel Is Crucial for the Regulatory T Cell Immune Checkpoint in Cancer

“…No observable differences in the size or composition of lymphoid tissues were detected, and no adverse events were observed (data not shown). As it has been reported that PTXF can induce tumor cell apoptosis in vitro (Edward and MacKie, 1991; Ratheesh et al, 2007), we wanted to determine whether the effects of PTXF on tumor growth were tumor intrinsic or related to improved immune responses. Analysis of tumor infiltrates at D16 revealed an increased infiltration of total T cells, as well as IFN-γ producing CD4 and CD8 T cells (Figures 4B–4D).…”