Abstract
Dynamic and reciprocal interactions generated by the communication between tumor cells and their matrix microenvironment, play a major role in the progression of a tumor. Indeed, the adhesion of specific sites to matrix components, associated with the repeated and coordinated formation of membrane protrusions, allow tumor cells to move along a determined pathway. Our study analyzed the mechanism of action of low-diluted Phenacetinum on murine cutaneous melanoma process in a fibronectin matrix environment. We demonstrated a reduction of dispersed cell migration, early and for as long as 24 h, by altering the formation of cell protrusions. Moreover, low-diluted Phenacetinum decreased cell stiffness highly on peripheral areas, due to a disruption of actin filaments located just under the plasma membrane. Finally, it modified the structure of the plasma membrane by accumulating large ordered lipid domains and disrupted B16 cell migration by a likely shift in the balance between ordered and disordered lipid phases. Whereas the correlation between the excess of lipid raft and cytoskeleton disrupting is not as yet established, it is clear that low-diluted Phenacetinum acts on the actin cytoskeleton organization, as confirmed by a decrease of cell stiffness affecting ultimately the establishment of an effective migration process.
Highlights
Directional motility is a physiological cellular process which is essential for embryogenesis, immune response, tissue repair, and organ formation
Under Phenacetinum 4CH treatment, the migratory capacities of B16 cells were significantly reduced by 27% at 510 ± 9 μm for B16F1 cells, and by 31% at 670 ± 18 μm for B16F10 cells
Under Phenacetinum 4CH treatment, the migration capabilities were significantly reduced by 29% at 20 ± 0.8 μm/h for B16F1 cells, and by 31% at 27.9 ± 0.8 μm/h for B16F10 cells (Fig. 1C)
Summary
Directional motility is a physiological cellular process which is essential for embryogenesis, immune response, tissue repair, and organ formation. Until 1983, phenacetine was used over-the-counter in remedies for pain and fever and in rheumatoid arthritis, but the established presence of carcinogenicity in renal pelvis and urinary bladder caused its withdrawal from the market[16] Despite these harmful effects, some studies have demonstrated that the use of a substance potentially toxic yet highly diluted (such as cadmium and arsenic), can produce an effective reduction of their usual toxic aspect in vitro/in vivo and increase beneficial application[17,18,19]. The combination of different original methodologies makes it possible for Phenacetinum 4CH to disrupt lipid organization at the plasma membrane, affecting underlying cytoskeleton performance and thereby, dispersed cell migration
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