Abstract
Hypertrophic scar is characterized by the overgrowth of fibroblasts and often considered as a kind of benign skin tumor, thus chemotherapeutic drugs have been used to treat scars. In view of the similarity, this study aims to investigate whether drug resistance in cancer that contributes to the failure of chemotherapy also exists in hypertrophic scar, and what is the possible mechanism. Fibroblasts derived from hypertrophic scar and normal skin tissues were first compared for their resistance to verapamil and etoposide phosphate. Scar fibroblasts showed stronger resistance to both verapamil and etoposide than normal fibroblasts, also scar fibroblasts expressed more P-glycoprotein and MRP1 than normal fibroblasts. When scar fibroblasts were pre-treated with PSC833 or probenecid, a P-glycoprotein or MRP1 inhibitor respectively, the resistance to verapamil or etoposide was strongly attenuated. Moreover, co-immunoprecipitation revealed more association of P-glycoprotein/MRP1 with actin filaments in scar fibroblasts than normal fibroblasts. The resistance in scar fibroblasts to verapamil and etoposide was almost abolished when pre-treated with latrunculin-A or a specific anti-actin antibody. Taken together, this study suggests that the enhanced expression of drug resistance-related transporters and their increased association with actin cytoskeleton contribute to the resistance to chemotherapeutic drugs in hypertrophic scar. Thus, down-regulating the expession of drug transporters or disrupting drug transporter-actin filament interaction might be novel and effective ways for hypertrophic scar treatment.
Highlights
Hypertrophic scar (HS) is often considered as a kind of benign skin tumor because of its excessive fibroblast proliferation
A major challenge in cancer treatment is the resistance of cancer cells to chemotherapeutic agents, which is mediated by several drug resistance-related drug transporters [1,2], P-glycoprotein and multidrug resistance-associated protein 1 (MRP1)
Hypertrophic scar-derived fibroblasts were more resistant to both verapamil and etoposide phosphate
Summary
Hypertrophic scar (HS) is often considered as a kind of benign skin tumor because of its excessive fibroblast proliferation. P-glycoprotein and MRP1 are overexpressed in various tumors [3,4], they exclude therapeutic drugs out of cells and decrease the intracellular drug accumulation. Given that HS shares certain similarity with tumor, this study aims to determine whether drug resistance exists in HS and whether this is mediated by P-glycoprotein and/ or MRP1. Of interest, emerging evidences have suggested an important role of the actin-based cytoskeleton in P-glycoprotein-mediated drug resistance in cancer cells [8]. It is worthy to elucidate whether the interaction between drug transporters, such as P-glycoprotein or MRP1, and actin cytoskeleton would be one of the mechanisms that confer HS resistance
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