title: Disruption of the association between drug transporter and actin cytoskeleton abolishes drug resistance in hypertrophic scar.
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.
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Linlin
authors.initials: L
authors.lastname: Su
authors.affiliation: Department of Orthopedics, Jingzhou Central Hospital, Tongji Medical College of Huazhong University of Science and Technology, Jingzhou, Hubei 434020, China.
authors.forename: Lanqing
authors.initials: L
authors.lastname: Fu
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Burns and Cutaneous Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shaanxi 710032, China.
authors.forename: Dahai
authors.initials: D
authors.lastname: Hu
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics / Q000378:metabolism*; D008841:Actin Cytoskeleton / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017439:Cicatrix, Hypertrophic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D004351:Drug Resistance / Q000235:genetics; D005047:Etoposide / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008297:Male; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil; D055815:Young Adult
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D005047:Etoposide; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009943:Organophosphorus Compounds; D014700:Verapamil; C061400:etoposide phosphate; C421109:multidrug resistance-associated protein 1
keywords: P-glycoprotein; fibroblasts; hypertrophic scar