Parp1 Inhibition As A Novel Therapeutic Target For Keloid Disease
Tae Hwan Park1, Yun Joo Park2.
1Department of Plastic and Reconstructive Surgery, CHA Bundang Medical Center, CHA University College of Medicine, Seongnam, Republic of Korea, Seongnam, Korea, Republic of, 2Department of Radiology, Hallym University College of Medicine and Hallym University Sacred Heart Hospital, Anyang, Republic of Korea, Anyang, Korea, Republic of.
BACKGROUND Inactivation of poly(ADP-ribose) polymerase 1 (PARP1) has been found to have protective effect in several fibrotic diseases; however, the role of PARP1 in keloid has not been studied yet. Herein, we evaluated the therapeutic efficacy of PARP1 inhibitor (rucaparib) for keloids. METHODS A total of eight patients with eight keloids were achieved. The protein expressions of PARP1 and smad3 in keloid tissue or normal human dermal tissue were evaluated with western blotting. Primary cultures from keloids or control normal skin were performed. The effect of PARP1 inhibitor was evaluated using MTT assay and migration assay. We further analyze the effect of PARP1 inhibitor on patient derived keloid xenograft murine model. RESULTS The protein expressions of PARP1 and smad3 were significantly higher in keloid tissue as compared to normal dermal tissue. Rucaparib (20 μM) significantly suppressed the proliferation of keloid fibroblasts. Moreover, the combination of rucaparib (20 μM) and triamcinolone (50 μM) showed additive suppressive effect on keloid fibroblasts as compared to rucaparib therapy alone. Migration assay showed rucaparib (10 μM) significantly suppressed the migration of keloid fibroblasts as compared to control. Fibrosis markers including matrix metallopeptidase (MMP)-1, 2, 3, 9 and α-smooth muscle actin (SMA), fibronectin, and connective tissue growth factor (CTGF) in keloid fibroblasts significantly decreased after rucaparib treatment (20 μM). In patient-derived keloid xenograft model, rucaparib significantly reduced the size of keloid tissue compared to control by 55 %. CONCLUSIONS Our data suggest PARP1 might be a novel therapeutic target for keloid disease. Rucaparib might be a promising therapeutic drug for the treatment of keloid disease.
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