Abstract
Abstract
Mastocytosis is classified into three major types: cutaneous mastocytosis (CM), systemic mastocytosis (SM), and mast cell sarcoma. SM can present with cutaneous lesions while CM is characterized by the cutaneous proliferation of mast cells. Systemically administered mTOR inhibitors are effective against SM, but there are, as of yet, no reports of effectiveness of topical agent for CM and in vivo experiments using a topical formulation. First, the effect of rapamycin, an mTOR inhibitor, on the cell growth and cycle of human mast cell lines (HMC-1.1 and HMC-1.2) was assessed via cell growth, cell cycle apoptosis assays and evaluating phosphorylation of the mTOR pathway signal. Next, the therapeutic efficacy of a topical formulation of rapamycin was tested in a subcutaneous HMC-1 xenograft model. Human mast cells (HMC-1.2) were subcutaneously injected into the dorsum of mice with severe combined immunodeficiency (SCID) before topical rapamycin application. In vitro analysis demonstrated that rapamycin had not induced apoptosis in the human mast cell line but had significantly suppressed cell proliferation by inducing cell cycle arrest. In a murine severe combined immunodeficiency model of HMC-1 xenograft, by day 35, tumor growth was markedly suppressed in the rapamycin group than in a control group. Immunohistochemistry and western blotting of tumor tissue demonstrated that rapamycin had suppressed mTOR signaling in the tumors, thereby inhibiting their growth. Topical rapamycin suppressed mTOR signaling and the growth of D816V-mutated c-Kit mast cells in a HMC-1 xenograft model.