title: Silibinin inhibits accumulation of myeloid-derived suppressor cells and tumor growth of murine breast cancer.
abstract: Myeloid-derived suppressor cells (MDSC)s increase in blood and accumulate in the tumor microenvironment of tumor-bearing animals, contributing to immune suppression in cancer. Silibinin, a natural flavonoid from the seeds of milk thistle, has been developed as an anti-inflammatory agent and supportive care agent to reduce the toxicity of cancer chemotherapy. The goals of this study were to evaluate the effect of silibinin on MDSCs in tumor-bearing mice and antitumor activity of silibinin in a mouse model of breast cancer. 4T1 luciferase-transfected mammary carcinoma cells were injected into in the mammary fat pad female BALB/c mice, and female CB17-Prkdc Scid/J mice. Silibinin treatment started on day 4 or day 14 after tumor inoculation continued every other day. Tumor growth was monitored by bioluminescent imaging (BLI) measuring total photon flux. Flow cytometry measured total leukocytes, CD11b(+) Gr-1(+) MDSC, and T cells in the blood and tumors of tumor-bearing mice. The effects of silibinin on 4T1 cell viability in vitro were measured by BLI. Treatment with silibinin increased overall survival in mice harboring tumors derived from the 4T1-luciferase breast cancer cell line, and reduced tumor volumes and numbers of CD11b(+) Gr-1(+) MDSCs in the blood and tumor, and increased the content of T cells in the tumor microenvironment. Silibinin failed to inhibit tumor growth in immunocompromised severe combined immunodeficiency mice, supporting the hypothesis that anticancer effect of silibinin is immune-mediated. The antitumor activity of silibinin requires an intact host immune system and is associated with decreased accumulation of blood and tumor-associated MDSCs.
authors.affiliation: Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
authors.forename: Parvin
authors.initials: P
authors.lastname: Forghani
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Khorramizadeh
authors.forename: Edmund K
authors.initials: EK
authors.lastname: Waller
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D022423:Myeloid Cells / Q000187:drug effects / Q000473:pathology; D011897:Random Allocation; D000077385:Silybin; D012838:Silymarin / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000975:Antioxidants; D012838:Silymarin; D000077385:Silybin
keywords: 4T1; SCID; breast cancer; mice; myeloid-derived suppressor cells; silibinin