Transforming growth factor β signaling inhibitor, SB-431542, induces maturation of dendritic cells and enhances anti-tumor activity.

Abstract

The transforming growth factor β (TGFβ) stimulates tumor progression and metastasis. Secretion of TGFβ by tumor cells also suppresses an antitumor immune response in which dendritic cells (DCs) play an important role to activate cytotoxic T lymphocytes (CTLs). Herein we report that the small molecule TGFβ signaling inhibitor SB-431542, induces DC maturation in vitro and triggers antitumor activity in vivo. We added SB-431542 to cultures of murine bone-marrow derived DCs (BM-DCs) derived from BALB/c mice and human DCs generated from peripheral monocytes (human DCs) at different concentrations in triplicates and examined expression of co-stimulatory molecules by FACS and production of Interleukin-12 (IL-12) by ELISA. SB induced phenotypic maturation of BM-DCs and human DCs and improved their abilities to produce IL-12 in a dose-dependent manner. SB-431542 also augmented capacity of murine and human DCs to activate naive T cells in allogeneic mixed lymphocyte reaction. Interestingly, SB-431542 augmented the capacity of BM-DCs and human DCs to incorporate FITC-conjugated dextran. Intraperitoneal administration of SB-431542 initiated 3 and 7 days after the implantation of colon-26 cancer cells into the peritoneal cavity of BALB/c mice significantly induced CTL activity against colon-26. We incubated human DCs with SB-431542 and cell lysate of scirrhous gastric cancer cell line OCUM-8, and then examined CTL activities against OCUM-8. CD8 T cells activated by human DCs treated with SB-431542 showed modest augmentation CTL activity against cancer cells. Furthermore, pretreatment of human DCs with SB-431542 upregulated cytotoxic activity against K562 cells, suggesting SB should have potential to activate DCs to natural killer cells. In conclusion, TGFβ receptor I kinase inhibitor such as SB-431542 might induce anti-tumor immune response in immuno-tolerant patients associated with TGFβ activity.

• Authors: Hiroaki Tanaka, Osamu Shinto, Masakazu Yashiro, Sadaaki Yamazoe, Takehiko Iwauchi, Kazuya Muguruma, Naoshi Kubo, Masaichi Ohira, Kosei Hirakawa
• Journal: Oncology reports (Oncol Rep) Vol. 24 Issue 6 Pg. 1637-43 (Dec 2010) ISSN: 1791-2431 [Electronic] Greece
• PMID: 21042762 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
• Antineoplastic Agents
• Benzamides
• Dioxoles
• Transforming Growth Factor beta

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Benzamides (pharmacology, therapeutic use)
• Cell Differentiation (drug effects)
• Cells, Cultured
• Combined Modality Therapy
• Dendritic Cells (drug effects, immunology, physiology)
• Dioxoles (pharmacology, therapeutic use)
• Female
• Humans
• Immunotherapy, Active (methods)
• K562 Cells
• Mice
• Mice, Inbred BALB C
• Neoplasms (pathology, therapy)
• Transforming Growth Factor beta (antagonists & inhibitors)
• Xenograft Model Antitumor Assays