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Combination of HDAC inhibitor MS-275 and IL-2 increased anti-tumor effect in a melanoma model via activated cytotoxic T cells

Yukihiko Katoa, Ikuyo Yoshino, Chizu Egusa, Tatsuo Maeda, Roberto Pili, Ryoji Tsuboi

Journal of Dermatological Science, Available online 14 May 2014, Pages 986-997

Editors' comments:
This is a study that evaluates the efficacy of the association of Histone deacetylase (HDAC) inhibitor, MS-275, with IL-2 in murine melanoma model. This association has shown a benefit in terms of reduction of the tumor mass as well as survival in mice treated with the combination compared to the two drugs in monotherapy. These findings highlight the role of epigenetics in cancer treatment, and encourage research in this area.

Abstract


Background

Histone deacetylase (HDAC) inhibitors are immunomodulatory, and demonstrate antitumor activity in various tumor models including malignant melanoma.

Objective

The present study examines the effectiveness of IL-2 and HDAC inhibitor MS-275-combination therapy in a murine melanoma model.

Methods

B16F10 cells were implanted subcutaneously in C57BL/6 mice which were randomly divided into four groups and treated with either IL-2 by subcutaneous injection, MS-275 by oral gavage (5 days/week, daily for 2 weeks), or a combination of the two agents.

Results

MS-275 treatment showed a dose-dependent inhibitory effect on B16 cells in a colonogenic assay. Flow cytometry analysis indicated that MS-275 induced G1 arrest but not apoptosis in vitro, but IL-2 failed to inhibit cell proliferation. The combination of MS-275 and IL-2 had a statistically significant additive inhibitory effect on melanoma tumor weight and volume in vivo. Significantly higher survival was evident in the combination group compared with the control or single-agent groups. The combination therapy produced a greater ratio of CD8+ CD69+ T cells in lymph nodes than was seen in the MS-275-treatment and no-treatment groups among tumoriferous mice. Splenocytes from mice treated with MS-275 and the combination therapy demonstrated greater lysis of melanoma cells in vitro than splenocytes from mice treated with IL-2 or those without treatment. A significant antitumor effect from IL-2 and MS-275-combination therapy in vivo was seen in the increased number of activated CD8+ T cells.

Conclusions

These data provide a convincing rationale for considering the role of epigenetics in future treatments for malignant melanoma.