Add time:08/10/2019         Source:sciencedirect.com

AbstrctIncreasing evidences suggested that cisplatin can be involved in a tumor-specific immune response as an immunomodulator to improve antitumor immunity, but the designation and development are limited. Here, we report a series of novel Pt(IV) complexes derived from the conjugation of platinum(II) anticancer agents with an immune checkpoint TDO inhibitor. These complexes not only showed significant cytotoxic effects on the tested cancer cell lines, but also could enhance antitumor immune response. Particularly, complex T2, the mono-conjuagte of oxoplatin and (E)-4-oxo-4-(3-(2-(pyridin-3-yl)vinyl)-1H-indol-1-yl)butanoic acid, displayed 35-fold more potency than cisplatin against TDO-overexpressed HepG-2 cancer cells. Further study indicated that T2 could inhibit TDO via releasing a derivative of a TDO inhibitor and block kynurenine production, resulting in T-cell activation and proliferation in vitro. In vivo tests proved that T2 as a potent immunomodulator could highly promote the antitumor activity of cisplatin and effectively suppress the expression of TDO. This immunochemotherapeutic strategy can be promisingly applied to treat with TDO-overexpressed cancers.

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