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Dual-functional conjugates improving cancer immunochemotherapy by inhibiting tubulin polymerization and indoleamine-2,3-dioxygenase.

Abstract：

:A series of novel conjugates comprising tublin and IDO inhibitors were designed, synthesized and evaluated for their antiproliferative activity. Among them, HI5, composed of combretastatin A-4 (CA-4) and (D)-1-methyltryptophan (D-MT) by a linker, exhibited the most potent antitumor activity, in particular with higher IC50 value (0.07 μM) than CA-4 (0.21 μM) against HeLa cancer cell line. Mechanism studies indicated that HI5 can inhibit tubulin polymerization and cell migration, cause G2/M phase arrest, concurrent induce apoptosis via the mitochondrial dependent apoptosis pathway and cause reactive oxidative stress generation in HeLa cells. Furthermore, HI5 can inhibit IDO expression and decrease kynurenine production, leading to stimulating T cells activation and proliferation to enhance antitumor immunity in vitro. Interestingly, HI5 can effectively limit the tumor growth in the HeLa xenograft mice models without causing significant loss of body weight. Consequently, such a conjugation can be a potent and safe immunochemotherapeutic method for improving cancer therapy.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Hua S,Chen F,Wang X,Gou S

doi

10.1016/j.ejmech.2020.112041

subject

Has Abstract

pub_date

2020-03-01 00:00:00

pages

112041

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(20)30008-8

journal_volume

189

pub_type

杂志文章

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