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Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.

ABSTRACT: Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Previously, we have cloned the lnm gene cluster from S. atroolivaceus S-140 and characterized the biosynthetic machinery responsible for the 18-membered lactam backbone and the alkyl branch at C3 of LNM. We now report the isolation and characterization of leinamycin E1 (LNM E1) from S. atroolivacues SB3033, a ?lnmE mutant strain of S. atroolivaceus S-140. Complementary to the reductive activation of LNM by cellular thiols, LNM E1 can be oxidatively activated by cellular reactive oxygen species (ROS) to generate a similar episulfonium ion intermediate, thereby alkylating DNA and leading to eventual cell death. The feasibility of exploiting LNM E1 as an anticancer prodrug activated by ROS was demonstrated in two prostate cancer cell lines, LNCaP and DU-145. Because many cancer cells are under higher cellular oxidative stress with increased levels of ROS than normal cells, these findings support the idea of exploiting ROS as a means to target cancer cells and highlight LNM E1 as a novel lead for the development of anticancer prodrugs activated by ROS. The structure of LNM E1 also reveals critical new insights into LNM biosynthesis, setting the stage to investigate sulfur incorporation, as well as the tailoring steps that convert the nascent hybrid peptide-polyketide biosynthetic intermediate into LNM.

SUBMITTER: Huang SX

PROVIDER: S-EPMC4500275 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.

Huang Sheng-Xiong SX Yun Bong-Sik BS Ma Ming M Basu Hirak S HS Church Dawn R DR Ingenhorst Gudrun G Huang Yong Y Yang Dong D Lohman Jeremy R JR Tang Gong-Li GL Ju Jianhua J Liu Tao T Wilding George G Shen Ben B

Proceedings of the National Academy of Sciences of the United States of America 20150608 27

Leinamycin (LNM) is a potent antitumor antibiotic produced by Streptomyces atroolivaceus S-140, featuring an unusual 1,3-dioxo-1,2-dithiolane moiety that is spiro-fused to a thiazole-containing 18-membered lactam ring. Upon reductive activation in the presence of cellular thiols, LNM exerts its antitumor activity by an episulfonium ion-mediated DNA alkylation. Previously, we have cloned the lnm gene cluster from S. atroolivaceus S-140 and characterized the biosynthetic machinery responsible for ...[more]

PMID: 26056295

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Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.

Publications

Leinamycin E1 acting as an anticancer prodrug activated by reactive oxygen species.

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