Enzyme-Instructed Assembly and Disassembly Processes for Targeting Downregulation in Cancer Cells.

Zhaoqianqi Feng,Rong Zhou,Jie Li,Huaimin Wang,Bing Xu

doi:10.1021/jacs.7b00070

Zhaoqianqi Feng, Rong Zhou + Show 3 more

Open Access

https://doi.org/10.1021/jacs.7b00070

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Journal: Journal of the American Chemical Society	Publication Date: Mar 13, 2017
Citations: 125	License type: cc-by

Affiliation: Brandeis University

Abstract

Cancer cells differ from normal cells in both gain of functions (i.e., upregulation) and loss of functions (i.e., downregulation). While it is common to suppress gain of function for chemotherapy, it remains challenging to target downregulation in cancer cells. Here we show the combination of enzyme-instructed assembly and disassembly to target downregulation in cancer cells by designing peptidic precursors as the substrates of both carboxylesterases (CESs) and alkaline phosphatases (ALPs). The precursors turn into self-assembling molecules to form nanofibrils upon dephosphorylation by ALP, but CES-catalyzed cleavage of the ester bond on the molecules results in disassembly of the nanofibrils. The precursors selectively inhibit the cancer cells that downregulate CES (e.g., OVSAHO) but are innocuous to a hepatocyte that overexpresses CES (HepG2), while the two cell lines exhibit comparable ALP activities. This work illustrates a potential approach for the development of chemotherapy via targeting downregulation (or loss of functions) in cancer cells.

Highlights

Cancer therapy, which remains a challenge in translational medicine
Upon the action of alkaline phosphatases (ALPs), the precursors turn into self-assembling molecules to form assemblies, but the assemblies dissociate upon the action of CES
Because the assemblies are cytotoxic and the unassembled products are innocuous to cells, the precursors would inhibit only the cells expressing ALP and downregulating CES

Summary

Introduction

Cancer therapy, which remains a challenge in translational medicine. Scheme 1 shows the concept. Because the assemblies are cytotoxic and the unassembled products are innocuous to cells, the precursors would inhibit only the cells expressing ALP and downregulating CES. The overall result is to target the downregulation of the enzyme (e.g., CES) in cancer cells.

Results

Conclusion