Water-soluble 4-(dimethylaminomethyl)heliomycin exerts greater antitumor effects than parental heliomycin by targeting the tNOX-SIRT1 axis and apoptosis in oral cancer cells

Author:

Islam Atikul1ORCID,Chang Yu-Chun1,Chen Xiao-Chi1,Weng Chia-Wei12ORCID,Chen Chien-Yu1,Wang Che-Wei34,Chen Mu-Kuan34,Tikhomirov Alexander S5,Shchekotikhin Andrey E5,Chueh Pin Ju1467ORCID

Affiliation:

1. Institute of Biomedical Sciences, National Chung Hsing University

2. Institute of Medicine, Chung Shan Medical University

3. Department of Otorhinolaryngology-Head and Neck Surgery, Changhua Christian Hospital

4. Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University

5. Gause Institute of New Antibiotics

6. Department of Medical Research, China Medical University Hospital

7. Graduate Institute of Basic Medicine, China Medical University

Abstract

The antibiotic heliomycin (resistomycin), which is generated from Streptomyces resistomycificus, has multiple activities, including anticancer effects. Heliomycin was first described in the 1960s, but its clinical applications have been hindered by extremely low solubility. A series of 4-aminomethyl derivatives of heliomycin were synthesized to increase water solubility; studies showed that they had anti-proliferative effects, but the drug targets remained unknown. In this study, we conducted cellular thermal shift assays (CETSA) and molecular docking simulations to identify and validate that heliomycin and its water-soluble derivative, 4-(dimethylaminomethyl)heliomycin (designated compound 4-dmH) engaged and targeted with sirtuin-1 (SIRT1) in p53-functional SAS and p53-mutated HSC-3 oral cancer cells. We further addressed the cellular outcome of SIRT1 inhibition by these compounds and found that, in addition to SIRT1, the water-soluble 4-dmH preferentially targeted a tumor-associated NADH oxidase (tNOX, ENOX2). The direct binding of 4-dmH to tNOX decreased the oxidation of NADH to NAD+ which diminished NAD+-dependent SIRT1 deacetylase activity, ultimately inducing apoptosis and significant cytotoxicity in both cell types, as opposed to the parental heliomycin-induced autophagy. We also observed that tNOX and SIRT1 were both upregulated in tumor tissues of oral cancer patients compared to adjacent normal tissues, suggesting their clinical relevance. Finally, the better therapeutic efficacy of 4-dmH was confirmed in tumor-bearing mice, which showed greater tNOX and SIRT1 downregulation and tumor volume reduction when treated with 4-dmH compared to heliomycin. Taken together, our in vitro and in vivo findings suggest that the multifaceted properties of water-soluble 4-dmH enable it to offer superior antitumor value compared to parental heliomycin, and indicated that it functions through targeting the tNOX-NAD+-SIRT1 axis to induce apoptosis in oral cancer cells.

Funder

The Ministry of Sciences and Technology, Taiwan

The Minsitry of Sciences and Technology, Taiwan

Russian Foundation for Basic Research

National Chung Hsing University and Changhua Christian Hospital

Publisher

eLife Sciences Publications, Ltd

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