Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells
Anthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused wit...
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MDPI AG
2022-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/19/4719 |
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| author | Jeng Shiun Chang Chien-Yu Chen Alexander S. Tikhomirov Atikul Islam Ru-Hao Liang Chia-Wei Weng Wei-Hou Wu Andrey E. Shchekotikhin Pin Ju Chueh |
| author_facet | Jeng Shiun Chang Chien-Yu Chen Alexander S. Tikhomirov Atikul Islam Ru-Hao Liang Chia-Wei Weng Wei-Hou Wu Andrey E. Shchekotikhin Pin Ju Chueh |
| author_sort | Jeng Shiun Chang |
| collection | DOAJ |
| description | Anthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused with different heterocycles have been chemically synthesized and screened for higher anticancer potency. Among the compounds reported in our previous study, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated <b>2c</b>) was found to be apoptotic, but the direct cellular target responsible for the cytotoxicity remained unknown. Here, we report the synthesis and anticancer properties of two other derivatives, 4,11-bis(2-(2-chloroacetamidine)ethylamino)naphtho[2,3-f]indole-5,10-dione dihydrochloride (<b>2a</b>) and 4,11-bis(2-(2-chloroacetamidine)ethylamino)-2-methylanthra[2,3-b]furan-5,10-dione dihydrochloride (<b>2b</b>). We sought to identify and validate the protein target(s) of these derivatives in oral cancer cells, using molecular docking simulations and cellular thermal shift assays (CETSA). Our CETSA results illustrate that these derivatives targeted the tumor-associated NADH oxidase (tNOX, ENOX2), and their direct binding downregulated tNOX in p53-functional SAS and p53-mutated HSC-3 cells. Interestingly, the compounds targeted and downregulated tNOX to reduce SIRT1 deacetylase activity and increase Ku70 acetylation, which triggers c-Flip ubiquitination and induces apoptosis in oral cancer cells. Together, our data highlight the potential value of these heteroarene-fused anthraquinones in managing cancer by targeting tNOX and augmenting apoptosis. |
| first_indexed | 2024-03-09T21:57:36Z |
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| id | doaj.art-5c5eb23e36034c8290e7a515e885c24b |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-09T21:57:36Z |
| publishDate | 2022-09-01 |
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| spelling | doaj.art-5c5eb23e36034c8290e7a515e885c24b2023-11-23T19:55:30ZengMDPI AGCancers2072-66942022-09-011419471910.3390/cancers14194719Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer CellsJeng Shiun Chang0Chien-Yu Chen1Alexander S. Tikhomirov2Atikul Islam3Ru-Hao Liang4Chia-Wei Weng5Wei-Hou Wu6Andrey E. Shchekotikhin7Pin Ju Chueh8Department of Otolaryngology, Head and Neck Surgery, Jen-Ai Hospital, Taichung 41265, TaiwanInstitute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., Taichung 40227, TaiwanGause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, RussiaInstitute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., Taichung 40227, TaiwanInstitute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., Taichung 40227, TaiwanInstitute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., Taichung 40227, TaiwanInstitute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., Taichung 40227, TaiwanGause Institute of New Antibiotics, 11 B. Pirogovskaya Street, 119021 Moscow, RussiaInstitute of Biomedical Sciences, National Chung Hsing University, 145 Xingda Rd., Taichung 40227, TaiwanAnthraquinone-based intercalating compounds, namely doxorubicin and mitoxantrone, have been used clinically based on their capacity to bind DNA and induce DNA damage. However, their applications have been limited by side effects and drug resistance. New-generation anthraquinone derivatives fused with different heterocycles have been chemically synthesized and screened for higher anticancer potency. Among the compounds reported in our previous study, 4,11-bis(2-(2-chloroacetamidine)ethylamino)anthra[2,3-b]thiophene-5,10-dione dihydrochloride (designated <b>2c</b>) was found to be apoptotic, but the direct cellular target responsible for the cytotoxicity remained unknown. Here, we report the synthesis and anticancer properties of two other derivatives, 4,11-bis(2-(2-chloroacetamidine)ethylamino)naphtho[2,3-f]indole-5,10-dione dihydrochloride (<b>2a</b>) and 4,11-bis(2-(2-chloroacetamidine)ethylamino)-2-methylanthra[2,3-b]furan-5,10-dione dihydrochloride (<b>2b</b>). We sought to identify and validate the protein target(s) of these derivatives in oral cancer cells, using molecular docking simulations and cellular thermal shift assays (CETSA). Our CETSA results illustrate that these derivatives targeted the tumor-associated NADH oxidase (tNOX, ENOX2), and their direct binding downregulated tNOX in p53-functional SAS and p53-mutated HSC-3 cells. Interestingly, the compounds targeted and downregulated tNOX to reduce SIRT1 deacetylase activity and increase Ku70 acetylation, which triggers c-Flip ubiquitination and induces apoptosis in oral cancer cells. Together, our data highlight the potential value of these heteroarene-fused anthraquinones in managing cancer by targeting tNOX and augmenting apoptosis.https://www.mdpi.com/2072-6694/14/19/4719anthraquinoneapoptosisc-Flip downregulationheterocyclic compoundsoral cancer cellstumor-associated NADH oxidase (tNOX, ENOX2) |
| spellingShingle | Jeng Shiun Chang Chien-Yu Chen Alexander S. Tikhomirov Atikul Islam Ru-Hao Liang Chia-Wei Weng Wei-Hou Wu Andrey E. Shchekotikhin Pin Ju Chueh Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells Cancers anthraquinone apoptosis c-Flip downregulation heterocyclic compounds oral cancer cells tumor-associated NADH oxidase (tNOX, ENOX2) |
| title | Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells |
| title_full | Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells |
| title_fullStr | Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells |
| title_full_unstemmed | Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells |
| title_short | Bis(chloroacetamidino)-Derived Heteroarene-Fused Anthraquinones Bind to and Cause Proteasomal Degradation of tNOX, Leading to c-Flip Downregulation and Apoptosis in Oral Cancer Cells |
| title_sort | bis chloroacetamidino derived heteroarene fused anthraquinones bind to and cause proteasomal degradation of tnox leading to c flip downregulation and apoptosis in oral cancer cells |
| topic | anthraquinone apoptosis c-Flip downregulation heterocyclic compounds oral cancer cells tumor-associated NADH oxidase (tNOX, ENOX2) |
| url | https://www.mdpi.com/2072-6694/14/19/4719 |
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