A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs
<b>Background.</b> Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1<i>E</i>)-2-phenylethenyl]-4<i>H</i>-1...
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-07-01
|
| Series: | Medicines |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2305-6320/10/7/43 |
| _version_ | 1827732449201750016 |
|---|---|
| author | Tomoyuki Abe Hiroshi Sakagami Shigeru Amano Shin Uota Kenjiro Bandow Yoshihiro Uesawa Shiori U Hiroki Shibata Yuri Takemura Yu Kimura Koichi Takao Yoshiaki Sugita Akira Sato Sei-ichi Tanuma Hiroshi Takeshima |
| author_facet | Tomoyuki Abe Hiroshi Sakagami Shigeru Amano Shin Uota Kenjiro Bandow Yoshihiro Uesawa Shiori U Hiroki Shibata Yuri Takemura Yu Kimura Koichi Takao Yoshiaki Sugita Akira Sato Sei-ichi Tanuma Hiroshi Takeshima |
| author_sort | Tomoyuki Abe |
| collection | DOAJ |
| description | <b>Background.</b> Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1<i>E</i>)-2-phenylethenyl]-4<i>H</i>-1-benzopyran-4-one (Compound <b>A</b>) and 3-[(1<i>E</i>)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4<i>H</i>-1-benzopyran-4-one (Compound <b>B</b>), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. <b>Methods:</b> Tumor-specificity (TS<sub>M</sub>, TS<sub>E</sub>, TS<sub>N</sub>) was evaluated as the ratio of mean CC<sub>50</sub> for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. <b>Results:</b> Compounds <b>A</b> and <b>B</b> showed one order of magnitude higher TS<sub>M</sub> than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TS<sub>M</sub>, but two orders of magnitude lower TS<sub>E</sub> than Compounds <b>A</b> and <b>B</b>. Compounds <b>A</b> and <b>B</b> showed higher TS<sub>M</sub>, TS<sub>E,</sub> and TS<sub>N</sub> values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds <b>A</b> and <b>B</b> may inhibit the signaling pathway of estrogen-related receptors. |
| first_indexed | 2024-03-11T00:50:39Z |
| format | Article |
| id | doaj.art-31dc0e9c3dec488e805ec9ceba69031b |
| institution | Directory Open Access Journal |
| issn | 2305-6320 |
| language | English |
| last_indexed | 2024-03-11T00:50:39Z |
| publishDate | 2023-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Medicines |
| spelling | doaj.art-31dc0e9c3dec488e805ec9ceba69031b2023-11-18T20:25:46ZengMDPI AGMedicines2305-63202023-07-011074310.3390/medicines10070043A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer DrugsTomoyuki Abe0Hiroshi Sakagami1Shigeru Amano2Shin Uota3Kenjiro Bandow4Yoshihiro Uesawa5Shiori U6Hiroki Shibata7Yuri Takemura8Yu Kimura9Koichi Takao10Yoshiaki Sugita11Akira Sato12Sei-ichi Tanuma13Hiroshi Takeshima14Division of Geriatric Dentistry, Meikai University School of Dentistry, Saitama 350-0283, JapanMeikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, JapanMeikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, JapanMeikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, JapanDivision of Biochemistry, Meikai University School of Dentistry, Saitama 350-0283, JapanDepartment of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo 204-858, JapanDepartment of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, JapanDepartment of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, JapanDepartment of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, JapanDepartment of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, JapanDepartment of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, JapanDepartment of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, JapanDepartment of Biochemistry and Molecular Biology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, JapanMeikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, JapanDivision of Geriatric Dentistry, Meikai University School of Dentistry, Saitama 350-0283, Japan<b>Background.</b> Many anti-cancer drugs used in clinical practice cause adverse events such as oral mucositis, neurotoxicity, and extravascular leakage. We have reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1<i>E</i>)-2-phenylethenyl]-4<i>H</i>-1-benzopyran-4-one (Compound <b>A</b>) and 3-[(1<i>E</i>)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4<i>H</i>-1-benzopyran-4-one (Compound <b>B</b>), showed the highest tumor-specificity against human oral squamous cell carcinoma (OSCC) cell lines among 291 related compounds. After confirming their superiority by comparing their tumor specificity with newly synthesized 65 derivatives, we investigated the neurotoxicity of these compounds in comparison with four popular anti-cancer drugs. <b>Methods:</b> Tumor-specificity (TS<sub>M</sub>, TS<sub>E</sub>, TS<sub>N</sub>) was evaluated as the ratio of mean CC<sub>50</sub> for human normal oral mesenchymal (gingival fibroblast, pulp cell), oral epithelial cells (gingival epithelial progenitor), and neuronal cells (PC-12, SH-SY5Y, LY-PPB6, differentiated PC-12) to OSCC cells (Ca9-22, HSC-2), respectively. <b>Results:</b> Compounds <b>A</b> and <b>B</b> showed one order of magnitude higher TS<sub>M</sub> than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TS<sub>M</sub>, but two orders of magnitude lower TS<sub>E</sub> than Compounds <b>A</b> and <b>B</b>. Compounds <b>A</b> and <b>B</b> showed higher TS<sub>M</sub>, TS<sub>E,</sub> and TS<sub>N</sub> values than doxorubicin, 5-FU, and cisplatin, damaging OSCC cells at concentrations that do not affect the viability of normal epithelial and neuronal cells. QSAR prediction based on the Tox21 database suggested that Compounds <b>A</b> and <b>B</b> may inhibit the signaling pathway of estrogen-related receptors.https://www.mdpi.com/2305-6320/10/7/43chromone derivativesoral squamous cell carcinomatumor-specificitykeratinocyte toxicityneurotoxicitysignaling pathway |
| spellingShingle | Tomoyuki Abe Hiroshi Sakagami Shigeru Amano Shin Uota Kenjiro Bandow Yoshihiro Uesawa Shiori U Hiroki Shibata Yuri Takemura Yu Kimura Koichi Takao Yoshiaki Sugita Akira Sato Sei-ichi Tanuma Hiroshi Takeshima A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs Medicines chromone derivatives oral squamous cell carcinoma tumor-specificity keratinocyte toxicity neurotoxicity signaling pathway |
| title | A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs |
| title_full | A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs |
| title_fullStr | A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs |
| title_full_unstemmed | A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs |
| title_short | A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs |
| title_sort | comparative study of tumor specificity and neurotoxicity between 3 styrylchromones and anti cancer drugs |
| topic | chromone derivatives oral squamous cell carcinoma tumor-specificity keratinocyte toxicity neurotoxicity signaling pathway |
| url | https://www.mdpi.com/2305-6320/10/7/43 |
| work_keys_str_mv | AT tomoyukiabe acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT hiroshisakagami acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT shigeruamano acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT shinuota acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT kenjirobandow acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yoshihirouesawa acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT shioriu acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT hirokishibata acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yuritakemura acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yukimura acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT koichitakao acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yoshiakisugita acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT akirasato acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT seiichitanuma acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT hiroshitakeshima acomparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT tomoyukiabe comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT hiroshisakagami comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT shigeruamano comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT shinuota comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT kenjirobandow comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yoshihirouesawa comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT shioriu comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT hirokishibata comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yuritakemura comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yukimura comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT koichitakao comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT yoshiakisugita comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT akirasato comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT seiichitanuma comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs AT hiroshitakeshima comparativestudyoftumorspecificityandneurotoxicitybetween3styrylchromonesandanticancerdrugs |