A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

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

doi:10.3390/medicines10070043

A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs

Medicines (Basel). 2023 Jul 14;10(7):43. doi: 10.3390/medicines10070043.

Authors

Affiliations

¹ Division of Geriatric Dentistry, Meikai University School of Dentistry, Saitama 350-0283, Japan.
² Meikai University Research Institute of Odontology (M-RIO), 1-1 Keyakidai, Saitama 350-0283, Japan.
³ Division of Biochemistry, Meikai University School of Dentistry, Saitama 350-0283, Japan.
⁴ Department of Medical Molecular Informatics, Meiji Pharmaceutical University, Tokyo 204-858, Japan.
⁵ Department of Pharmaceutical Sciences, Faculty of Pharmacy and Pharmaceutical Sciences, Josai University, Saitama 350-0295, Japan.
⁶ Department of Biochemistry and Molecular Biology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.

Abstract

Background. 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-[(1E)-2-phenylethenyl]-4H-1-benzopyran-4-one (Compound A) and 3-[(1E)-2-(4-hydroxyphenyl)ethenyl]-7-methoxy-4H-1-benzopyran-4-one (Compound 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. Methods: Tumor-specificity (TS_M, TS_E, TS_N) was evaluated as the ratio of mean CC₅₀ 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. Results: Compounds A and B showed one order of magnitude higher TS_M than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TS_M, but two orders of magnitude lower TS_E than Compounds A and B. Compounds A and B showed higher TS_M, TS_E, and TS_N 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 A and B may inhibit the signaling pathway of estrogen-related receptors.

Keywords: QSAR; chromone derivatives; estrogen-related receptor; keratinocyte toxicity; neurotoxicity; oral squamous cell carcinoma; signaling pathway; tumor-specificity.

Grants and funding

This research was supported by the Grants-in-Aid for Scientific Research of the Japan Society for the Promotion of Japan ((1) Grant-in-Aid for Scientific Research (C) 20K09885: Elucidation of the selective toxicity mechanism of chromone derivatives for cancer cells, Principal Investigator: Hiroshi Sakagami; (2) Grant-in-Aid for Scientific Research (C) 16K11519: Basic research on the potential of a novel 3-styrylchromone derivative as a therapeutic agent for oral cancer, Principal Investigator Hiroshi Sakagami).