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

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 (TSM, TSE, TSN) 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 TSM than newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two orders of magnitude lower TSE than Compounds A and B. Compounds A and B showed higher TSM, TSE, and TSN 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.

In vitro cytotoxicity of Withania somnifera (L.) roots and fruits on oral squamous cell carcinoma cell lines: a study supported by flow cytometry, spectral, and computational investigations

“…We have recently reported that two 3-styrylchromone derivatives, 7-methoxy-3-[(1 E )-2-phenylethenyl]-4 H -1-benzopyran-4-one (Compound A) and 3-[(1 E )-2-(4-hydroxyphenyl) ethenyl]-7-methoxy-4 H -1-benzopyran-4-one (Compound B), showed comparable TS values against human OSCC cell lines with 5-FU, cisplatin and doxorubicin. Quantitative structure-activity relationship (QSAR) prediction based on the Tox21 (21st century toxicology program) database suggested that compounds A and B may inhibit the signalling pathway of estrogen-related receptor α (ERRα), but not the other 58 signalling pathways ( Abe et al, 2023 ). Thus, it is urgent to test the possibility that selective inhibition of ERRα may also be involved in the anticancer activity of kaempferol ( 11 ) and withanolide D ( 18 ), and related compounds.…”