Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

A Comparative Study of Tumor-Specificity and Neurotoxicity Between 3-Styrylchromones and Anticancer Drugs

Tomoyuki Abe
,
Hiroshi Sakagami
* ORCID logo ,
Shigeru Amano
,
Shin Uota
,
Kenjiro Bandow
ORCID logo ,
Yoshihiro Uesawa
ORCID logo ,
Shiori U
,
Hiroki Shibata
,
Yuri Takemura
,
Yu Kimura
,
Koichi Takao
,
Yoshiaki Sugita
,
Akira Sato
ORCID logo ,
Sei-ichi Tanuma
,
Hiroshi Takeshima
Version 1 : Received: 5 June 2023 / Approved: 5 June 2023 / Online: 5 June 2023 (15:45:48 CEST)

A peer-reviewed article of this Preprint also exists.

Abe, T.; Sakagami, H.; Amano, S.; Uota, S.; Bandow, K.; Uesawa, Y.; U, S.; Shibata, H.; Takemura, Y.; Kimura, Y.; Takao, K.; Sugita, Y.; Sato, A.; Tanuma, S.-I.; Takeshima, H. A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs. Medicines 2023, 10, 43. Abe, T.; Sakagami, H.; Amano, S.; Uota, S.; Bandow, K.; Uesawa, Y.; U, S.; Shibata, H.; Takemura, Y.; Kimura, Y.; Takao, K.; Sugita, Y.; Sato, A.; Tanuma, S.-I.; Takeshima, H. A Comparative Study of Tumor-Specificity and Neurotoxicity between 3-Styrylchromones and Anti-Cancer Drugs. Medicines 2023, 10, 43.

Abstract

Background. Many anticancer 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 4 popular anticancer 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 as compared with newly synthesized derivatives, confirming its prominent tumor-specificity. Docetaxel showed one order of magnitude higher TSM, but two order 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.

Keywords

chromone derivatives; oral squamous cell carcinoma; tumor-specificity; keratinocyte toxicity; neurotoxicity; signaling pathway

Subject

Medicine and Pharmacology, Pharmacology and Toxicology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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