[P3-3-28] A search for factors that enhance the cytotoxicity of novel chromone derivatives on human oral squamous cell carcinoma
Keywords:新規クロモン誘導体、腫瘍選択性、増強因子
We are manufacturing new anticancer drugs that selectively damage human oral squamous cell carcinoma cells (OSCC) and have low toxicity to normal cells. As a result of a comprehensive examination of total of 346 natural and synthetic compounds, polyphenols such as flavonoids and tannins, curcumin, vitamin C, saponins, terpenes, azulene, tropolone, and αβ-unsaturated ketones have low tumor-selectivity, whereas derivatives in which a styryl group is introduced at position 3 of the chromone skeleton (two-ring structure distributed into flavonoid molecules) showed higher tumor selectivity. Among about 300 compounds of 17 groups of chromone 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 tumor-selectivity comparable to the anticancer drugs DOX, 5-FU, and cisplatin, and had minor toxicity against keratinocytes and neuronal cells. Furthermore, in silico analysis based on structure-activity relationships suggested that the OSCC damaging effect of compound A/B may be due to their inhibition of estrogen receptor-mediated signaling pathway. OSCC was also found to be highly sensitive to mild hyperthermia and UVC irradiation. While continuing to manufacture more active new chromone derivatives, we plan to launch a new project that searches for various factors (cytotoxic substances, metals, redox compounds, mechanical stress such as X-rays, UVC and laser, expression of stress-responsive receptors etc.) that could enhance the antitumor activity of new chromone derivatives.