Induction of Apoptosis in Human Oral Keratinocyte by Doxorubicin

Abstract

Abstract. Background For the exploration of new anticancer drugs, experiments with tumor-bearing animals are mandatory. However, the results obtained with animals have to be carefully evaluated, since drug metabolisms are quite different between animals and humans (1, 2). The other approach is to use cell cultures that mimic whole body. We have established an in vitro assay method of anti-tumor activity, based on the relative cytotoxicity against human oral squamous cell carcinoma (OSCC) cell lines (Ca9-22, HSC-2, HSC-3, HSC-4) and human normal oral mesenchymal cells (gingival fibroblast, HGF; periodontal ligament fibroblast, HPLF; pulp cell, HPC) (3). The validity of this model for estimating the antitumor activity was obtained by our finding that anticancer drugs such as topoisomerase I inhibitors (camptothecin, SN-38) and topoisomerase II inhibitors (etoposide, teniposide), anthracyclines (doxorubicin, daunorubicin, epirubicin, mitoxantrone), mitomycin C, docetaxel, 5-FU and bacterial products (nocobactin NA-a, -b) showed one or two-orders higher tumor-specificity than hundreds of other natural products including tannins, flavonoids and other lower molecular weight polyphenols (3).We recently found that doxorubicin showed very potent cytotoxicity against human normal oral epithelial cells (mucosa keratinocyte, HOK; primary gingival epithelial cell, HGEP) (4-6). However, the mechanism of keratinocyte toxicity is obscure. In the present study, we investigated whether keratinocyte toxicity is reproducibly observable, regardless the culturing conditions and types of anticancer drugs, and whether it is coupled with apoptosis induction. We also present our preliminary data that searched natural products for their ability to alleviate the keratinocyte toxicity.

Search of Neuroprotective Polyphenols Using the “Overlay” Isolation Method

“…SE, a group of three over-the-counter drugs, showed the highest neuroprotective activity against both undifferentiated and differentiated PC12 cells, as well as undifferentiated SH-SY5Y cells. This seems to be linked to growth stimulation at lower doses, known as hormesis [ 40 ], since we have experienced similar growth stimulation of SE towards human gingival epithelial fibroblast (HGEP) [ 41 ] and PC12 cells [ 33 ]. SE showed prominent anti-HIV [ 42 ] and anti-UV activity [ 43 ], like the lignin-carbohydrate complexes extracted with alkaline solution.…”

In Vitro Assessment of Antitumor Potential and Combination Effect of Classical and Molecular-targeted Anticancer Drugs

“…We have recently reported that classical anticancer drugs exerted both good effect [extremely higher cytotoxicity against human oral squamous cell carcinoma (OSCC) cell lines than human normal oral mesenchymal cells], and bad effect (potent cytotoxicity against human normal oral epithelial cells) (2,3). Recently, moleculartargeted drugs, such as cetuximab (Cmab) and nivolumab (Nmab) have been approved for the treatment of head and neck cancer in Japan (November 10, 2016).…”

Quantitative Structure–Cytotoxicity Relationship of Azulene Amide Derivatives

“…showed higher TS and PSE values, than [1][2][3][4][5][6][7] and [15][16][17][18][19][20][21]. The most active compound [8][9][10][11][12][13][14] induced apoptosis in C9-22 OSCC cells at 4-times higher CC 50 .…”

“…the ratio of mean CC 50 (HGF+HPLF+HPC) to mean CC 50 (Ca9-22+HSC-2+HSC-3+HSC-4), using seven cell lines [(D/B) in Table I] (19), and as the ratio of CC 50 (HGF) to CC 50 (Ca9-22) [(C/A) in Table I], using two cell lines derived from the gingival tissue (20). Normal keratinocytes, which are highly sensitive to many anticancer drugs (21), were not used in this study. Calculation of potency-selectivity expression (PSE).…”