Cytotoxic activity of styrylchromones against human tumor cell lines.
A total of 6 newly-synthesized styrylchromones (SC-1 approximately SC-6) were compared for their cytotoxic activity against three normal oral human cells (gingival fibroblast HGF, pulp cell HPC, periodontal ligament fibroblast HPLF) and four human tumor cell lines (squamous cell carcinoma HSC-2, HSC-3, submandibular gland carcinoma HSG, promyelocytic leukemia HL-60). All compounds showed higher cytotoxic activity against tumor cell lines than against normal cells. Among the 6 compounds, SC-3, SC-4 and SC-5, which have one to three methoxy groups, showed higher tumor specificity and water solubility. The cytotoxic activity of SC-3 and SC-5 was slightly reduced by a lower concentration of NADH, a quinone reductase, but that of SC-3 was enhanced by higher concentrations of NADH, possibly due to demethylation of the methoxy groups. Agarose gel electrophoresis demonstrated that SC-3 and SC-5 induced intemucleosomal DNA fragmentation in HL-60 cells and production of large DNA fragment in HSC-2 cells. Both SC-3 and SC-5 enhanced the enzymatic activity to cleave the substrates for caspases 3, 8 and 9, suggesting the activation of both extrinsic and intrinsic apoptosis pathways. ESR spectroscopy showed that these compounds produced no detectable amount of radical and did not scavenge superoxide anion generated by the hypoxanthine-xanthine oxidase reaction. The highly tumor-specific cytotoxic action and apoptosis-inducing capability of SC-3 and SC-5 suggest their applicability for cancer chemotherapy.
Momoi
Kanae
K
Faculty of Pharmaceutical Sciences, Josai University, Sakado, Saitama 350-0295, Japan.
Sugita
Yoshiaki
Y
Ishihara
Mariko
M
Satoh
Kazue
K
Kikuchi
Hirotaka
H
Hashimoto
Ken
K
Yokoe
Ichiro
I
Nishikawa
Hirofumi
H
Fujisawa
Seiichiro
S
Sakagami
Hiroshi
H
D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D002867:Chromones / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity*; D003782:Dental Pulp / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004578:Electron Spin Resonance Spectroscopy; D004587:Electrophoresis, Agar Gel; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005881:Gingiva / Q000166:cytology; D018922:HL-60 Cells; D006801:Humans; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010513:Periodontal Ligament / Q000166:cytology; D013329:Structure-Activity Relationship; D013365:Submandibular Gland Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
D000970:Antineoplastic Agents; D002867:Chromones; D020169:Caspases