Augmented antitumor effects of combination therapy of cisplatin with ethaselen as a novel thioredoxin reductase inhibitor on human A549 cell in vivo.
Ethaselen (1, 2-[bis (1, 2-Benzisoselenazolone-3 (2H) -ketone)] ethane, BBSKE), as a novel organoselenium compound targeting thioredoxin reductase (TrxR), has been reported to inhibit tumor growth and TrxR activity in several human tumor cell lines. It has now entered Phase I clinical trails. Here we report the effects of ethaselen and cisplatin (cis-diamminedichloroplatinum II, DDP) combination therapy (ethaselen 36 mg/kg, i.g., o.d. x 10 d and cisplatin 1 mg/kg, i.p., single at day 0) on human A549-grafted nude mouse model (female, BALB/c nude mouse, n = 5, treatment after tumor volume reached 100 mm(3)). Compared to single drug administration (either ethaselen: 36 mg/kg, i.g., o.d. x 10 d or cisplatin: 1.0 mg/kg, i.p., single at day 0), the combination therapy showed significantly reduced tumor size (presumably due to a synergistic effect) and no obvious toxic damage (both in terms of body weight maintenance and liver/kidney damage). These results will be significant in the development of novel anti-tumoral therapeutic strategies directed to non-small cell lung cancer (NSCLC).
Tan
Qiang
Q
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China.
Li
Jing
J
Yin
Han-wei
HW
Wang
Li-hui
LH
Tang
Wan-chen
WC
Zhao
Fang
F
Liu
Xin-min
XM
Zeng
Hui-hui
HH
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005260:Female; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007668:Kidney / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D007677:Kidney Function Tests; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism; D008111:Liver Function Tests; D051379:Mice; D008819:Mice, Nude; D016566:Organoselenium Compounds / Q000008:administration & dosage* / Q000494:pharmacology; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D004791:Enzyme Inhibitors; D016566:Organoselenium Compounds; C529432:ethaselen-1; D005979:Glutathione Peroxidase; D013880:Thioredoxin-Disulfide Reductase; D002945:Cisplatin