Use of cellular electrical impedance sensing to assess in vitro cytotoxicity of anticancer drugs in a human kidney cell nephrotoxicity model.
Nephrotoxicity is one of the major concerns for anticancer drug safety because most drugs are metabolized and excreted by the kidneys. Convenient tools able to perform rapid in vitro cytotoxicity analysis and identify drug side effects in kidney cells during early phases of drug discovery could be beneficial to drug development programs. Here we developed an electrical cell-substrate impedance sensing system (ECIS) capable of continuously measuring the dosage and time response of human proximal tubular epithelial (HK2) cells exposed to four drugs throughout the experimental period. These drugs induced HK2 cell apoptosis/death in a dose-dependent manner, although with very different dose-response effects. DDP (50 μM) was the most cytotoxic and induced obvious HK2 cell apoptosis rapidly after exposure. The other three drugs had much lower cytotoxicity, even at concentrations approaching 1 mM. The results obtained from our ECIS system correlated well with conventional in vitro assays such as flow cytometry and cell viability assays. Notably, the continuous and automatic measurements provided by ECIS system allow for better resolution for drugs with different temporal toxicity profiles. Furthermore, we investigated the effect of DDP's antidotes, glutathione and sodium subsulfite, on DDP-induced cytotoxicity, both of which decreased nephrotoxicity of DDP in a dose-dependent manner. Overall this study illustrates the convenience of ECIS for direct, continuous assessment of the cytotoxicity of anticancer drugs in vitro. ECIS has the potential to become a useful, non-invasive analytical method for early evaluation of drugs and antidotes of toxins.
Medical Systems Biology Research Center, Tsinghua University, Beijing, 100084, China.
Fengbo
F
Xie
Youchun
Y
Xu
Lei
L
Wang
Keith
K
Mitchelson
Wanli
W
Xing
Jing
J
Cheng
D000818:Animals; D000931:Antidotes / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay / Q000295:instrumentation / Q000379:methods; D016190:Carboplatin / Q000009:adverse effects / Q000494:pharmacology; D002460:Cell Line / Q000187:drug effects; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology; D003520:Cyclophosphamide / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017097:Electric Impedance; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects*; D005472:Fluorouracil / Q000009:adverse effects / Q000494:pharmacology; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007668:Kidney / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000166:cytology; D013885:Thiosulfates / Q000494:pharmacology
D000931:Antidotes; D000970:Antineoplastic Agents; D013885:Thiosulfates; D003520:Cyclophosphamide; D016190:Carboplatin; D005978:Glutathione; C017717:sodium thiosulfate; D002945:Cisplatin; D005472:Fluorouracil