Concurrent blockade of the NF-kappaB and Akt pathways potently sensitizes cancer cells to chemotherapeutic-induced cytotoxicity.
Nuclear factor-kappaB (NF-kappaB) and Akt are two major cell survival pathways that are often constitutively activated and can be further stimulated by chemotherpeutics in cancer cells. Although individually targeting the NF-kappaB or Akt has been reported to sensitize caner therapy, the effectiveness of concurrent blocking these two pathways for chemosensitizing of cancer cells to genotoxic therapeutics has not been investigated. In the present study, we investigate the activation of the NF-kappaB and Akt pathways by two frontline anticancer drugs cisplatin and etopside in a variety of cancer cell lines. The effects of blocking these two survival pathways individually or concurrently on cisplatin- or etopside-induced cytotoxicity were detected. The results show that cisplatin and etopside activate both NF-kappaB and Akt in cancer cells. Blockade of either of these pathways with chemical inhibitors or siRNA moderately sensitized cancer cells to cisplatin- or etopside-induced cytotoxicity. Strikingly, much more effective potentiation of cytotoxicity to these anticancer drugs was achieved when NF-kappaB and Akt were concurrently blocked. These data suggest that NF-kappaB and Akt cooperatively attenuate therapeutic-induced cytotoxicity and concurrently blocking these pathways is an effective strategy for improving the anticancer efficacy of therapeutics.
He
Hai-Ning
HN
Laboratory of Molecular and Translational Medicine, West China Second University Hospital, Sichuan University, 20 Renminnanlu, Chengdu 610041, China.
Wang
Xia
X
Zheng
Xue-Lian
XL
Sun
Hong
H
Shi
Xun-Wei
XW
Zhong
Ying-Jia
YJ
Huang
Bo
B
Yang
Lan
L
Li
Jin-Ke
JK
Liao
Lin-Chuan
LC
Zhang
Lin
L
Hu
Li-Na
LN
Lin
Yong
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects*; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D016328:NF-kappa B; C498143:RELA protein, human; D034741:RNA, Small Interfering; D051996:Transcription Factor RelA; D005047:Etoposide; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase; D002945:Cisplatin