Quinolone-indolone conjugate induces apoptosis by inhibiting the EGFR-STAT3-HK2 pathway in human cancer cells.
The epidermal growth factor receptor (EGFR) is involved in the proliferation of human tumors and is an effective target for the treatment of cancer. In the present study, a novel quinolone-indolone conjugate, QIC1 [9-Fluoro-3,7-dihydro-3-methyl-10-(4-methyl -1-piperazinyl) -6-(2-oxo-1,2-dihydro-indol-3-ylidenemethyl) -7-oxo-2H-(1,4) oxazino(2,3,4-ij)quinoline], which targeted EGFR, was synthesized in order to investigate the anticancer activity and the potential mechanisms underlying the effect of this compound in human cancer cells. Using MTT assays it was observed that QIC1 inhibited the growth of HepG2 human hepatoma cells, MCF7 human breast cancer cells, HeLa human cervical cancer cells and A549 human lung adenocarcinoma cells. QIC1 arrested cell cycle progression at the G2/M phase in HepG2 cells. QIC1 inhibited the synthesis of DNA in A549 cells. In addition, it resulted in cell apoptosis, in association with increased expression of Bax and reduced expression of Bcl-2. Further analyses demonstrated that QIC1 attenuated the activity of EGFR, and the downstream signal transducer and activator of transcription 3 (STAT3)-mediated hexokinase II (HK2) signaling pathways. Furthermore, QIC1 exhibited antiproliferative effects in MCF7/DOX human doxorubicin-resistant breast cancer cells and also enhanced the anticancer activity of doxorubicin in these cells. In conclusion, the inhibition of proliferation and the induction of apoptosis was associated with reduced expression of phospho-EGFR-phospho-STAT3-HK2. The present results suggest a potential role for QIC1 in the treatment of human cancer.
Biopharmaceutical Department, Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan 475004, P.R. China.
Ying-Hua
YH
Liu
Biopharmaceutical Department, Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan 475004, P.R. China.
Xiao-Li
XL
Wei
Biopharmaceutical Department, Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan 475004, P.R. China.
Guo-Qiang
GQ
Hu
Biopharmaceutical Department, Institute of Traditional Chinese Medicine, College of Pharmacy, Henan University, Kaifeng, Henan 475004, P.R. China.
Tian-Xiao
TX
Wang
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006593:Hexokinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015363:Quinolones / Q000737:chemistry / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000970:Antineoplastic Agents; D015363:Quinolones; D050796:STAT3 Transcription Factor; D006593:Hexokinase; D066246:ErbB Receptors