Mechanisms underlying the synergistic effect of SU5416 and cisplatin on cytotoxicity in human ovarian tumor cells.
SU5416 is a selective inhibitor of vascular endothelial growth factor (VEGF) receptors with anti-angiogenesis activity for human cancers. We have previously reported that SU5416 sensitizes ovarian cancer cells to cisplatin via suppression of nucleotide excision repair activity. This study sought to gain further insights into the mechanisms underlying the synergistic effect of SU5416 and cisplatin on cytotoxicity in human ovarian tumor cells. Here, we show that SU5416 inhibited the expression of G1 cell cycle checkpoint regulators, p53, p21, p27 and MDM2 in ovarian carcinoma cells. We also demonstrate that SU5416 triggered the apoptosis of these cells, in addition to augmenting the apoptosis induced by cisplatin, as determined by a Sub-G1 profile analysis using a flow cytometer. Furthermore, we show that SU5416-induced apoptosis is associated with a decrease in the expression of the apoptosis inhibitors, MDM2 and Bcl-2, and an increase in the level of NF-kappaB inhibitor, IkappaBalpha. NF-kappaB is an anti-apoptotic transcription factor, which induces the apoptosis inhibitors, Bcl-XL and IAPs (inhibitor of apoptosis proteins), and IkappaBalpha is an inhibitor of NF-kappaB, which binds to the NF-kappaB and retains it in the cytoplasm. Finally, the compound was found to block cisplatin-induced increases in AP-1 expression and JNK activity, as well as Raf-1 protein level in these cells. Together, these results suggest that the chemosensitizing effect of SU5416 on ovarian tumor cells may be mediated, at least in part, through inhibiting G1 checkpoint control and up-regulating the apoptotic response to cisplatin.
Zhong
Xiaosong
X
Mary Babb Randolph Cancer Center, and Department of Microbiology, Immunology and Cell Biology, West Virginia University School of Medicine and Robert C. Byrd Health Sciences Center, Morgantown, WV 26506, USA.
Li
Xiping
X
Wang
Gangduo
G
Zhu
Yunfeng
Y
Hu
Guodong
G
Zhao
Jinshun
J
Neace
Cheryl
C
Ding
Hong
H
Reed
Eddie
E
Li
Qingdi Q
QQ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D017209:Apoptosis; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D002945:Cisplatin / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D000072000:NF-KappaB Inhibitor alpha; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D015854:Up-Regulation
D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D020672:I-kappa B Proteins; D007211:Indoles; C000606204:NFKBIA protein, human; D011518:Proto-Oncogene Proteins; D011758:Pyrroles; D018808:Transcription Factor AP-1; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000072000:NF-KappaB Inhibitor alpha; D050760:Cyclin-Dependent Kinase Inhibitor p27; C116890:Semaxinib; D048031:JNK Mitogen-Activated Protein Kinases; D048670:MAP Kinase Kinase 4; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin