A novel platinum compound inhibits constitutive Stat3 signaling and induces cell cycle arrest and apoptosis of malignant cells.
Previous studies have established constitutive activation of Stat3 protein as one of the molecular changes required for tumorigenesis. To develop novel therapeutics for tumors harboring constitutively active Stat3, compounds from the NCI 2000 diversity set were evaluated for inhibition of Stat3 DNA-binding activity in vitro. Of these, a novel platinum (IV) compound, IS3 295, interacted with Stat3 and inhibited its binding to specific DNA-response elements. Further analysis suggested noncompetitive-type kinetics for the inhibition of Stat3 binding to DNA. In human and mouse tumor cell lines with constitutively active Stat3, IS3 295 selectively attenuated Stat3 signaling, thereby inducing cell growth arrest at G0/G1 phase and apoptosis. Moreover, in transformed cells, IS3 295 repressed expression of cyclin D1 and bcl-xL, two of the known Stat3-regulated genes that are overexpressed in malignant cells, suggesting that IS3 295 mediates anti-tumor cell activity in part by blocking Stat3-mediated sub-version of cell growth and apoptotic signals. Together, our findings provide evidence for the inhibition of Stat3 activity and biological functions by IS3 295 through interaction with Stat3 protein. This study represents a significant advance in small molecule-based approaches to target Stat3 and suggests potential new applications for platinum (IV) complexes as modulators of the Stat3 pathway for cancer therapy.
Turkson
James
J
Molecular Oncology and Drug Discovery Programs, H. Lee Moffitt Cancer Center & Research Institute, Orlando, FL 32826, USA. jturkson@mail.ucf.edu
Zhang
Shumin
S
Mora
Linda B
LB
Burns
Audrey
A
Sebti
Said
S
Jove
Richard
R
D000362:Agar / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004247:DNA / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism; D005434:Flow Cytometry; D016193:G1 Phase; D005786:Gene Expression Regulation; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000096:biosynthesis; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D041681:NIH 3T3 Cells; D009369:Neoplasms / Q000188:drug therapy*; D009841:Oligonucleotides / Q000737:chemistry; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D010984:Platinum / Q000494:pharmacology*; D017671:Platinum Compounds / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction; D013997:Time Factors
D019394:Ki-67 Antigen; C505448:NSC 295558; D009841:Oligonucleotides; D010879:Piperazines; D017671:Platinum Compounds; D019938:Cyclin D1; D010984:Platinum; D000362:Agar; D004247:DNA; D008156:Luciferases; D015688:Oncogene Protein pp60(v-src); D001973:Bromodeoxyuridine