Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity.
DNA-alkylating agents that are platinum complexes induce apoptotic responses and have wide application in cancer therapy. The potential for platinum compounds to modulate signal transduction events that contribute to their therapeutic outcome has not been extensively examined. Among the signal transducer and activator of transcription (STAT) proteins, Stat3 activity is frequently up-regulated in many human tumors. Various lines of evidence have established a causal role for aberrant Stat3 activity in malignant transformation and provided validation for its targeting in the development of small-molecule inhibitors as novel cancer therapeutics. We report here that platinum-containing compounds disrupt Stat3 signaling and suppress its biological functions. The novel platinum (IV) compounds, CPA-1, CPA-7, and platinum (IV) tetrachloride block Stat3 activity in vitro at low micromolar concentrations. In malignant cells that harbor constitutively activated Stat3, CPA-1, CPA-7, and platinum (IV) tetrachloride inhibit cell growth and induce apoptosis in a manner that reflects the attenuation of persistent Stat3 activity. By contrast, cells that do not contain persistent Stat3 activity are marginally affected or are not affected by these compounds. Moreover, CPA-7 induces the regression of mouse CT26 colon tumor, which correlates with the abrogation of persistent Stat3 activity in tumors. Thus, the modulation of oncogenic signal transduction pathways, such as Stat3, may be one of the key molecular mechanisms for the antitumor effects of platinum (IV)-containing complexes.
Turkson
James
J
Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA. turksonj@moffitt.usf.edu
Zhang
Shumin
S
Palmer
Jay
J
Kay
Heidi
H
Stanko
Joseph
J
Mora
Linda B
LB
Sebti
Said
S
Yu
Hua
H
Jove
Richard
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D017606:Chlorine Compounds / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009944:Organoplatinum Compounds / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017671:Platinum Compounds / Q000494:pharmacology*; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000037:antagonists & inhibitors*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D017606:Chlorine Compounds; D004268:DNA-Binding Proteins; D009944:Organoplatinum Compounds; D017671:Platinum Compounds; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; C529200:trichloronitritodiammineplatinum(IV)