Article

Inhibition of constitutive signal transducer and activator of transcription 3 activation by novel platinum complexes with potent antitumor activity.

Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida 33612, USA.
Molecular Cancer Therapeutics (impact factor: 5.23). 01/2005; 3(12):1533-42. pp.1533-42
Source: PubMed

ABSTRACT 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.

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Keywords

aberrant Stat3 activity
 
antitumor effects
 
causal role
 
cell growth
 
harbor constitutively activated Stat3
 
human tumors
 
IV)-containing complexes
 
key molecular mechanisms
 
low micromolar concentrations
 
modulate signal transduction events
 
mouse CT26 colon tumor
 
novel cancer therapeutics
 
novel platinum
 
oncogenic signal transduction pathways
 
persistent Stat3 activity
 
platinum complexes induce apoptotic responses
 
small-molecule inhibitors
 
Stat3 signaling
 
Various lines
 
wide application
 

James Turkson