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

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.

STAT3 pathway in cancers: Past, present, and future

“…300 Turkson et al reported that platinum-containing compounds can selectively block STAT3, and it has been shown that platinum (IV)-containing complexes, CPA-1 and CPA-7, disrupt the DNA-binding capacity of STAT3 and induce tumor regression. 301 Recently, a novel smallmolecule lead compound called (E)-2-methoxy-4-(3-(4methoxyphenyl)prop-1-en-1-yl)phenol (MMPP) was synthesized by Son et al, and it can suppress cancer growth by directly interacting with the DBD of STAT3. 256 Compared to the bioactive compound (E)-2,4-bis(p-hydroxyphenyl)-2-butenal (BHPB), which was synthesized previously, MMPP circumvented the problem caused by the presence of α, β-unsaturated carbonyl groups in BHPB that form a non-selective covalent bond, which is conducive to side effects.…”

“…Turkson et al. reported that platinum‐containing compounds can selectively block STAT3, and it has been shown that platinum (IV)‐containing complexes, CPA‐1 and CPA‐7, disrupt the DNA‐binding capacity of STAT3 and induce tumor regression 301 . Recently, a novel small‐molecule lead compound called (E)‐2‐methoxy‐4‐(3‐(4‐methoxyphenyl)prop‐1‐en‐1‐yl)phenol (MMPP) was synthesized by Son et al., and it can suppress cancer growth by directly interacting with the DBD of STAT3 256 .…”

Strategies and Approaches of Targeting STAT3 for Cancer Treatment

“…Each monomer within an active STAT3 dimer has a total of four loops, three from the DBD and one from the linker domain that form interactions with the double helix of DNA . Platinum compounds are known to form DNA adducts and therefore can disrupt the ability of STAT3 to bind DNA, leading to apoptosis in STAT3 dependent human cancer cell lines. , Platinum compounds proposed as STAT3 inhibitors are classified as platinum­(IV) complexes and differ from chemotherapeutics such as cisplatin, a platinum­(II) complex, which displays no inhibitory effect on STAT3. , The most well-known platinum­(IV) DBD inhibitors are CPA-1, CPA-7, and platinum­(IV) tetrachloride. More recently another platinum­(IV) compound, IS3–295, was determined to inhibit the DNA-binding capacity of STAT3 although its mechanism of action still requires elucidation .…”

“…8 Platinum compounds are known to form DNA adducts and therefore can disrupt the ability of STAT3 to bind DNA, leading to apoptosis in STAT3 dependent human cancer cell lines. 86,87 Platinum compounds proposed as STAT3 inhibitors are classified as platinum(IV) complexes and differ from chemotherapeutics such as cisplatin, a platinum(II) complex, which displays no inhibitory effect on STAT3. 86,87 The most well-known platinum(IV) DBD inhibitors are CPA-1, CPA-7, and platinum(IV) tetrachloride.…”

“…86,87 Platinum compounds proposed as STAT3 inhibitors are classified as platinum(IV) complexes and differ from chemotherapeutics such as cisplatin, a platinum(II) complex, which displays no inhibitory effect on STAT3. 86,87 The most well-known platinum(IV) DBD inhibitors are CPA-1, CPA-7, and platinum(IV) tetrachloride. More recently another platinum(IV) compound, IS3−295, was determined to inhibit the DNA-binding capacity of STAT3 although its mechanism of action still requires elucidation.…”