A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells

Song, Hui; Wang, Renxiao; Wang, Shaomeng; Lin, Jiayuh

doi:10.1073/pnas.0409894102

Cited by 455 publications

(391 citation statements)

References 29 publications

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“…( Grandis et al, 2000;Epling-Burnette et al, 2001;Calvin et al, 2003;Chiarle et al, 2005), siRNA (Konnikova et al, 2003;Lee et al, 2004), small molecules (Song et al, 2005;Turkson et al, 2005) and decoy-oligos (Leong et al, 2003;Chan et al, 2004). In summary, our results demonstrated for the first time that Stat3 phosphorylation is elevated in clinical human endometrial and cervical cancer samples.…”

Section: Discussionsupporting

confidence: 61%

Stat3 activation in human endometrial and cervical cancers

et al. 2007

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The activation of signal transducer and activator of transcription 3 (Stat3) has been implicated in the oncogenesis of cancer and is regarded as a novel target for cancer therapy. Stat3 is classified as a proto-oncogene, because an activated form of Stat3 can mediate oncogenic transformation in cultured cells and tumour formation in nude mice. The constitutive activation of Stat3 has been frequently detected in various types of human cancers. However, the constitutive activation of Stat3 in endometrial and cervical cancers has not been studied. We examined tyrosine phosphorylation of Stat3 (activated form of Stat3) in multiple endometrial and cervical cancer tissues using tissue microarray slides as well as cancer cell lines to explore the possible activation of Stat3. Our results indicated that elevated phosphorylation of Stat3 was detected in cervical and endometrial cancer cell lines. Our results also showed that elevated levels of phosphorylation of Stat3 protein were detected in the endometrial and cervical cancer specimens. This is the first study to demonstrate that Stat3 is activated in human endometrial and cervical cancer tissues. Immunohistochemical staining showed that activated Stat3 is associated with increased expression of downstream antiapoptotic genes, Bcl-xL, survivin, and Mcl-1 in these tissues. Expression of a dominant-negative Stat3 mutant using adenovirus-mediated gene transfer inhibited cell growth and induced apoptosis in HeLa and SiHa cervical cancer cell lines expressing elevated levels of Stat3 phosphorylation. Further, a JAK/Stat3 small molecular inhibitor, JSI-124, induced apoptosis more selectively in HeLa and SiHa cancer cell lines than Ishikawa cell line without elevated levels of Stat3 phosphorylation. These results indicate that Stat3 is activated in human endometrial and cervical cancers and the inhibition of constitutive Stat3 signaling may be an effective target for cancer intervention in these two cancers.

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Section: Discussionsupporting

confidence: 61%

Stat3 activation in human endometrial and cervical cancers

et al. 2007

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“…However, as STAT3 phosphorylation in normal cells is transient, LLL-3 would likely have little effect on the proliferation of normal cells as suggested by its effect on normal bladder smooth muscle cells. Furthermore, studies using normal mouse fibroblasts showed that disrupting STAT3 signalling has much less profound effect in normal human and murine cells Niu et al, 1999;Bowman et al, 2001;Burke et al, 2001;Song et al, 2005), suggesting that blocking STAT3 signalling may not be grossly toxic. Based on our findings, LLL-3 appears to be a potential therapeutic agent for human glioblastoma cells and possibly other tumours that have constitutively active STAT3.…”

Section: Discussionmentioning

confidence: 99%

“…This leads to dimerisation of STAT3 and subsequent transcription to the nucleus where further activation promotes DNA binding and translation of target genes (Carballo et al, 1999). Earlier findings have shown that STA-21, a polyphenol, can inhibit STAT3 activities and induce cell death in breast cancer cells (Song et al, 2005). Using a structure-based strategy, we selected a structural analogue of STA-21 termed as LLL-3 ( Figure 1A), for further evaluation.…”

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confidence: 99%

LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

Sobo

et al. 2009

Br J Cancer

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Persistent activation of the signal transducer and activator of transcription 3 (STAT3) signalling has been linked to oncogenesis and the development of chemotherapy resistance in glioblastoma and other cancers. Inhibition of the STAT3 pathway thus represents an attractive therapeutic approach for cancer. In this study, we investigated the inhibitory effects of a small molecule compound known as LLL-3, which is a structural analogue of the earlier reported STAT3 inhibitor, STA-21, on the cell viability of human glioblastoma cells, U87, U373, and U251 expressing constitutively activated STAT3. We also investigated the inhibitory effects of LLL-3 on U87 glioblastoma cell growth in a mouse tumour model as well as the impact it had on the survival time of the treated mice. We observed that LLL-3 inhibited STAT3-dependent transcriptional and DNA binding activities. LLL-3 also inhibited viability of U87, U373, and U251 glioblastoma cells as well as induced apoptosis of these glioblastoma cell lines as evidenced by increased poly (ADP-ribose) polymerase (PARP) and caspase-3 cleavages. Furthermore, the U87 glioblastoma tumour-bearing mice treated with LLL-3 exhibited prolonged survival relative to vehicle-treated mice (28.5 vs 16 days) and had smaller intracranial tumours and no evidence of contralateral invasion. These results suggest that LLL-3 may be a potential therapeutic agent in the treatment of glioblastoma with constitutive STAT3 activation.

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“…A Iwamaru et al compound STA-21, a cucurbitacin analog cucurbitacin Q, a new platinum compound CPA-7 and an integrinlinked kinase inhibitor QLT0254 have been reported to inhibit STAT3 and cancer growth in vitro or both in vitro and in vivo (Turkson et al, 2004;Song et al, 2005;Sun et al, 2005;Yau et al, 2005). In line with these studies, we showed that WP1066 significantly inhibited the growth of malignant glioma cells not only in cultured cells, but also in an animal model (Figure 4a).…”

Section: A New Stat3 Inhibitor For Malignant Glioma Cellsmentioning

confidence: 99%

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

et al. 2006

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Signal transducer and activator of transcription-3 (STAT3) is constitutively activated in a variety of cancer types, including malignant gliomas. STAT3 is activated by phosphorylation of a tyrosine residue, after which it dimerizes and translocates into the nucleus. There it regulates the expression of several genes responsible for proliferation and survival at the transcriptional level. A selective inhibitor of STAT3 phosphorylation, AG490, has been shown to inhibit growth and induce apoptosis in some cancer cell types. However, although AG490 routinely shows in vitro anticancer activity, it has not consistently demonstrated an in vivo anticancer effect in animal models. Here, we have tested WP1066, a novel inhibitor structurally related to AG490 but significantly more potent and active, against human malignant glioma U87-MG and U373-MG cells in vitro and in vivo. IC 50 values for WP1066 were 5.6 lM in U87-MG cells and 3.7 lM in U373-MG cells, which represents 18-fold and eightfold increases in potency, respectively, over that of AG490. WP1066 activated Bax, suppressed the expression of c-myc, Bcl-X L and Mcl-1, and induced apoptosis. Systemic intraperitoneal administration of WP1066 in mice significantly (Po0.001) inhibited the growth of subcutaneous malignant glioma xenografts during the 30-day follow-up period. Immunohistochemical analysis of the excised tumors revealed that phosphorylated STAT3 levels in the WP1066 treatment group remained inhibited at 3 weeks after the final WP1066 injection, whereas tumors from the control group expressed high levels of phosphorylated STAT3. We conclude that WP1066 holds promise as a therapeutic agent against malignant gliomas.

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A low-molecular-weight compound discovered through virtual database screening inhibits Stat3 function in breast cancer cells

Cited by 455 publications

References 29 publications

Stat3 activation in human endometrial and cervical cancers

Stat3 activation in human endometrial and cervical cancers

LLL-3 inhibits STAT3 activity, suppresses glioblastoma cell growth and prolongs survival in a mouse glioblastoma model

A novel inhibitor of the STAT3 pathway induces apoptosis in malignant glioma cells both in vitro and in vivo

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