Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity

Sun, Jiazhi; Blaskovich, Michelle A.; Jove, Richard; Livingston, Sandra; Coppola, Domenico; Sebti, Saı̈d M.

doi:10.1038/sj.onc.1208470

Cited by 238 publications

(171 citation statements)

References 32 publications

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“…Besides siRNA and Cucurbitacin I, the efficacy of other Stat3 inhibitors could additionally be explored, including other pharmacological agents such as Cucurbitacin Q, which is an analog of Cucurbitacin I and a selective Stat3 inhibitor (Sun et al, 2005), STA-21 , Stat3 decoy oligonucleotide (Leong et al, 2003), or phosphotyrosyl peptides (Turkson et al, 2001), all of which either exhibited antitumor activity, increased apoptosis and inhibited proliferation or suppressed cell transformation of cancer-derived or v-Src-transformed cell lines. These potential cancer therapeutic agents that target the inhibition of Stat3 may also be useful for the prospective clinical treatment of keloid scars.…”

Section: Discussionmentioning

confidence: 99%

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

et al. 2006

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Keloids, partially considered as benign tumors, represent the most extreme example of cutaneous scarring that uniquely afflicts humans as a pathological response to wound healing. It is characterized by excessive deposition of collagen and other extracellular matrix components by dermal fibroblasts. Upon cutaneous injury, cocktails of chemokines, cytokines and growth factors are secreted temporally and spatially to direct appropriate responses from neutrophils, macrophages, keratinocytes and fibroblasts to facilitate normal wound healing. Signal transducer and activator of transcription 3 (Stat3) is an oncogene and a latent transcription factor activated by various cytokines and growth factors. We investigated the possible role of Stat3 in keloid scar pathogenesis by examining skin tissue and cultured fibroblasts from keloid-scarred patients. We observed enhanced expression and phosphorylation of Stat3 in keloid scar tissue, and in cultured keloid fibroblasts (KFs) in vitro. Increased activation of Janus kinase (Jak)2, but not Jak1, was detected in KFs, and suppression of Jak2 by its inhibitor repressed Stat3 Y705 phosphorylation. Inhibition of Stat3 expression and phosphorylation by short interfering RNA or Cucurbitacin I resulted in the loss of collagen production, impaired proliferation and delayed cell migration in KFs. We show, for the first time, a role of Stat3 in keloid pathogenesis. Inhibitors of Stat3 may be useful therapeutic strategies for the prospective treatment of keloid scars.

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Section: Discussionmentioning

confidence: 99%

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

et al. 2006

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“…We have shown before that both cucurbitacins exert potent anti-inflammatory activity both in vitro and in vivo [2,3,5]. Here we examined their anti-tumorigenic activity in colon cancer cell lines, and compared their potency with CCI, a cucurbitacin with established anti-tumorigenic activity [11,30]. All three cucurbitacins showed overlapping biological activity in colon cancer cells.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, the IC50 for CCI in colon cancer cell lines that we examined was lower than concentrations of CCI that were effective in inhibiting phosphorylation of STAT3 and JAK2 in lung cancer cell lines with constitutive STAT3 activation [30]. It has been suggested that the ability of CCI to inhibit proliferation is independent of STAT3 activation state, while the ability of cucurbitacins to induce apoptosis depends on tyrosine phosphorylated STAT3 [11]. In contrast, our results demonstrated that activated STAT3 is not required for cucurbitacins to induce apoptosis.…”

Section: Discussionmentioning

confidence: 99%

“…Cucurbitacins are known to exert antitumorigenic activity through inhibition of the constitutive STAT3 activity [11,30]. Of note, neither HCT116 nor HKe-3 cells have detectable levels of phosphorylated STAT3, and the levels of total STAT3 are comparable in the two cell lines (Supplemental Figure 2).…”

Section: Cucurbitacins Induce Profound Cytoskeleton Changes and Inducmentioning

confidence: 99%

“…Although these characteristics are likely to contribute to the ability of cucuritacins to inhibit tumor progression, their anti-tumorigenic activity has been ascribed mainly to their propensity to inhibit JAK/STAT3 signaling, an important oncogenic pathway activated in a number of cancers [8][9][10]. Several cucurbitacins (such as cucurbitacin I, cucurbitacin Q and cucurbitacin B) were shown to inhibit phosphorylation of STAT3 and to induce apoptosis in v-src transformed NIH3T3 cells, but had limited biological activity in cells with no activated STAT3 [11], which led to the conclusion that cucurbitacins exert anti-tumorigenic activity selectively in cells with activated STAT3.…”

Section: Introductionmentioning

confidence: 99%

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Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Escandell

Kaler

Recio

et al. 2008

Biochemical Pharmacology

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Cucurbitacins have been shown to inhibit proliferation in a variety of cancer cell lines. The aim of this study was to determine their biological activity in colon cancer cell lines that do not harbor activated STAT3, the key target of cucurbitacin. In order to establish the role of activated kRas in the responsiveness of cells to cucurbitacins, we performed experiments in isogenic colon cancer cell lines, HCT116 and Hke-3, which differ only by the presence of an activated kRas allele. We compared the activity of 23, 24-dihydrocucurbitacin B (DHCB) and cucurbitacin R (CCR), two cucurbitacins that we recently isolated, with cucurbitacin I (CCI), a cucurbitacin with established antitumorigenic activity. We showed that cucurbitacins induced dramatic changes in the cytoskeleton (collapse of actin and bundling of tubulin microfilaments), inhibited proliferation and finally induced apoptosis of both HCT116 and Hke3 cells. However, the presence of oncogenic k-Ras significantly decreased the sensitivity of cells to the three cucurbitacins tested, CCR, DHCB and CCI. We confirmed that mutational activation of kRas protects cells from cucurbitacin-induced apoptosis using nontransfromed intestinal epithelial cells with inducible expression of k-RasV12. Cucurbitacins induced the expression of p53 and p21 predominantly in HCT116 cells that harbor mutant Ras. Using HCT116 cells with targeted deletion of p53 or p21 we confirmed that p53 and p21 protect cells from apoptosis induced by cucurbitacins. These results demonstrated that sensitivity of human colon cancer cell lines to cucurbitacins depends on the kRas and p53/p21 status, and established that cucurbitacins can exert antitumorigenic activity in the absence of activated STAT3.

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Signal Transducers and Activators of Transcription as Targets for Small Organic Molecules

Berg

2008

ChemBioChem

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Signal transducers and activators of transcription (STATs) are a family of transcription factors that are of central importance for cellular signaling and have therefore emerged as attractive target proteins for cell-permeable small molecules. This review outlines the basic concept of STAT signaling, the relevance of individual members of the STAT family for cellular signaling and human disease, and generally applicable approaches taken to the identification of small-molecule inhibitors of STATs.

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Cucurbitacin Q: a selective STAT3 activation inhibitor with potent antitumor activity

Cited by 238 publications

References 32 publications

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

Stat3 contributes to keloid pathogenesis via promoting collagen production, cell proliferation and migration

Activated kRas protects colon cancer cells from cucurbitacin-induced apoptosis: The role of p53 and p21

Signal Transducers and Activators of Transcription as Targets for Small Organic Molecules

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