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Omeprazole is a proton pump inhibitor that has recently been reported to exhibit anticancer activity against several types of cancer. However, the anticancer mechanisms of omeprazole remain elusive. Snail is an oncogenic zinc finger transcription factor; aberrant activation of Snail is associated with the occurrence and progression of cancer. In this study, we investigated whether Snail acted as a direct anticancer target of omeprazole. We showed that omeprazole displayed a high binding-affinity to recombinant Snail protein (K(d) = 0.076 mM), suggesting that omeprazole directly and physically binds to the Snail protein. We further revealed that omeprazole disrupted CREB-binding protein (CBP)/p300-mediated Snail acetylation and then promoted Snail degradation through the ubiquitin–proteasome pathway in HCT116 cells. Omeprazole treatment markedly suppressed Snail-driven epithelial-mesenchymal transition (EMT) in aggressive HCT116, SUM159, and 4T1 cancer cells in vitro and reduced EMT-associated tumor invasion and metastasis in cancer cell xenograft models. Omeprazole also inhibited tumor growth by limiting Snail-dependent cell cycle progression. Overall, this study, for the first time, identifies Snail as a target of omeprazole and reveals a novel mechanism underlying the therapeutic effects of omeprazole against cancer. This study strongly suggests that omeprazole may be an excellent auxiliary drug for treating patients with malignant tumors.

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium–enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti–programmed cell death protein 1 (anti–PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

Recent interest in the control of bone metabolism has focused on a specialized subset of CD31hiendomucinhi vessels, which are reported to couple angiogenesis with osteogenesis. However, the underlying mechanisms that link these processes together remain largely undefined. Here we show that the zinc-finger transcription factor ZEB1 is predominantly expressed in CD31hiendomucinhi endothelium in human and mouse bone. Endothelial cell-specific deletion of ZEB1 in mice impairs CD31hiendomucinhi vessel formation in the bone, resulting in reduced osteogenesis. Mechanistically, ZEB1 deletion reduces histone acetylation on Dll4 and Notch1 promoters, thereby epigenetically suppressing Notch signaling, a critical pathway that controls bone angiogenesis and osteogenesis. ZEB1 expression in skeletal endothelium declines in osteoporotic mice and humans. Administration of Zeb1-packaged liposomes in osteoporotic mice restores impaired Notch activity in skeletal endothelium, thereby promoting angiogenesis-dependent osteogenesis and ameliorating bone loss. Pharmacological reversal of the low ZEB1/Notch signaling may exert therapeutic benefit in osteoporotic patients by promoting angiogenesis-dependent bone formation., An endothelial cell subtype, expressing endomucin and CD31, has been reported to couple angiogenesis with osteogenesis. Here, the authors show that loss of ZEB1 in these cells epigenetically suppresses Notch signaling, leading to impaired angiogenesis and osteogenesis, and that Zeb1 delivery via liposomes ameliorates bone loss in osteoporotic mice

BACKGROUND AND PURPOSE The zinc finger transcription factor Snail is aberrantly activated in many human cancers and strongly associated with poor prognosis. As a transcription factor, Snail has been traditionally considered an "undruggable" target. Here, we identified a potent small molecule inhibitor of Snail, namely trimethoprim, and investigated its potential antitumor effects and the underlying mechanisms. EXPERIMENTAL APPROACH The inhibitory action of trimethoprim on Snail protein and the related molecular mechanisms were revealed by molecular docking, biolayer interferometry, immunoblotting, immunoprecipitation, qRT-PCR, pull-down, and cycloheximide pulse-chase assays. The anti-proliferative and anti-metastatic effects of trimethoprim via targeting Snail were tested in multiple cell-based assays and animal models. KEY RESULTS This study identified trimethoprim, an antimicrobial drug, as a potent anti-tumor agent via targeting Snail. Molecular modeling analysis predicted that trimethoprim directly binds to the arginine-174 pocket of Snail protein. We further discovered that trimethoprim strongly interrupts the interaction of Snail with CREB-binding protein (CBP)/p300, which consequently suppresses Snail acetylation and promotes Snail degradation through ubiquitin-proteasome pathway. Furthermore, trimethoprim sufficiently inhibited the proliferation, epithelial-mesenchymal transition (EMT), and migration of cancer cells in vitro via specifically targeting Snail. More importantly, trimethoprim effectively reduced Snail-driven tumor growth and metastasis to vital organs such as lung, bone, and liver. CONCLUSIONS AND IMPLICATIONS These findings indicate, for the first time, that trimethoprim suppresses tumor growth and metastasis via targeting Snail. This study provides insights for a better understanding of the anticancer effects of trimethoprim and offers a potential anti-cancer therapeutic agent for clinical treatment.

Compound CYD19 has been identified as a CBP/p300-Snail interaction inhibitor that exhibits potent anticancer efficacy., The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered “undruggable,” and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail’s interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.

Background The transforming growth factor β (TGFβ) and bone morphogenetic protein (BMP) signaling pathways are both constitutively activated in triple-negative breast cancer (TNBC). We are interested in isolating the naturally-derived small-molecule inhibitor that could simultaneously targeting TGFβ/BMP pathways and further studying its anti-proliferative/−metastatic effects as well as the underlying mechanisms in multiple tumor models. Methods Multiple in vitro cell-based assays are used to examine the compound’s inhibitory efficacy on TNBC cell growth, stemness, epithelial-mesenchymal transition (EMT), invasion and migration by targeting TGFβ/BMP signaling pathways. Transgenic breast cancer mouse model (MMTV-PyMT), subcutaneous xenograft and bone metastasis models are used to examine ZL170’s effects on TNBC growth and metastasis potentials in vivo. Results ZL170 dose-dependently inhibits cell proliferation, EMT, stemness, invasion and migration in vitro via specifically targeting canonical TGFβ/BMP-SMADs pathways in TNBC cells. The compound significantly hinders osteolytic bone metastasis and xenograft tumor growth without inflicting toxicity on vital organs of tumor-bearing nude mice. ZL170 strongly inhibits primary tumor growth and lung metastases in MMTV-PyMT transgenic mice. ZL170-treated tumors exhibit impaired TGFβ/BMP signaling pathways in both epithelial and stromal compartments, thereby creating a suppressive tumor microenvironment characterized by reduced extracellular matrix deposition and decreased infiltration of stromal cells. Conclusions ZL170 inhibits tumor EMT, stemness and metastasis and could be further developed as a potent anti-metastatic agent used in combination with cytotoxic drugs for treatment of TNBC and other advanced metastatic cancers. Electronic supplementary material The online version of this article (10.1186/s13046-019-1130-2) contains supplementary material, which is available to authorized users.

Figure S1. Extraction, total synthesis and characterization of ZL170. Figure S2. ZL170 treatment does not induce C57BL6 mice death or any obvious adverse health effects. Figure S3. ZL170 is a potent dual inhibitor of TGFβ and BMP kinase receptors. Figure S4. ZL170 reverses the EMT program in TNBC cells. Figure S5. Administration of ZL170 does not induce apoptosis or elicit toxicity on key organs of tumor-bearing mice. Figure S6. ZL170 treatment does not induce apoptosis or elicit toxicity on key organs of PyMT transgenic mice. (DOCX 6822 kb)

Angiogenesis is associated with the progression of multiple myeloma (MM). Wogonin is an active mono-flavonoid with remarkable antitumor activity. However, its impact on MM-stimulated angiogenesis remains largely unknown. Here, we demonstrated that wogonin decreased expression and secretion of pro-angiogenic factors in MM cells via c-Myc/HIF-1α signaling axis, reducing MM-stimulated angiogenesis and MM cell proliferation in vivo. Overexpression of c-Myc in MM cells disrupted the balance between VHL SUMOylation and ubiquitination, and thus inhibited proteasome-mediated HIF-1α degradation. Impaired function of VHL ubiquitination complex in c-Myc-overexpressing cells was fully reversed by wogonin treatment via increasing HIF-1α-VHL interaction and promoting HIF-1α degradation. Collectively, our in vitro and in vivo studies reveal for the first time that wogonin represses MM-stimulated angiogenesis and tumor progression via c-Myc/VHL/HIF-1α signaling axis.

Accumulating evidence indicates that the zinc-finger transcription factor ZEB1 is predominantly expressed in the stroma of several tumours. However, the role of stromal ZEB1 in tumour progression remains unexplored. In this study, while interrogating human databases, we uncover a remarkable decrease in relapse-free survival of breast cancer patients expressing high ZEB1 levels in the stroma. Using a mouse model of breast cancer, we show that ZEB1 inactivation in stromal fibroblasts suppresses tumour initiation, progression and metastasis. We associate this with reduced extracellular matrix remodeling, immune cell infiltration and decreased angiogenesis. ZEB1 deletion in stromal fibroblasts increases acetylation, expression and recruitment of p53 to FGF2/7, VEGF and IL6 promoters, thereby reducing their production and secretion into the surrounding stroma. Importantly, p53 ablation in ZEB1 stroma-deleted mammary tumours sufficiently recovers the impaired cancer growth and progression. Our findings identify the ZEB1/p53 axis as a stroma-specific signaling pathway that promotes mammary epithelial tumours., In epithelial cells Zeb1 is involved in the epithelial to mesenchymal transition. In this study, the authors show in a mouse model of breast cancer, that Zeb1 expression in stromal cells is required for tumour formation and metastasis.

BACKGROUND AND PURPOSE: Indoleamine 2,3‐dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small‐molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small‐molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models. EXPERIMENTAL APPROACH: C57BL6 mice, athymic nude mice or Ido1 (−/−) mice were inoculated with IDO1‐expressing and ‐nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. KEY RESULTS: LW106 dose‐dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1 (−/−) mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative T(eff) cells, while reducing recruitment of proliferative T(reg) cells and non‐haematopoietic stromal cells such as endothelial cells and cancer‐associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed. CONCLUSIONS AND IMPLICATIONS: LW106 inhibits tumour outgrowth by limiting stroma‐immune crosstalk and CSC enrichment in the tumour micro‐environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment.

Multiple myeloma (MM) is the second most commonly hematologic malignancy characterized by proliferation of monoclonal plasmas cells in bone marrow. Despite the availability of new drugs targeting the neoplastic clone and its microenvironment, MM is still an incurable disease, with patients experiencing subsequent phases of remission and relapse, eventually leading to disease resistance and patient death. In the past decades, natural products have attracted increasing attention in the field of anti-myeloma treatment by virtue of their multiple bioactivities and lower toxicity. This review focuses on the research progress and mechanisms through which these natural extracts inhibit tumor cell proliferation and normalize microenvironment in multiple myeloma. These include the induction of apoptosis, inhibition of bone injury and angiogenesis, and reversion of multidrug resistance.

Slug (Snail2) plays critical roles in regulating the epithelial–mesenchymal transition (EMT) programs operative during development and disease. However, the means by which Slug activity is controlled remain unclear. Herein we identify an unrecognized canonical Wnt/GSK3β/β-Trcp1 axis that controls Slug activity. In the absence of Wnt signaling, Slug is phosphorylated by GSK3β and subsequently undergoes β-Trcp1–dependent ubiquitination and proteosomal degradation. Alternatively, in the presence of canonical Wnt ligands, GSK3β kinase activity is inhibited, nuclear Slug levels increase, and EMT programs are initiated. Consistent with recent studies describing correlative associations in basal-like breast cancers between Wnt signaling, increased Slug levels, and reduced expression of the tumor suppressor Breast Cancer 1, Early Onset (BRCA1), further studies demonstrate that Slug—as well as Snail—directly represses BRCA1 expression by recruiting the chromatin-demethylase, LSD1, and binding to a series of E-boxes located within the BRCA1 promoter. Consonant with these findings, nuclear Slug and Snail expression are increased in association with BRCA1 repression in a cohort of triple-negative breast cancer patients. Together, these findings establish unique functional links between canonical Wnt signaling, Slug expression, EMT, and BRCA1 regulation.

In a search for Polo-like kinase 1 (Plk1)-interacting proteins using a yeast two-hybrid system, we have identified histone acetyltransferase binding to the origin recognition complex 1 (Hbo1) as a potential Plk1 target. Here, we show that the interaction between Plk1 and Hbo1 is mitosis-specific and that Plk1 phosphorylates Hbo1 on Ser-57 in vitro and in vivo . During mitosis, Cdk1 phosphorylates Hbo1 on Thr-85/88, creating a docking site for Plk1 to be recruited. Significantly, the overexpression of Hbo1 mutated at the Plk1 phosphorylation site (S57A) leads to cell-cycle arrest in the G 1 /S phase, inhibition of chromatin loading of the minichromosome maintenance (Mcm) complex, and a reduced DNA replication rate. Similarly, Hbo1 depletion results in decreased DNA replication and a failure of Mcm complex binding to chromatin, both of which can be partially rescued by the ectopic expression of WT Hbo1 but not Hbo1-S57A. These results suggest that Plk1 phosphorylation of Hbo1 may be required for prereplicative complex (pre-RC) formation and DNA replication licensing.

We determined the effect of baicalein on prostatic hyperplasia in experimental animal models. Prostatic hyperplasia was induced by testosterone propionate in mice and castrated rats and by transplantation of homologous strain fetal mice urogenital sinus in mice. With the histopathological examination, the efficacy of baicalein on prostate hyperplasia in experimental animals was evaluated by the activity of serum acid phosphatase (ACP) and the following norm of the prostate gland: the volume, wet weight, wet weight index, dry weight index, DNA contents and prostatic epithelial height and cavity diameter. Results showed that baicalein at doses of 260 and 130 mg/kg administrated intragastrically (i.g.) significantly inhibited prostatic hyperplasia in castrated rats induced by testosterone propionate compared with the negative control group (p

Previous studies have demonstrated that wogonoside, the glucuronide metabolite of wogonin, has anti-inflammatory, anti-angiogenic and anticancer effects. However, the anti-inflammatory mechanism of wogonoside has not been fully elucidated. Recently, NLRP3 inflammasome has been reported to be correlated with inflammatory bowel disease for its ability to induce IL-1β release. Nevertheless, there are few drug candidates targeting NLRP3 inflammasome for this disease. In this study, we investigated the anti-inflammatory effect of wogonoside in dextran sulfate sodium (DSS)-induced murine colitis and further revealed the underlying mechanisms by targeting NF-κB and NLRP3 inflammasome. Wogonoside treatment dose-dependently attenuated DSS-induced body weight loss and colon length shortening. Moreover, wogonoside prevented DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and significantly decreased myeloperoxidase (MPO) and inducible nitric oxide synthase (iNOS) activities. The production of pro-inflammatory mediators in serum and colon was also significantly reduced by wogonoside. The underlying mechanisms for the protective effect of wogonoside in DSS-induced colitis may be attributed to its inhibition on NF-κB and NLRP3 inflammasome activation in colons. Furthermore, wogonoside markedly decreased production of IL-1β, TNF-α and IL-6 and suppressed mRNA expression of pro-IL-1β and NLRP3 in phorbol myristate acetate (PMA)-differentiated monocytic THP-1 cells via inhibiting the activation of NF-κB and NLRP3 inflammasome. In conclusion, our study demonstrated that wogonoside may exert its anti-inflammatory effect via dual inhibition of NF-κB and NLRP3 inflammasome, suggesting that wogonoside might be a potential effective drug for inflammatory bowel diseases.

Notch1-Delta-like 4 (Dll4) signalling controls vascular development by regulating endothelial cell (EC) targets that modulate vessel wall remodelling and arterial-venous specification. The molecular effectors that modulate Notch signalling during vascular development remain largely undefined. Here we demonstrate that the transcriptional repressor, Snail1, acts as a VEGF-induced regulator of Notch1 signalling and Dll4 expression. EC-specific Snail1 loss-of-function conditional knockout mice die in utero with defects in vessel wall remodelling in association with losses in mural cell investment and disruptions in arterial-venous specification. Snail1 loss-of-function conditional knockout embryos further display upregulated Notch1 signalling and Dll4 expression that is partially reversed by inhibiting γ-secretase activity in vivo with Dll4 identified as a direct target of Snail1-mediated transcriptional repression. These results document a Snail1-Dll4/Notch1 axis that controls embryonic vascular development.

In a search for Polo-like kinase 1 (Plk1) interaction proteins, we have identified TRF1 (telomeric repeat binding factor 1) as a potential Plk1 target. In this communication we report further characterization of the interaction. We show that Plk1 associates with TRF1, and Plk1 phosphorylates TRF1 at Ser-435 in vivo. Moreover, Cdk1, serving as a priming kinase, phosphorylates TRF1 to generate a docking site for Plk1 toward TRF1. In the presence of nocodazole, ectopic expression of wild type TRF1 but not TRF1 with alanine mutation in the Plk1 phosphorylation site induces apoptosis in cells containing short telomeres but not in cells containing long telomeres. Unexpectedly, down-regulation of TRF1 by RNA interference affects cell proliferation and results in obvious apoptosis in cells with short telomeres but not in cells with long telomeres. Importantly, we observe that telomeric DNA binding ability of TRF1 is cell cycle-regulated and reaches a peak during mitosis. Upon phosphorylation by Plk1 in vivo and in vitro, the ability of TRF1 to bind telomeric DNA is dramatically increased. These results demonstrate that Plk1 interacts with and phosphorylates TRF1 and suggest that Plk1-mediated phosphorylation is involved in both TRF1 overexpression-induced apoptosis and its telomeric DNA binding ability.

The striatum is believed to be a crucial brain region associated with drug reward. Adaptive alteration of neurochemistry in this area might be one potential mechanism underlying drug dependence. It has been proposed that the dysfunction of Na+,K+-ATPase function is involved in morphine tolerance and dependence. The present study, therefore, was undertaken to study the adaptation of the striatal Na+,K+-ATPase activity in response to morphine treatment. The results demonstrated that in vivo short-term morphine treatment stimulated Na+,K+-ATPase activity in a dose-dependent manner. This action could be significantly inhibited by D2-like dopamine receptor antagonist S(-)-3-chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2-methoxybenzamine (eticlopride). Contrary to shortterm morphine treatment, long-term morphine treatment significantly suppressed Na+,K+-ATPase activity. This effect could be significantly inhibited by D(1)-like dopamine receptor antagonist R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH 23390). However, both short-term and long-term morphine treatment-induced changes in Na+,K+-ATPase activity could be reversed by opioid receptor antagonist naltrexone. It was further found that cAMP-dependent protein kinase (PKA) was crucially involved in regulating Na+,K+-ATPase activity by morphine. Different regulation of the phosphorylation levels of the alpha3 subunit of Na+,K+-ATPase by PKA was related to the distinct modulations of Na+,K+-ATPase by short-term and long-term morphine treatment. Short-term morphine treatment inhibited PKA activity and then decreased the phosphorylation of Na+,K+-ATPase, leading to increase in enzyme activity. These effects were sensitive to eticlopride or naltrexone. Conversely, long-term morphine treatment stimulated PKA activity and then increased the phosphorylation of Na+,K+-ATPase, leading to the reduction of enzyme activity. These effects were sensitive to SCH 23390 or naltrexone. These findings demonstrate that dopamine receptors are involved in regulation of Na+,K+-ATPase activity after activation of opioid receptors by morphine.

We determined the in vivo and in vitro antitumor activities of gambogic acid (GA) and one of the possible mechanisms for its inhibitory activities. In vivo antitumor activity of GA was evaluated by the relative tumor growth ratio (T/C) in nude mice, and in vitro inhibition of SPC-A1 cells was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay and trypan blue exclusion assay. Telomere repeats amplification protocol (TRAP)-polymerase chain reaction (PCR)-enzyme-linked immunosorbent assay (ELISA) and RT-PCR were used to quantitatively detect telomerase activity and the expression of human telomerase reverse transcriptase (hTERT) mRNA, respectively. Results from our in vivo study showed that transplantable tumor growth remained suppressed for up to 21 d with minimal animal weight loss in nude mice treated with gambogic acid (i.v.). Proliferation of SPC-A1 cells cultured in vitro was significantly inhibited (p

The selective induction of apoptosis of gambogic acid (GA) on MGC-803 cells and its probable molecular mechanism were studied. GA greatly inhibited (24, 48, 72 h) the growth of MGC-803 cells (by MTT); the IC(50) value was 0.96 microg/ml at 48 h. Meanwhile, no influence was observed on body weight, number of WBC (white blood cells) in blood or karyote in marrow of rats after GA was injected intravenously. We conclude that GA does not affect normal cells, but that it can induce apoptosis in tumor cells selectively and there were marked morphological changes. A great quantity of apoptotic cells and increasing G(2)/M phase cells were observed by flow cytometry, and a significant percentage of early apoptotic cells were observed by Annexin-V/PI double staining assay. The increase of bax gene and the decrease of bc1-2 gene expressions were detected by immunohistochemistry. Activation of bax and suppression of bc1-2 may contribute to the apoptosis mechanism.

To study the inhibitory effect of general gambogic acids (GGA) on transplantation tumor SMMC-7721 in experimental animal model and SMMC-7721 cells in vitro.Anti-tumor activity of GGA in the experimental transplantation tumor SMMC-7721 was evaluated by relative tumor growth ratio. Cell morphology was observed with inverted microscope and electron microscope. Cell proliferation was measured by MTT assay and the telomerase activity was determined by PCR.In vivo study indicated that GGA (2, 4, and 8 mg/kg, iv, 3 times per week for 3 weeks) displayed an inhibitory effect on the growth of transplantation tumor SMMC-7721 in nude mice compared with the normal saline group (P0.01). At the concentrations of 0.625-5.0 mg/L, GGA remarkably inhibited the proliferation of SMMC-7721 cells in vitro. GGA 2 mg/L dramatically changed morphology of SMMC-7721 cells and inhibited the telomerase activity in SMMC-7721 cells.GGA had inhibitory effect on the growth of SMMC-7721, which might be related to its inhibition of telomerase activity.