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CYP19A1/aromatase (Ar) is a prognostic biomarker of gastric cancer (GCa). Ar is a critical enzyme for converting androstenedione to oestradiol in the steroidogenesis cascade. For decades, Ar has been targeted with Ar inhibitors (ARIs) in gynaecologic malignancies; however, it is unexplored in GCa. A single‐cohort tissue microarray examination was conducted to study the association between Ar expression and disease outcome in Asian patients with GCa. The results revealed that Ar was a prognostic promoter. Bioinformatics analyses conducted on a Caucasian‐based cDNA microarray databank showed Ar to be positively associated with GCa prognosis for multiple clinical modalities, including surgery, 5‐Fluorouracil (5‐FU) for adjuvant chemotherapy, or HER2 positivity. These findings imply that targeting Ar expression exhibits a potential for fulfilling unmet medical needs. Hence, Ar‐targeting compounds were tested, and the results showed that exemestane exhibited superior cancer‐suppressing efficacy to other ARIs. In addition, exemestane down‐regulated Ar expression. Ablating Ar abundance with short hairpin (sh)Ar could also suppress GCa cell growth, and adding 5‐FU could facilitate this effect. Notably, adding oestradiol could not prevent exemestane or shAr effects, implicating a nonenzymatic mechanism of Ar in cancer growth. Regarding translational research, treatment with exemestane alone exhibited tumour suppression efficacy in a dose‐dependent manner. Combining subminimal doses of 5‐FU and exemestane exerted an excellent tumour suppression effect without influencing bodyweight. This study validated the therapeutic potentials of exemestane in GCa. Combination of metronomic 5‐FU and exemestane for GCa therapy is recommended.

To improve the clinical outcome of tumor chemotherapy, more effective combination treatments against tumor metastasis and recurrence are required. Licochalcone A (LicA) is the root of Glycyrrhiza inflata and has been reported to possess anti-inflammatory, antimicrobial, and antitumor effects. Sorafenib (Sor), a multikinase inhibitor, is used to treat patients with solid tumors such as advanced hepatocellular carcinoma (HCC). However, the synergistic effects of LicA and Sor on the metastasis of human HCC cells have not been reported. We found that LicA and Sor did not have cytotoxic effects or arrest growth in human SK-Hep-1 and Huh-7 cells. In addition, treatment with LicA or Sor alone inhibited migration and invasion in human SK-Hep-1 and Huh-7 HCC cells. Furthermore, cotreatment with LicA and Sor synergistically inhibited the migration and invasion of HCC cells and significantly inhibited uPA protein expression. Notably, cotreatment of LicA and Sor synergistically and significantly downregulated MKK4-JNK expression. Through tail vein injection in nude mice, the aforementioned cotreatment synergistically suppressed SK-Hep-1 cell-mediated lung metastasis. These findings first revealed the synergistic effects of LicA and Sor cotreatment against human HCC cells, further suggesting that beneficial effects on tumor regression could be confirmed through prospective clinical trials.

Different types of proton pump inhibitor (PPI)-based triple therapies could result in different Helicobacter pylori eradication rates. This study aimed to compare the efficacy and safety of rabeprazole- and lansoprazole-based triple therapies in primary treatment of H. pylori infection. From September 2005 to July 2008, 426 H. pylori -infected patients were randomly assigned to receive a 7-day eradication therapy with either rabeprazole 20mgbid (RAC group, n =222) or lansoprazole 30mgbid (LAC group, n =228) in combination with amoxicillin 1gbid and clarithromycin 500mgbid. The patients received follow-up esophagogastroduodenoscopy (EGD) and/or 13 C-urea breath test 12–16 weeks later to define H. pylori status. Their personal and medical history, compliance and side effects were obtained by using a standardized questionnaire. Intention-to-treat analysis revealed that the eradication rate was 87.84% in the RAC group and 85.96% in the LAC group ( p =0.56). All patients returned for assessment of compliance (100% in the LAC group vs. 99.50% in the RAC group; p =0.32) and adverse events (7.20% in the RAC group vs. 5.70% in the LAC group, p =0.51). Univariate analysis suggested that patients with nonsteroid anti-inflammatory agent (NSAID) use had lower eradication rates than those without (76.71% vs. 88.74%; p =0.006). Our results showed that efficacy and safety were similar in rabeprazole- and lansoprazole-based primary therapies. The influence of NSAID usage on H. pylori eradication needs to be further investigated.

Epidemiological studies demonstrate that the incidence and mortality rates of colorectal cancer in women are lower than in men. However, it is unknown if 17β-estradiol (E2) treatment is sufficient to inhibit cell proliferation and cell migration in human colon cancer cells. Up-regulation of urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and matrix metallopeptidases (MMPs) is reported to associate with the development of cancer cell mobility, metastasis, and subsequent malignant tumor. In the present study, we treated human LoVo colon cancer cells with E2 to explore whether E2 down-regulates cell proliferation and migration, and to identify the precise molecular and cellular mechanisms behind the down-regulatory responses. Here, we found that E2 treatment decreased cell proliferation and cell cycle-regulating factors such as cyclin A, cyclin D1 and cyclin E. At the same time, E2 significantly inhibited cell migration and migration-related factors such as uPA, tPA, MMP-2, and MMP-9. However, E2 treatment showed no effects on upregulating expression of plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloproteinase-1, -2, -3, and -4 (TIMP-1, -2, -3, and -4). After administration of inhibitors including QNZ (NFκB inhibitor), LY294002 (Akt activation inhibitor), U0126 (ERK1/2 inhibitor), SB203580 (p38 MAPK inhibitor) or SP600125 (JNK1/2 inhibitor), E2-downregulated cell migration and expression of MMP-2 and MMP-9 in LoVo cells is markedly inhibited only by p38 MAPK inhibitors, SB203580. Application of specific target gene siRNA (ERα, ERβ, p38α, and p38β) to LoVo cells further confirmed that p38 MAPK mediates E2/ERs inhibition of MMP-2 and -9 expression and cell motility in LoVo cells. Collectively, these results suggest that E2 treatment down-regulates cell proliferation by modulating the expression of cyclin A, cyclin D1 and cyclin E. E2 treatment simultaneously impaired cell migration by inhibiting the expression of uPA, tPA, MMP-2, and MMP-9 through E2/ERs − p38α MAPK signaling pathway in human LoVo colon cancer cells. J. Cell. Physiol. 227: 3648–3660, 2012. © 2012 Wiley Periodicals, Inc.

Evidence shows that women have lower tumour necrosis factor-alpha (TNF-alpha) levels and lower incidences of heart dysfunction and sepsis-related morbidity and mortality. To identify the cardioprotective effects and precise cellular/molecular mechanisms behind estrogen and estrogen receptors (ERs), we investigated the effects of 17beta-estradiol (E(2)) and estrogen receptor alpha (ERalpha) on LPS-induced apoptosis by analyzing the activation of survival and death signalling pathways in doxycycline (Dox)-inducible Tet-On/ERalpha H9c2 myocardial cells and ERalpha-transfected primary cardiomyocytes overexpressing ERalpha. We found that LPS challenge activated JNK1/2, and then induced IkappaB degradation, NFkappaB activation, TNF-alpha up-regulation and subsequent myocardial apoptotic responses. In addition, treatments involving E(2), membrane-impermeable BSA-E(2) and/or Dox, which induces ERalpha overexpression, significantly inhibited LPS-induced apoptosis by suppressing LPS-up-regulated JNK1/2 activity, IkappaB degradation, NFkappaB activation and pro-apoptotic proteins (e.g. TNF-alpha, active caspases-8, t-Bid, Bax, released cytochrome c, active caspase-9, active caspase-3) in myocardial cells. However, the cardioprotective properties of E(2), BSA-E(2) and ERalpha overexpression to inhibit LPS-induced apoptosis and promote cell survival were attenuated by applying LY294002 (PI3K inhibitor) and PI3K siRNA. These findings suggest that E(2), BSA-E(2) and ERalpha expression exert their cardioprotective effects by inhibiting JNK1/2-mediated LPS-induced TNF-alpha expression and cardiomyocyte apoptosis through activation of Akt.