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In this report, the mechanism of the antitumor activities of Kushen flavonoids (KS-Fs) were explored. KS-Fs and kurarinone (Kur), a single flavonoid compound, were able to induce apoptosis of H460 and Eca-109 cells in vitro and H460 cells in vivo. The apoptosis inducing effect was enhanced in the presence of Taxol. In H460 xenograft mice treated with Kur, down-regulation of Bcl-2 and up-regulation of caspase 8 and caspase 3 in tumors were observed by immunohistochemical staining. In addition, KS-Fs and Kur were able to inhibit TNFalpha-induced NF-kappaB activation in 293 cells mediated by the decreased IkappaBalpha phosphorylation. Further the effects of KS-Fs and Kur on multiple receptor tyrosine kinase activities were explored. In cell-based assays, KS-Fs and Kur inhibited the EGF-induced EGF receptor phosphorylation in A431 cells and a constitutively activated Her-2 in MDA-MB-453s cells. In enzymatic assays, KS-Fs and Kur inhibited KDR, but not PDGF BR activities. In A431 xenograft mice treated with Kur, an inhibition of EGF receptor phosphorylation in tumors was observed. These results reveal a novel mechanism by which KS-Fs induces apoptosis in tumors by acting on multiple cellular targets including the inhibition of NF-kappaB activation and multiple receptor tyrosine kinase activities.

Picroside II is an active constituent extracted from the traditional Chinese medicine (TCM) hu-huang-lian. To evaluate the neuroprotective effect of picroside II, PC12 cells were treated with glutamate in vitro and male ICR mice were treated with AlCl(3) in vivo. Pre-treatment of PC12 cells with picroside II could enhance the cell viability and decrease the level of intracellular reactive oxygen species (ROS) induced by glutamate. By DNA fragmentation and flow cytometry assay, picroside II (1.2 mg/ml) significantly prevented glutamate-induced cell apoptosis. In the animal study, amnesia was induced in mice by AlCl(3) (100 mg/kg/d, i.v.). Pricroside II, at the dose of 20 and 40 mg/kg/d (i.g.), markedly ameliorated AlCl(3)-induced learning and memory dysfunctions and attenuated AlCl(3)-induced histological changes. This was associated with the significant increased superoxide dismutase (SOD) activity in the brain of experimental mice. All these results indicated that picroside II possessed the therapeutic potential in protecting against neurological injuries damaged by oxidative stress.

Background. Previous observational studies and meta-analysis suggested a possible association between metformin use and reduced mortality in women with ovarian cancer (OC). However, clinical factors that may influence the relationship remain poorly evaluated. We performed an updated meta-analysis to systematically evaluate the above association and to observe the potential influences of study characteristics on the association. Methods. Relevant studies reporting the association between metformin use and mortality in women with OC in the multivariate adjusted model were identified by search of electronic databases that included PubMed, Embase, and Web of Science. The random-effects model was adopted to combine the results. Results. Nine studies including 10030 women with OC were included. Overall, metformin use was independently associated with reduced overall mortality (hazard ratio (HR): 0.72, 95% confidence interval (CI): 0.55–0.93, P = 0.01 ; I2 = 62%). Consistent results were observed for studies comparing metformin users with nondiabetic women and studies comparing metformin users with diabetic women who did not use metformin ( P for subgroup analysis = 0.70). Further subgroup analyses showed consistent results in studies with metformin use before or after the diagnosis of OC, with or without adjustment of body mass index (BMI) and with or without adjustment of concurrent medications ( P for subgroup analyses all >0.10). Conclusion. Metformin use is associated with reduced mortality in women with OC, which may be independent of the diabetic status of the controls, timing of metformin use, or adjustment of BMI and concurrent medications. Clinical trials are needed to validate the potential benefits of metformin on survival of OC.

PIK3CA gene amplification and mutations have been identified in many types of tumors, suggesting the deregulation of PI3K/AKT/mTOR axis plays pivotal roles in tumorigenesis and development. K-Ras/Raf mutation is recognized as one of the key drug resistant factors for tumors against TKIs. HM-032 was reported here as a potent, selective and reversible ATP-competitive PI3K/mTOR dual inhibitor with special apoptotic activity in tumor cells harboring K-Ras mutations. HM-032 showed potent kinase inhibition with IC50 of 0.0008, 0.002, 0.001, 0.002 and 0.001 µM on PI3Kα, β, δ, ≤ and mTOR, respectively. In human prostate PC3 cells, it inhibited p-AKTS473, p-S6 and p-4EPB1 with IC50s of 0.002, 0.015 and 0.056 μM. Of the 89 tumor cell lines from lung, colon, breast, ovarian, and other tumor types, it was found that tumor cells with HER2 gene amplification, or PIK3CA mutation were relatively more sensitive to HM-032. Attractively, HM-032 showed apoptotic induction activity in the tumor cells harboring Ras/Raf mutations through inhibiting p-Erk and increasing gene expression of pro-apoptotic protein Bim. This result suggested that HM-032 might bring benefits to patients carrying K-Ras/Raf mutations in the clinic. Consistent with in vitro studies, HM-032 exhibited significant tumor growth inhibition in a dose dependent manner on multiple human xenograft models, including breast tumor MDA-MB-361(PIK3CAE545K, Her2 amplification), lung tumors H460 (PIK3CAE545K, K-RasQ61H) and A549 (LKB1 del, K-RasG12S), and glioblastoma U87MG (PTEN del) after 3 weeks oral dosing. Correspondingly, decrease of p-AKT and p-S6 was observed in the tumor xenograft tissues upon treatment with HM-032. In addition, HM-032 exhibited unique in vivo PK properties characterized by low clearance and long t1/2, which supported the intermittent dosing schedule in xenograft models. Based on the pre-clinical study results, HM-032 is anticipated to be a promising agent against solid tumors including carrying Ras/Raf mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1808. doi:1538-7445.AM2012-1808