Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat-shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, because of its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib markedly reduced the growth of MGC-803 and also significantly inhibited the growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected epidermal growth factor receptor (EGFR) signaling cascades by markedly decreasing the levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support that EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found that the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, whereas SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Although SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited the growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of hematoxylin/eosin staining, TUNEL (terminal deoxynucleotidyl transferase dUTP nick-end labeling) assays, and immunohistochemistry staining of phosphorylated cyclin-dependent kinase 1 (pCDK1), EGFR and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR. Cell Death and Disease (2015) 6, e1595; doi:10.1038/cddis.2014.555; published online 15 January 2015Gastric cancer (GC) remains the fifth most common cancer worldwide, with an estimated 9 52 000 new cases (7% of total cancer incidence) and 7 23 000 deaths (9% of total cancer mortality) in 2012. 1 As a highly aggressive and lethal malignancy, the aggressive nature of GC is linked to mutations in tumor suppressor genes, oncogenes, growth factors and their receptors, and so on. 2 Till now, there are few effective treatment options for advanced patients with distant metastasis or recurrence. 3 The detailed mechanisms that regulate GC are not yet fully understood; therefore, such situations underscore the persistent unmet need to identify therapeutics that target pa...

Ovarian cancer is one of the most frequent causes of cancer death among all gynecologic cancers. Though standard therapy often results in temporary clinical remission, most patients suffer from recurrence and metastasis of ovarian cancer, which highlights the need for developing new therapeutic agents targeting specific molecules. Previous studies have demonstrated that the native ligand of epidermal growth factor receptor (EGFR) and ErbB4, heparin-binding EGF-like growth factor (HB-EGF), plays a critical role in the progression of ovarian cancer and is associated with prognosis of ovarian cancer. In the current study, we tried to develop a peptide-based treatment for ovarian cancer by targeting HB-EGF. After the functions of HB-EGF in promoting migration and invasion of SKOV3 and HO-8910 cells were confirmed, phage display was used to discover peptides binding to HB-EGF. Two peptides, no. 7 and no. 29 were found mildly binding to HB-EGF. Then the effects of these peptides on HB-EGF functions were examined and both peptides no. 7 and no. 29 were found indeed inhibiting the functions of HB-EGF in promoting migration and invasion of SKOV3 and HO-8910 cells in vitro. Further mechanism investigation showed that peptides no. 7 and no. 29 inhibited HB-EGF-promoted cell migration and invasion through attenuating activation of the EGFR signaling pathway manifested by decreased p-Erk1/2 and Snail levels. More importantly, peptides no. 7 and no. 29 showed strong activities in inhibiting migration of SKOV3 cells in vivo. These results provide a proof of concept method for developing novel peptide drugs to combat ovarian cancer through interfering with HB-EGF mediated signaling pathways.

Heparin-binding epidermal growth factor-like growth factor (HB-EGF) belongs to the EGF family and exhibits its activity after binding to its receptors in autocrine, paracrine, and juxtacrine interactions. HB-EGF plays important roles in several biological and pathological processes, such as wound healing, blastocyst implantation, atherosclerosis, and heart development. Clinical studies have shown that HB-EGF is closely correlated with tumorigenesis, metastasis, and drug resistance in breast cancer. Specifically, targeted inhibition of HB-EGF improves the therapeutic efficacy and suppresses the tumor progression. This review discusses the importance of HB-EGF in mammary carcinoma progression and the potential value of HB-EGF as a therapeutic target for breast cancer treatment.

Iron (Fe) and zinc (Zn) are essential micronutrient for both human and plants, but Fe and Zn deficiency is prevalent in the world especially developing countries including India and China. Biofortification is considered the most promising approach to alleviate Fe and Zn malnutrition in developing countries. While agricultural approaches are also useful to gain Fe and Zn enriched cereals. Therefore, agro-biofortification of Fe and Zn by agricultural approaches was reviewed for possible solution in intensive agriculture system at developing countries.

Gastric cancer (GC) remains the fifth most common cancer worldwide. Heat shock protein 90 (HSP90) has become an attractive therapeutic target in treating cancers, due to its abnormally high expression in cancers. Several successful cases of HSP90 inhibitors capable of inhibiting GC inspired us to try ganetespib, a clinically promising and actively investigated second-generation HSP90 inhibitor in GC treatment. In our study, we show that ganetespib dramatically reduced growth of MGC-803 and also significantly inhibited growth of SGC-7901 and MKN-28 in a dose-dependent manner. It induced G2/M cell-cycle arrest and apoptosis in all three cell lines, together with the related markers affected significantly. Mechanistically, ganetespib caused pronounced decrease of expression of classic HSP90 client proteins. Specifically, it greatly affected EGFR signaling cascades by dramatically decreasing levels of total EGFR and EGFR on cell membranes. EGFR knockdown also induced cell-cycle arrest and apoptosis accompanied with a decrease of several EGFR downstream proteins. These results strongly support EGFR signaling greatly contributes to the ganetespib inhibitory effects. Besides, we found the responses of GC cell lines to ganetespib correlated well with their EGFR expression levels: MGC-803, as well as AGS and BGC-803, with higher EGFR expression responded to ganetespib better, while SGC-7901 and MKN-28 with lower EGFR levels were much less sensitive to ganetespib. Though SGC-7901 and MKN-28 were not very sensitive to ganetespib, ganetespib worked synergistically with radiation and cisplatin in killing them. Importantly, ganetespib significantly inhibited growth of xenograft tumors in vivo as a single agent or in combination with cisplatin. Results of H&E staining, TUNEL assays, and immunohistochemistry staining of pCDK1, EGFR, and Ki-67 revealed significant differences in ganetespib-treated tumors. Collectively, our data suggest that ganetespib, as a new potent treatment option, can be used for the molecularly targeted therapy of GC patients according to their expression profiles of EGFR. Acknowledgments: This work was supported by the Jiangsu Specially-Appointed Professor Program (to H. Liu); Jiangsu Recruitment Program of Leading Creative and Entrepreneurial Talents (to H. Liu and Z. Tu); National Natural Science Foundation 81402145 (to H. Liu) and 31471294 (to Z. Tu); Natural Science Foundation of Jiangsu Province BK20140572 (to H. Liu); Start-up Scientific Research Fund for the Returned Oversea Scholars from Chinese Ministry of Education (to Z. Tu); National Basic Research Program of China 2012CB114604 (to K. Chen); Senior Talent Start-up Funds of Jiangsu University 14JDG050 (to H. Liu) and 14JDG011 (to Z. Tu); Priority Academic Program Development of Jiangsu Higher Education Institutions (to School of Pharmacy and Institute of Life Sciences of Jiangsu University). Citation Format: Hanqing Liu, Peishan Zhang, Zhiquan Liang, Lingling Ruan, Caixia Lian, Jian Lu, Ye Hua, Haifeng Shi, Keping Chen, Zhigang Tu. Targeting HSP90 with ganetespib for targeted therapy of gastric cancer. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr A64.