We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch-1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade- II and III) versus normal breast tissues. Injection of BCSC (ALDH and CD44 /CD22 ) cells resulted in aggressive tumor growth in athymic mice versus ALDH cells. The ALDH and CD44 /CD22 tumors grow rapidly and are larger than ALDH tumors which were slow growing and smaller. Molecularly, ALDH tumors expressed higher expression of Notch-1 and EMT markers than ALDH tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH and ALDH tumors as well. Psoralidin inhibited Notch-1 mediated EMT activation in ALDH and ALDH tumors-this confirms our in vitro findings. Our results suggest that Notch-1 could be an attractive target and inhibition of Notch-1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis. © 2016 Wiley Periodicals, Inc.

In cloud environment, profile matching is a key technique in applications such as health care and social networks. Ciphertext-Policy Attribute-Based Encryption (CP-ABE) is a suitable technique for data sharing in such environments. In this paper, we propose an asymmetric pairing based Hierarchical Multi-Authority CP-ABE (HM-CP-ABE) construction for profile matching. We utilize the fast Ate pairing to make the proposed HM-CP-ABE scheme efficient. The performance analysis of the proposed scheme shows improved efficiency in terms of computational costs for initialization, key generation and encryption using ELiPS library when compared with existing works.

Androgen ablation therapy is the primary therapeutic option for locally advanced and metastatic castration-resistant prostate cancer (CRPC). We investigated therapeutic effect of a dietary metabolite Urolithin A (UroA) and dissected the molecular mechanism in CRPC cells. Treatment with UroA inhibited cell proliferation in both androgen receptor-positive (AR ) (C4-2B) and androgen receptor-negative (AR ) (PC-3) cells however, AR CaP cells were more sensitive to UroA treatment as compared with AR CaP cells. Inhibition of the AR signaling was responsible for the UroA effect on AR CaP cells. Ectopic expression of AR in PC-3 cells sensitized them to UroA treatment as compared to the vector-expresseing PC-3 cells, which suggests that AR could be a target of UroA. Similarly, in enzalutamide-resistant C4-2B cells, a downregulation of AR expression also suppressed cell proliferation which was observed with the UroA treatment. Oral administration of UroA significantly suppressed the growth of C4-2B xenografts (P = 0.05) compared with PC-3 xenografts (P = 0.069) without causing toxicity to animals. Immunohistochemistry analysis confirmed in vitro findings such as downregulation of AR/pAKT signaling in UroA-treated C4-2B tumors, which suggests that UroA may be a potent chemo-preventive and therapeutic agent for CRPC.

Epithelial to mesenchymal transition (EMT) in colorectal cancer (CRC) has been attributed to activation of AKT and Notch1 signaling pathways. As EMT corresponds to increased aggressiveness of CRC, approaches that prevent metastasis by targeting AKT/Notch1 pathways are at the forefront of current research paradigms. This study examined the anti-metastatic potential of Verrucarin J (VJ), a small molecule, in CRC cells overexpressing AKT and Notch1. VJ significantly inhibited AKT/HCT 116 cell growth by acting on the AKT/NFκB/Bcl-2 signaling axis and initiated apoptotic signaling as was evident from increased expression of pro-apoptotic markers such as cleaved PARP, cleaved caspase 3, and cleaved caspase 9. Also, VJ inhibited the cell growth in AKT/Notch1-overexpressing CRC cells and abrogated EMT. The down-regulation of AKT and Notch1 signaling was apparent in immunoblot analysis and corresponded with down-regulation of mesenchymal markers including Snail, and β-catenin. Intraperitoneal administration of VJ in control (pCMV/HCT 116) and AKT/HCT 116 mice significantly suppressed AKT-induced tumor growth in a xenograft model. In addition, down-regulation of prosurvival markers as well as AKT and Notch1 was observed in the immunohistochemical analysis of the xenografted tumors. In conclusion, our study substantiates the role of AKT and Notch1 in cell proliferation, angiogenesis, and EMT of CRC cells and demonstrates that VJ may be a viable therapeutic option to counter AKT-induced cell proliferation and tumor outgrowth in CRC.

Chemopreventive effects and associated mechanisms of Withaferin A (WA) against intestinal and colon carcinogenesis remain unknown. We investigated the chemopreventive effect of WA on transgenic mouse APCMin/+ and chemically induced azoxymethane/dextran sodium sulfate (AOM/DSS) models of intestinal and colon carcinogenesis. Oral WA administration (4 mg/kg and 3mg/kg) inhibited tumor initiation and progression of intestinal polyp formation in APCMin/+ mice and colon carcinogenesis in the AOM/DSS mouse model. WA-administered mice showed a significant reduction in both number (duodenum, 33% (p>0.05); jejunum, 32% (p<0.025); ileum, 43% (p<0.001); and colon 59% (p<0.01) and size of polyps in APCMin/+ mice compared to the respective controls. Similarly, tumor multiplicity was significantly reduced (p<0.05) in the colon of WA-administered AOM/DSS mice. Pathological analysis showed reduced adenomas and tissue inflammation in WA-administered mouse models. Molecular studies suggested that WA inhibited the expression of inflammatory (IL-6, TNFα and COX2), pro-survival (pAKT, Notch1, and NF-κB), markers in APCMin/+ and AOM/DSS models. The results suggest that WA is a potent agent for preventing colon carcinogenesis and further investigation is required to show clinical utility of the agent.

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