Triple-negative breast cancer (TNBC) is a breast cancer subtype that has an aggressive phenotype, is highly metastatic, has limited treatment options and is associated with a poor prognosis. In addition, metastatic TNBC has no preferred standard chemotherapy due to resistance to anthracyclines and taxanes. The present study demonstrated that a herbal extract, SH003, reduced cell viability and induced apoptosis in TNBC without cell cytotoxicity. Cell viability was examined using trypan blue exclusion and colony formation assays, which revealed a decrease in the cell viability. Additionally, apoptosis was determined using flow cytometry and a sub‑G1 assay, which revealed an increase in the proportion of cells in the sub‑G1 phase. The present study investigated the anticancer effect of SH003 in the Hs578T, MDA‑MB‑231 and ZR‑751 TNBC cell lines, and in the MCF7 and T47D non‑TNBC cell lines. Western blot analysis revealed that the expression levels of poly‑ADP‑ribose polymerase (PARP) cleavage protein in cells treated with SH003 were increased dose‑dependent manner, indicating that SH003 induced apoptosis via a caspase‑dependent pathway. Pre‑treatment with the caspase inhibitor Z‑VAD reduced SH003‑induced apoptosis was examined using trypan blue exclusion. Moreover, SH003 treatment enhanced the p73 levels in MDA‑MB‑231 cells but not in MCF7 cells. Transfection of p73 small interfering RNA (siRNA) in MDA‑MB0231 cells revealed that the apoptotic cell death induced by SH003 was significantly impaired in comparison with scramble siRNA transfected MDA‑MB‑231 cells. This was examined using trypan blue exclusion and flow cytometry analysis (sub‑G1). In addition, SH003 and paclitaxel exhibited synergistic anticancer effects on TNBC cells. The results indicate that SH003 exerts its anticancer effect via p73 protein induction and exhibits synergistic anticancer effects when combined with paclitaxel.

The MET receptor tyrosine kinase, the receptor for hepatocyte growth factor (HGF), has been implicated in cancer growth, invasion, migration, angiogenesis, and metastasis in a broad variety of human cancers, including human hepatocellular carcinoma (HCC). Recently, MET was suggested to be a potential target for the personalized treatment of HCC with an active HGF-MET signaling pathway. However, the mechanisms of resistance to MET inhibitors need to be elucidated to provide effective treatment. Here, we show that HCC cells exhibit different sensitivities to the MET inhibitor PHA665752, depending on the phosphorylation status of FGFR. Treatment of cells expressing both phospho-FGFR and phospho-MET with the inhibitor PHA665752 did not cause growth inhibition and cell death, whereas treatment with AZD4547, a pan-FGFR inhibitor, resulted in decreased colony formation and cleavage of caspase-3. Moreover, silencing of endogenous FGFR1 and FGFR2 by RNAi of HCC cells expressing phospho-FGFR, phospho-FGFR2, and phospho-MET overcame the resistance to PHA665752 treatment. Treatment of primary cancer cells from patients with HCC expressing both phospho-FGFR and phospho-MET with PHA665752 did not induce cell death, whereas AZD4547 treatment induced cell death through the cleavage of caspase-3. In addition, treatment of cells resistant to PHA665752 with AZD4547 abrogated the activation of downstream effectors of cell growth, proliferation, and survival. On the basis of these results, we conclude that the FGFR pathway is critical for HCC survival, and that targeting this pathway with AZD4547 may be beneficial for the treatment of patients with HCC-expressing phospho-FGFR and phospho-MET. Mol Cancer Ther; 14(11); 2613-22. Ó2015 AACR.

ABSTRACT

Pancreatic cancer is one of the most lethal cancers and remains a major unsolved health problem. Less than 20 % of patients are surgical candidates, and the median survival for non-resected patients is approximately 3 to 4 months. Despite the existence of many conventional cancer therapies, few targeted therapies have been developed for pancreatic cancer. Combination therapy using erlotinib and gemcitabine is an approved standard chemotherapy for advanced pancreatic cancer, but it has marginal therapeutic benefit. To try to improve the therapeutic outlook, we studied the efficacy of another combination treatment and the relevance to E-cadherin in human pancreatic cancer cells. We treated two human pancreatic cancer cell lines with the histone deacetylase inhibitor (HDACi) SAHA. Interestingly, in these Panc-1 and Capan1 cells, we observed that the expression levels of E-cadherin and phosphorylated EGFR were gradually upregulated after treatment with SAHA. Furthermore, these cells underwent induced cell death after exposure to the combination treatment of SAHA and erlotinib. In Panc-1 cells, overexpression of E-cadherin activated the phosphorylation of EGFR and increased the cell sensitivity to erlotinib. In Capan1 cells, knocking down E-cadherin decreased the expression of phosphorylated EGFR, and these cells did not respond to erlotinib. Therefore, we demonstrated the efficacy of the combined treatment with SAHA and erlotinib in human pancreatic cancer cells, and we determined that the increased efficacy was due, at least in part, to the effects of SAHA on the expression of E-cadherin. Our studies suggest that E-cadherin may be a potent biomarker for pancreatic cancer.

Abstract.Iris nertschinskia, an ornamental plant, is utilized in traditional East Asian medicine for the treatment of skin diseases. However, the biological activity underlying its therapeutic effects remains to be established. In this study, we investigated the anti-tumor effect of the plant extract on McF7 human breast cancer cells. An ethanol extract of Iris nertschinskia triggered cell death in a dose-dependent manner. Moreover, treatment with the extract promoted p53 phosphorylation in McF7 cells. Increased phosphorylation of p53, in turn, led to induction of Bax protein, a key regulator of p53-dependent apoptotic cell death, as well as of caspase-7 cleavage in McF7 cells. consistently, cells treated with p53-specific siRNA or the caspase inhibitor, Z-VAD, resisted apoptotic cell death induced by the Iris nertschinskia extract. Our results suggest that p53 sensitizes tumor cells to the ethanol extract of Iris nertschinskia by Bax protein induction and caspase-dependent apoptosis.

Dysregulation of the PI3K-AKT & mTOR pathway by (mutation and/or) deletion of tumor suppressor gene PTEN frequently occurs in human prostate cancer and is therefore considered to be attractive molecule as therapeutic targets. Here, we investigated the antitumor effect of NVP-BEZ235 in human prostate cancer cells dependent on PTEN genotype. In this setting, NVP-BEZ235 induced cell death in the PTEN-independent manner. However, NVP-BEZ235 selectively induced apoptotic cell death in prostate cancer cells presenting wild-type PTEN, DU145, but not in cells with deletion of PTEN, PC3. Treatment with NVP-BEZ235 resulted in autophagic cell death in PC3 cells with PTEN loss of function. Consistently, NVP-BEZ235 treatment did not result in the cleavage of caspase-3 and was link to active LC3-I/II as an indicator of autophagic cell death process, suggesting an alternate route for induction of cell death after exposure to NVP-BEZ235 in PTEN-null prostate cancer cells. These results suggest that PTEN/PI3K/Akt pathways are critical for prostate cancer survival and targeting PI3K signaling by NVP-BEZ235 may be beneficial in prostate cancer independent on PTEN genotype. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A63. Citation Format: Jeong Eun Kim, Seoung-Woo Hong, Jae-Sik Shin, Jai-Hee Moon, Ye-Seul Kim, Kyu-pyo Kim, Yong Sang Hong, Jae-Lyun Lee, Dong-Hoon Jin, Tae Won Kim. NVP-BEZ235, a dual PI3K/mTOR inhibitor, elicits an alternate route for induction of cell death in PTEN null prostate cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A63.

Inhibitor of apoptosis proteins (IAPs) plays an important role in controlling cancer cell survival. IAPs have therefore attracted considerable attention as potential targets in anticancer therapy. In this study, we investigated the anti-tumor effect of AZD5582, a novel small-molecule IAP inhibitor, in human pancreatic cancer cells. Treating human pancreatic cancer cells with AZD5582 differentially induced apoptosis, dependent on the expression of p-Akt and p-XIAP. Moreover, the knockdown of endogenous Akt or XIAP via RNA interference in pancreatic cancer cells, which are resistant to AZD5582, resulted in increased sensitivity to AZD5582, whereas ectopically expressing Akt or XIAP led to resistance to AZD5582. Additionally, AZD5582 targeted cIAP1 to induce TNF-α-induced apoptosis. More importantly, AZD5582 induced a decrease of Mcl-1 protein, a member of the Bcl-2 family, but not that of Bcl-2 and Bcl-xL. Interestingly, ectopically expressing XIAP and cIAP1 inhibited the AZD5582-induced decrease of Mcl-1 protein, which suggests that AZD5582 elicits Mcl-1 decrease for apoptosis induction by targeting of XIAP and cIAP1. Taken together, these results indicate that sensitivity to AZD5582 is determined by p-Akt-inducible XIAP phosphorylation and by targeting cIAP1. Furthermore, Mcl-1 in pancreatic cancer may act as a potent marker to analyze the therapeutic effects of AZD5582. Citation Format: Eun-Yeung Gong, Eun Young Lee, Jai-Hee Moon, Jae-Sik Shin, Seung-Woo Hong, Soo-A Jung, Ih-Yeon Hwang, Jeong Hee Kim, Dong-Hoon Jin, Tae Won Kim. A novel small-molecule IAP antagonist, AZD5582, draws Mcl-1 down-regulation for induction of apoptosis through targeting of cIAP1 and XIAP in human pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A65.

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