A growing body of evidence indicates that digitoxin cardiac glycoside is a promising anticancer agent when used at therapeutic concentrations. Digitoxin has a prolonged half-life and a well-established clinical profile. New scientific avenues have shown that manipulating the chemical structure of the saccharide moiety of digitoxin leads to synthetic analogs with increased cytotoxic activity. However, the anticancer mechanism of digitoxin or synthetic analogs is still subject to study while concerns about digitoxin's cardiotoxicity preclude its clinical application in cancer therapeutics. This review focuses on digitoxin and its analogs, and their cytotoxicity against cancer cells. Moreover, a new perspective on the pharmacological aspects of digitoxin and its analogs is provided to emphasize new research directions for developing potent chemotherapeutic drugs.

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Digitoxin and its analogs as novel cancer therapeutics.

A 15-gene signature for prediction of colon cancer recurrence and prognosis based on SVM.

Fucoidan, a heparin-like sulfated polysaccharide, is rich in brown algae. It has a wide assortment of protective activities against cancer, for example, induction of hepatocellular carcinoma senescence, induction of human breast and colon carcinoma apoptosis, and impediment of lung cancer cells migration and invasion. However, the anti-metastatic mechanism that fucoidan exploits remains elusive. In this report, we explored the effects of fucoidan on cachectic symptoms, tumor development, lung carcinoma cell spreading and proliferation, as well as expression of metastasis-associated proteins in the Lewis lung carcinoma (LLC) cells-inoculated mice model. We discovered that administration of fucoidan has prophylactic effects on mitigation of cachectic body weight loss and improvement of lung masses in tumor-inoculated mice. These desired effects are attributed to inhibition of LLC spreading and proliferation in lung tissues. Fucoidan also down-regulates expression of matrix metalloproteinases (MMPs), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and vascular endothelial growth factor (VEGF). Moreover, the tumor-bearing mice supplemented with fucoidan indeed benefit from an ensemble of the chemo-phylacticity. The fact is that fucoidan significantly decreases viability, migration, invasion, and MMPs activities of LLC cells. In summary, fucoidan is suitable to act as a chemo-preventative agent for minimizing cachectic symptoms as well as inhibiting lung carcinoma metastasis through down-regulating metastatic factors VEGF and MMPs.

Prophylactic Administration of Fucoidan Represses Cancer Metastasis by Inhibiting Vascular Endothelial Growth Factor (VEGF) and Matrix Metalloproteinases (MMPs) in Lewis Tumor-Bearing Mice

Background and Objectives 
Human papillomavirus (HPV)-16 infection may be related to non-smoking associated lung cancer. Our previous studies have found that HPV-16 oncoproteins promoted angiogenesis via enhancing hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and interleukin-8 (IL-8) expression in non-small cell lung cancer (NSCLC) cells. In this study, we further investigated the roles of PI3K/Akt and c-Jun signaling pathways in it.


Methods 
Human NSCLC cell lines, A549 and NCI-H460, were stably transfected with pEGFP-16 E6 or E7 plasmids. Western blotting was performed to analyze the expression of HIF-1α, p-Akt, p-P70S6K, p-P85S6K, p-mTOR, p-JNK, and p-c-Jun proteins. VEGF and IL-8 protein secretion and mRNA levels were determined by ELISA and Real-time PCR, respectively. The in vitro angiogenesis was observed by human umbilical vein endothelial cells (HUVECs) tube formation assay. Co-immunoprecipitation was performed to analyze the interaction between c-Jun and HIF-1α.


Results 
HPV-16 E6 and E7 oncoproteins promoted the activation of Akt, P70S6K, P85S6K, mTOR, JNK, and c-Jun. LY294002, a PI3K inhibitor, inhibited HPV-16 oncoprotein-induced activation of Akt, P70S6K, and P85S6K, expression of HIF-1α, VEGF, and IL-8, and in vitro angiogenesis. c-Jun knockdown by specific siRNA abolished HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Additionally, HPV-16 oncoproteins promoted HIF-1α protein stability via blocking proteasome degradation pathway, but c-Jun knockdown abrogated this effect. Furthermore, HPV-16 oncoproteins increased the quantity of c-Jun binding to HIF-1α.


Conclusions 
PI3K/Akt signaling pathway and c-Jun are involved in HPV-16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis. Moreover, HPV-16 oncoproteins promoted HIF-1α protein stability possibly through enhancing the interaction between c-Jun and HIF-1α, thus making a contribution to angiogenesis in NSCLC cells.

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Roles of PI3K/Akt and c-Jun signaling pathways in human papillomavirus type 16 oncoprotein-induced HIF-1α, VEGF, and IL-8 expression and in vitro angiogenesis in non-small cell lung cancer cells.

Survivin, a member of the inhibitor of apoptosis family of proteins (IAPs) that controls cell division, apoptosis, metastasis and angiogenesis, is overexpressed in essentially all human cancers. As a consequence, the gene/protein is considered an attractive target for cancer treatment. Here, we discuss recent findings related to the regulation of survivin expression and its role in angiogenesis, particularly in the context of hypoxia. We propose a novel role for survivin in cancer, whereby expression of the protein in tumor cells promotes VEGF synthesis, secretion and angiogenesis. Mechanistically, we propose the existence of a positive feed-back loop involving PI3-kinase/Akt activation and enhanced β-Catenin-TCF/LEF-dependent VEGF expression followed by secretion. Finally, we elaborate on the possibility that this mechanism operating in cancer cells may contribute to enhanced tumor vascularization by vasculogenic mimicry together with conventional angiogenesis.

https://link.springer.com/content/pdf/10.1186%2Fs12943-015-0467-1.pdf

The twisted survivin connection to angiogenesis

The expression of survivin, an inhibitor of apoptosis can be seen in most tumors and is correlated with the angiogenic factor vascular endothelial growth factor (VEGF). But little is known about their contribution in small-cell lung cancer (SCLC). This study was designed to investigate the expression of survivin and VEGF in SCLC, and to explore their correlation with clinical-pathological feature and prognosis. Forty-five patients with pathological histology of SCLC were entered into this study. Forty-five cases of matched adjacent non-tumor samples and 10 samples of operated patients with benign lung tumor were also included as control. The expression of survivin and VEGF was detected by immunohistochemistry (IHC, SP). These two sets of data were processed and tested for correlation with major patients' characteristics, and overall survival. The correlations between survivin and VEGF expressions and the clinical-pathological features were evaluated by chi-square test. The correlation between survivin and VEGF expressions was analyzed by Spearman's rank correlation test; the overall survival was analyzed by the Kaplan-Meier method; and the relationship between clinical and pathological features and overall survival was analyzed by the Cox proportional hazard models. Positive expression rate of survivin and VEGF was significantly higher in SCLC than those of adjacent non-tumor tissues and benign lung tumor tissues (73.3 vs. 15.6 vs. 0 %, P < 0.05) and (75.6 vs. 20 vs. 0 %, P < 0.05), respectively. Survivin and VEGF expressions were significantly associated with lymph node metastasis (P = 0.003, 0.011) and clinical stage (P = 0.006, 0.021). The expression of survivin was significantly coincident with the expression of VEGF (r = 0.644, P = 0.000). The median overall survival in survivin positive group and VEGF positive group was significantly shorter than those in survivin negative and VEGF negative group, respectively (log-rank P = 0.000). Moreover, multivariate analysis showed that survivin expression (HR 0.224; 95 % CI 0.074-0.675; P = 0.008) and VEGF expression (HR 0.172; 95 % CI 0.054-0.559; P = 0.003) were statistically independent predictive factors of poorer prognosis for SCLC patients. Our results indicated that survivin and VEGF were over-expressed in small-cell lung cancer, each of them may be an independent poor prognostic factor.

Over-expression of survivin and VEGF in small-cell lung cancer may predict the poorer prognosis

BACKGROUND AND OBJECTIVE Survivin, a member of inhibitors of apoptosis protein (IAP) family, is expressed in most tumors as well as in different subcelluar units of tumors. This study was to investigate the clinical significance of survivin in different subcellular units in non-small cell lung cancer (NSCLC). METHODS The protein expression of survivin was detected by immunohistochemistry (IHC) in the specimens from 51 cases of NSCLC and 21 cases of paracancerous tissues. The relationship between survivin expression and clinical characteristics of patients was analyzed using SPSS 13.0 software. RESULTS Positive expression of survivin was mainly detected in cytoplasm and / or nucleus of NSCLC tissues, and the positive rates were 49.0%(25/51), 72.5%(37/51), 3.9%(2/51), 27.5%(14/51) and 23.5%(12/51) in cytoplasm only, in cytoplasm, in nucleus only, in nucleus, and both in cytoplasm and nucleus, respectively. The positive expression rate of survivin was significantly higher in NSCLC tissues (76.5%, 39/51) than in paracancerous tissues (19.0%, 4/21) (P=0.000). The expression of survivin in cytoplasm was correlated with differentiation of tumors (P=0.007). Positive staining of survivin in nucleus, both in cytoplasm and nucleus were significantly related to clinical stage and N stage of NSCLC (P<0.05). The positive rate of survivin was higher in III+IV or N1+N2 stage patients than in I+II or N0 stage patients, respectively (P<0.05). The five-year survival rate was lower in patients with positive expression of survivin in nucleus than in those with negative expression in nucleus(P<0.05). The clinical stage and status of recurrence or metastasis were two independent prognostic factors for the survival of NSCLC patients. CONCLUSIONS Expression of survivin might be related to the origin and development of NSCLC. The positive expression of survivin in nucleus might be associated with invasion, progression and poor prognosis of NSCLC.

[Subcellular localization of survivin in non-small cell lung cancer].

背景与目的 剪切修复偶联因子1（Excision-Repair Cross-Complementing 1, ERCC1）是核苷酸外切修复家族中的重要成员，它在核酸损伤修复过程和凋亡过程中起着重要作用。蛋白激酶C-α（Protein kinase Calpha,PKCα）是蛋白激酶C（PKC）的一种同工酶，PKCα调控细胞的转化和增殖，是肿瘤细胞中重要的信号途径。本研究初步探索ERCC1和PKCα在非小细胞肺癌（non-small cell lung cancer, NSCLC）中表达所代表的临床意义。方法 运用免疫组化方法检测51例NSCLC组织、21例癌旁组织中ERCC1和PKCα的表达，并采用SPSS 13.0软件进行相关统计分析。结果 ERCC1和PKCα在肿瘤组阳性率明显高于癌旁组（Ρ<0.05）；ERCC1与临床分期和N分期等因素有关，临床III+IV期及N1-2期患者ERCC1阳性率要分别高于I+II期和N0期患者（Ρ=0.011, P=0.015）；ERCC1阴性组的5年生存时间高于阳性组（Ρ<0.05）；Spearman相关分析提示ERCC1与PKCα之间存在正相关（r=0.425, P=0.002）。结论 ERCC1和PKCα可能与NSCLC的发生相关，ERCC1可能与肿瘤的预后相关。ERCC1和PKCα之间可能存在共同作用通路。

Nie Xu

Papers

Over-expression of survivin and VEGF in small-cell lung cancer may predict the poorer prognosis

[Subcellular localization of survivin in non-small cell lung cancer].

[The clinical signifcance of expression of ERCC1 and PkCalpha in non-small cell lung cancer].