Çigdem Özen

Pomegranate (Punica granatum L.), one of the oldest known edible fruits, is nowadays broadly consumed throughout the world. Its fruits and seeds as well as other anatomical compartments (e.g., flowers and leaves) are rich in numerous bioactive compounds and therefore, the scientific interest in this plant has been constantly growing in recent years. It has been shown that pomegranate and its extracts exhibit potent antioxidative, antimicrobial, and anticarcinogenic properties. The present review summarizes some recent studies on pomegranate, highlighting mainly its vasculoprotective role attributed to the presence of hydrolyzable tannins ellagitannins and ellagic acid, as well as other compounds (e.g., anthocyanins and flavonoids). These in vitro and in vivo studies showed that substances derived from pomegranate reduce oxidative stress and platelet aggregation, diminish lipid uptake by macrophages, positively influence endothelial cell function, and are involved in blood pressure regulation. Clinical studies demonstrated that daily intake of pomegranate juice lessens hypertension and attenuates atherosclerosis in humans. Altogether, the reviewed studies point out the potential benefits of a broader use of pomegranate and its constituents as dietary supplements or as adjuvants in therapy of vascular diseases, such as hypertension, coronary artery disease, and peripheral artery disease.

Hepatocellular carcinoma (HCC) represents a major form of primary liver cancer in adults. Chronic infections with hepatitis B (HBV) and C (HCV) viruses and alcohol abuse are the major factors leading to HCC. This deadly cancer affects more than 500,000 people worldwide and it is quite resistant to conventional chemo- and radiotherapy. Genetic and epigenetic studies on HCC may help to understand better its mechanisms and provide new tools for early diagnosis and therapy. Recent literature on whole genome analysis of HCC indicated a high number of mutated genes in addition to well-known genes such as TP53, CTNNB1, AXIN1 and CDKN2A, but their frequencies are much lower. Apart from CTNNB1 mutations, most of the other mutations appear to result in loss-of-function. Thus, HCC-associated mutations cannot be easily targeted for therapy. Epigenetic aberrations that appear to occur quite frequently may serve as new targets. Global DNA hypomethylation, promoter methylation, aberrant expression of non-coding RNAs and dysregulated expression of other epigenetic regulatory genes such as EZH2 are the best-known epigenetic abnormalities. Future research in this direction may help to identify novel biomarkers and therapeutic targets for HCC.

Senescence is a permanent proliferation arrest in response to cell stress such as DNA damage. It contributes strongly to tissue aging and serves as a major barrier against tumor development. Most tumor cells are believed to bypass the senescence barrier (become "immortal") by inactivating growth control genes such as TP53 and CDKN2A. They also reactivate telomerase reverse transcriptase. Senescence-to-immortality transition is accompanied by major phenotypic and biochemical changes mediated by genome-wide transcriptional modifications. This appears to happen during hepatocellular carcinoma (HCC) development in patients with liver cirrhosis, however, the accompanying transcriptional changes are virtually unknown. We investigated genome-wide transcriptional changes related to the senescence-to-immortality switch during hepatocellular carcinogenesis. Initially, we performed transcriptome analysis of senescent and immortal clones of Huh7 HCC cell line, and identified genes with significant differential expression to establish a senescence-related gene list. Through the analysis of senescence-related gene expression in different liver tissues we showed that cirrhosis and HCC display expression patterns compatible with senescent and immortal phenotypes, respectively; dysplasia being a transitional state. Gene set enrichment analysis revealed that cirrhosis/senescence-associated genes were preferentially expressed in non-tumor tissues, less malignant tumors, and differentiated or senescent cells. In contrast, HCC/immortality genes were up-regulated in tumor tissues, or more malignant tumors and progenitor cells. In HCC tumors and immortal cells genes involved in DNA repair, cell cycle, telomere extension and branched chain amino acid metabolism were up-regulated, whereas genes involved in cell signaling, as well as in drug, lipid, retinoid and glycolytic metabolism were down-regulated. Based on these distinctive gene expression features we developed a 15-gene hepatocellular immortality signature test that discriminated HCC from cirrhosis with high accuracy. Our findings demonstrate that senescence bypass plays a central role in hepatocellular carcinogenesis engendering systematic changes in the transcription of genes regulating DNA repair, proliferation, differentiation and metabolism.

PURPOSE: A new series of thiazolyl-2,4-thiazolidinedione / rhodanine compounds T1-T23 was synthesized and tested for their anticancer activities. Hepatocellular carcinoma cell lines were chosen due to their strong drug resistance to test the new compounds. METHODS: All compounds were synthesized via Knoevenagel Condensation reaction and thiazolidinedione ester compounds (T3,T9,T15,T20) were hydrolyzed for obtaining the acidic compounds (T6,T12,T17,T23). All compounds were firstly screened for their anticancer activity against two hepatocellular carcinoma (HCC) cell lines, Huh7 and Plc/Prf/5 (Plc) cell lines by sulforhodamine B assay. Further IC50 values were calculated for three candidates (T4, T15, T21) in five different HCC (Huh7, Plc, Snu449, HepG2, Hep3B) and one breast cancer (Mcf7) cell line. RESULTS: Compounds T4, T15, T21 had very strong anticancer effects even though their 10 µM concentration in Huh7 cell line. According to IC50 values, T21 was the most effective compound with IC50 values in a range from 2 to 16 µM in 6 cancer cell lines. In terms of cytotoxicity T21 mostly affected Huh7 and interestingly it was less effective against Plc. CONCLUSIONS: Considering these results it can be suggested that compounds T4, T15 and T21 may lead to the development of more potent anticancer drugs in the future. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.