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Background: Colorectal cancer is the third leading cause of cancer-related mortality in most developed countries. This mortality is mainly due to the metastatic progression to the liver with frequent recurrence. Colorectal cancer remains a therapeutic challenge and this has intensified the search for new drug targets. In an effort to establish a novel targeted-therapy, we studied the molecular mechanisms of cancer stem cell inhibitor salinomycin., Materials and Methods: Co-immunoprecipitation was performed to examine STAT3-STAT1 protein interactions. Telomerase activity was measured by polymerase chain reaction (PCR) and ELISA assays. Apoptosis and cell stress arrays were analyzed to identify key proteins responding to salinomycin treatments., Results: IL-6 and TNF-α induced STAT3 and STAT1 interactions, however the interactions were abolished by salinomycin challenge. Salinomycin reduced cancer stem cell phenotype and decreased telomerase activity of colorectal cancer cells., Conclusion: Our work uncovers a new mechanism through which salinomycin inhibits cancer stemness suggesting a novel targeted-therapy for metastatic colorectal cancer., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The cancer stem cell (CSC) model postulates the existence of a small proportion of cancer cells capable of sustaining tumor formation, self-renewal and differentiation. Signal Transducer and Activator of Transcription 3 (STAT3) signaling is known to be selectively activated in breast CSC populations. However, it is yet to be determined which molecular mechanisms regulate STAT3 signaling in CSCs and what chemopreventive agents are effective for suppressing CSC growth. The aim of this study was to examine the potential efficacy of curcumin and epigallocatechin gallate (EGCG) against CSC and to uncover the molecular mechanisms of their anticancer effects., Materials and Methods: To suppress the CSC phenotype, two breast cancer cell lines (MDA-MB-231 cells and MCF7 cells transfected with HER2) were treated with curcumin (10 μM) with or without EGCG (10 μM) for 48 h. We used tumor-sphere formation and wound-healing assays to determine CSC phenotype. To quantify CSC populations, Fluorescence-activated cell sorting profiling was monitored. STAT3 phosphorylation and interaction with Nuclear Factor-kB (NFkB) were analyzed by performing western blot and immunoprecipitation assays., Results: Combined curcumin and EGCG treatment reduced the cancer stem-like Cluster of differentiation 44 (CD44)-positive cell population. Western blot and immunoprecipitation analyses revealed that curcumin and EGCG specifically inhibited STAT3 phosphorylation and STAT3-NFkB interaction was retained., Conclusion: This study suggests that curcumin and EGCG function as antitumor agents for suppressing breast CSCs. STAT3 and NFκB signaling pathways could serve as targets for reducing CSCs leading to novel targeted-therapy for treating breast cancer., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The mechanisms that could explain the poor sensitivity to 5-FU in certain colorectal cancer (CRC) cells were investigated and whether or not cotreatment with low doses of selenium would offer a therapeutic benefit was explored., Materials and Methods: Four CRC cell lines (Caco2, RKO, DLD1 and HT-29) with defined tumor signatures and seven different chemical forms of selenium were tested., Results: 5-FU partially inhibited the HT-29 and RKO cells, but had a weak effect on the DLD1 and almost none on the Caco2 cells. Selenous acid and sodium selenite induced growth inhibition of the DLD1, RKO and HT-29 cells, with a marginal effect on the Caco2 cells. The Caco2 cells with mutant p53, failure to activate caspase-8, -9, -7 and -3 and with hypermethylated caspase-8 were resistant to 5-FU. Conversely, RKO cells expressing wildtype p53, proteolytically activated caspase-8, -9, -7 and -3 and unmethylated caspase-8 were more responsive to 5-FU and selenous acid-induced apoptosis., Conclusion: Combination treatment with selenous acid may offer an efficacious strategy to overcome 5-FU resistance in certain CRC cells.

The anti-neoplastic properties of an Selenium compound were studied in vitro on several tumor cell lines: Breast (MCF-7, MCF-10, SKBR-3, BCAP37), Lung (RH2), Prostate (LNCap and PC-3), Colon (T84, Caco-2), Small Intestine (HCF8), and Liver (HepG2). We also examined additive or synergistic effect of Selenium in combination with standard anti-cancer drugs, Adriamycin (Doxorubicin) and Taxol. The effect of Selenium was assessed by apoptosis; DNA synthesis; growth rate by MTT assay; uptake of amino acid MeAIB by System A; and morphological changes. Our results demonstrate that MCF-7 and SKBR-3 showed increase in apoptosis as measured by DNA fragmentation and increase in "rounded" cells and membrane "blebbing", decrease in MeAIB uptake, and decrease in DNA synthesis. These changes were Selenium dose dependent with optimal inhibition at Selenium concentration between 4 and 40 ng/ml after 72 hrs of treatment. Similar observations were made with RH2, HCF8, Caco-2, and HepG2 cells. In contrast, LNCap, PC-3, and T-84 were not significantly affected by Selenium. However, addition of Adriamycin or Taxol in combination with Selenium caused small but significant inhibition of prostate cancer cells LNCap and PC-3. Addition of chemotherapeutic agents either Taxol or Doxorubicin with Selenium caused further inhibition of MCF-7, SKBR-3, RH2, HCF8, and HepG2 cells. In conclusion, Selenium has a significant anti-neoplastic effect on breast, lung, liver, and small intestinal tumor cells. Supplementation of Selenium enhanced chemotherapeutic effect of Taxol and Doxorubicin in these cells beyond that seen with the chemotherapeutic drugs used alone. These in vitro studies on several cancer cell lines suggest a potential benefit of Selenium-enhancement of anticancer effects other systems, and therefore offer further relevance to clinical trials efforts.

The mutations in the breast cancer susceptible gene BRCA1 are responsible for about 50% of inherited breast cancers and confer increased risk of breast and ovarian cancer to its carriers. BRCA1 gene mutations may also be related with other types of cancers such as prostate cancer and colorectal cancer. The goal of this study was to investigate if BRCA1 mutation could be detected in diverse types of cancers. We used PCR-NIRCA and PCR-SSCP methods for screening the BRCA1 mutation hot regions, exons 2, 5, 11, 16 and 20. The positive samples were sequenced to confirm the nature of the mutations. We have identified a rare sequence variant, A3537G (Ser 1140Gly) in a B cell lymphoma patient and two polymorphisms, A1186G (Gln356Arg) in a brain cancer patient and A3667G (Lys1183Arg) in a germline tumor patient. In conclusion, 3 missense alterations of BRCA1 gene have been identified in cancers other than breast cancer.