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      Hypoxia induces universal but differential drug resistance and impairs anticancer mechanisms of 5-fluorouracil in hepatoma cells

      , , , ,
      Acta Pharmacologica Sinica
      Springer Nature

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          gammaH2AX: a sensitive molecular marker of DNA damage and repair.

          Phosphorylation of the Ser-139 residue of the histone variant H2AX, forming gammaH2AX, is an early cellular response to the induction of DNA double-strand breaks. Detection of this phosphorylation event has emerged as a highly specific and sensitive molecular marker for monitoring DNA damage initiation and resolution. Further, analysis of gammaH2AX foci has numerous other applications including, but not limited to, cancer and aging research. Quantitation of gammaH2AX foci has also been applied as a useful tool for the evaluation of the efficacy of various developmental drugs, particularly, radiation modifying compounds. This review focuses on the current status of gammaH2AX as a marker of DNA damage and repair in the context of ionizing radiation. Although the emphasis is on gamma-radiation-induced gammaH2AX foci, the effects of other genotoxic insults including exposure to ultraviolet rays, oxidative stress and chemical agents are also discussed.
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            BrdU immunohistochemistry for studying adult neurogenesis: paradigms, pitfalls, limitations, and validation.

            Bromodeoxyuridine (BrdU) is a thymidine analog that incorporates DNA of dividing cells during the S-phase of the cell cycle. As such, BrdU is used for birth dating and monitoring cell proliferation. BrdU immunohistochemistry has been instrumental for the study of the development of the nervous system, and to confirm that neurogenesis occurs in the adult mammalian brain, including in human. However, the use of BrdU for studying neurogenesis is not without pitfalls and limitations. BrdU is a toxic and mutagenic substance. It triggers cell death, the formation of teratomas, alters DNA stability, lengthens the cell cycle, and has mitogenic, transcriptional and translational effects on cells that incorporate it. All of which have profound consequences on neurogenesis. BrdU is not a marker of the S-phase of the cell cycle. As a thymidine analog, it is a marker of DNA synthesis. Therefore, studying neurogenesis with BrdU requires distinguishing cell proliferation and neurogenesis from other events involving DNA synthesis, like DNA repair, abortive cell cycle reentry and gene duplication. BrdU labeling is currently the most used technique for studying adult neurogenesis in situ. However in many instances, appropriate controls have been overlooked and events reported as the generation of new neuronal cells in the adult brain misinterpreted, which makes BrdU labeling one of the most misused techniques in neuroscience.
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              Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma.

              The increasing incidence of hepatocellular carcinoma (HCC) is of great concern not only in the United States but throughout the world. Although sorafenib, a multikinase inhibitor with antiangiogenic and antiproliferative effects, currently sets the new standard for advanced HCC, tumor response rates are usually quite low. An understanding of the underlying mechanisms for sorafenib resistance is critical if outcomes are to be improved. In this study we tested the hypothesis that hypoxia caused by the antiangiogenic effects of sustained sorafenib therapy could induce sorafenib resistance as a cytoprotective adaptive response, thereby limiting sorafenib efficiency. We found that HCCs, clinically resistant to sorafenib, exhibit increased intratumor hypoxia compared with HCCs before treatment or HCCs sensitive to sorafenib. Hypoxia protected HCC cells against sorafenib and hypoxia-inducible factor 1 (HIF-1α) was required for the process. HCC cells acquired increased P-gp expression, enhanced glycolytic metabolism, and increased nuclear factor kappa B (NF-κB) activity under hypoxia. EF24, a molecule having structural similarity to curcumin, could synergistically enhance the antitumor effects of sorafenib and overcome sorafenib resistance through inhibiting HIF-1α by sequestering it in cytoplasm and promoting degradation by way of up-regulating Von Hippel-Lindau tumor suppressor (VHL). Furthermore, we found that sustained sorafenib therapy led to increased intratumor hypoxia, which was associated with sorafenib sensitivity in HCC subcutaneous mice tumor models. The combination of EF24 and sorafenib showed synergistically effects against metastasis both in vivo and in vitro. Synergistic tumor growth inhibition effects were also observed in subcutaneous and orthotopic hepatic tumors. Hypoxia induced by sustained sorafenib treatment confers sorafenib resistance to HCC through HIF-1α and NF-κB activation. EF24 overcomes sorafenib resistance through VHL-dependent HIF-1α degradation and NF-κB inactivation. EF24 in combination with sorafenib represents a promising strategy for HCC. Copyright © 2013 American Association for the Study of Liver Diseases.
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                Author and article information

                Journal
                Acta Pharmacologica Sinica
                Acta Pharmacol Sin
                Springer Nature
                1671-4083
                1745-7254
                July 17 2017
                July 17 2017
                :
                :
                Article
                10.1038/aps.2017.79
                5719160
                28713155
                994e1236-df15-4844-9242-26ef631a68a4
                © 2017
                History

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