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T. Nishizaki



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    MINI 25 - Trials, Radiation and Other (ID 142)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      MINI25.03 - Potent Anti-Mesothelioma Activity by the Novel Naftopidil Analogue HUHS1015; Preclinical Evidence for Treatment (ID 2733)

      16:45 - 18:15  |  Author(s): T. Nishizaki

      • Abstract
      • Presentation
      • Slides

      Background:
      Malignant pleural mesothelioma (MPM) is usually a fatal neoplasm, and current therapeutic interventions are far from satisfactory. Naftopidil, an α1-adrenoceptor antagonist, is used clinically for the treatment of benign prostate hypertrophy, and has been found to reduce the incidence of prostate cancer and to inhibit prostate cancer cell proliferation via G1 cell cycle arrest. Recently, naftopidil has been demonstrated to induce apoptosis in mesothelioma cells by activating caspase-8 and the effector caspase-3 independently of α1-adrenoceptor suppression. Hence, a more potent naftopidil analogue, HUHS1015, was synthesized. The current study evaluates the inhibitory effect of HUHS1015 on malignant mesothelioma cell proliferation in preclinical models and assesses whether HUHS1015 can be the basis for new drug for the treatment of MPM.

      Methods:
      We treated the human MPM cell lines MSTO-211H, NCI-H28, NCI-H2052 and NCI-H2452 with HUHS1015, and evaluated cell viability using the MTT method. Additionally, NCI-H2052 tumor xenograft models in BALB/c-nu/nu mice were utilized to investigate anti-mesothelioma activity in vivo.

      Results:
      HUHS1015 reduced the viability of MPM cells more potently than cisplatin or paclitaxel at concentrations higher than 30 μM, and the drug induced both necrosis and apoptosis of MSTO-211H and NCI-H2052 cells. The effect of HUHS1015 on the expression of Bcl-2 family mRNAs in MSTO-211H and NCI-H2052 cells was tested using real-time RT-PCR. Puma, Hrk, and Noxa mRNAs were up-regulated in both cell lines. In the NCI-H2052 mouse xenograft models, HUHS1015 strongly suppressed tumor growth.

      Conclusion:
      These results indicate that HUHS1015 may be an effective anticancer drug candidate for the treatment of MPM. HUHS1015 induces apoptosis of MPM cells through modulation of a mitochondrial pathway, and future clinical investigations with this drug are warranted for mesothelioma.

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    P3.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 226)

    • Event: WCLC 2015
    • Type: Poster
    • Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
    • Presentations: 1
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      P3.08-015 - Naftopidil Is Effective in the Treatment of Malignant Pleural Mesothelioma (ID 2732)

      09:30 - 17:00  |  Author(s): T. Nishizaki

      • Abstract
      • Slides

      Background:
      Naftopidil, an antagonist of the α1A/1D-adrenoceptor, was developed as a drug for the treatment of benign prostate hyperplasia and hypertension, and has recently been shown to exert antitumor activity in a variety of cancers. We previously discovered that naftopidil induces apoptosis of malignant pleural mesothelioma (MPM) cells in an α1-adrenoceptor-independent manner, as this was not reproducible using other α1-adrenoceptor-inhibitors such as prazosin. The present study was conducted to assess whether naftopidil is useful for the treatment of MPM.

      Methods:
      Cell viability of cultured NCI-H2052 human cells was evaluated using MTT. TUNEL staining was performed to detect in situ DNA fragmentation as a marker of apoptosis using an in situ apoptosis detection kit. Caspase activity was measured using a caspase fluorometric assay kit. NCI-H2052 cells were treated with naftopidil (100 μmol/L) and were subcutaneously inoculated into the right flank of BALB/c-nu/nu mice under pentobarbital-induced general anesthesia. Naftopidil was diluted with a physiological salt solution and injected intraperitoneally twice a week, starting 1 week after inoculation; the salt solution alone was used in control mice. The longer (L) and shorter (S) lengths of the induced tumors were measured using calipers, and tumor volume (V) was calculated according to the following equation: V = (L × S[2]) × 1/2.

      Results:
      Naftopidil reduced NCI-H2052 cell viability in a concentration-dependent manner and significantly increased the number of TUNEL-positive NCI-H2052 cells compared to untreated cells. Naftopidil activated caspase-3 and -8, but not caspase-9. Naftopidil did not affect the expression of FasL protein in NCI-H2052 cells. Notably, however, it did significantly increase the concentrations of extracellular FasL protein in a bell-shaped, time-dependent manner. Intraperitoneal injection of naftopidil significantly inhibited NCI-H2052 xenograft tumor growth compared to tumors in control mice. All mice injected with naftopidil survived 8 weeks after the first injection, and the drug had no effect on their mean weight.

      Conclusion:
      The results of the present study suggest that naftopidil induces apoptosis of NCI-H2052 cells by stimulating the secretion of FasL, a ligand of the death receptor Fas. This in turn activates caspase-8 and the effector caspase-3, leading to the inhibition of NCI-H2052 xenograft tumor growth in vivo. This supports the concept that naftopidil could be developed as a therapeutic agent for the treatment of malignant pleural mesothelioma.

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