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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
MINI25.03 - Potent Anti-Mesothelioma Activity by the Novel Naftopidil Analogue HUHS1015; Preclinical Evidence for Treatment (ID 2733)
16:45 - 18:15 | Author(s): A. Gotoh
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.
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.
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.
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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