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E. Masachika
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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
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.08-015 - Naftopidil Is Effective in the Treatment of Malignant Pleural Mesothelioma (ID 2732)
09:30 - 09:30 | Author(s): E. Masachika
- Abstract
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.
