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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
Benzophenanthridine alkaloids suppress lung adenocarcinoma by blocking TMEM16A Ca2+-activated Cl- channels
Gaohua Zhang1, Lin Zhu2, Yucong Xue1
1Department of Pharmacology, Hebei University of Chinese Medicine, No.326 South Xinshi Road, Shijiazhuang, 050091, Hebei, China.
Abstract:
An increasing amount of evidence suggests that transmembrane member 16A (TMEM16A)-encoded Ca2+-activated Cl- channels play a crucial role in regulating tumorigenesis. Therefore, specific and potent TMEM16A inhibitors have been proposed to potentially be useful for the treatment of cancer. During drug screening, we found that benzophenanthridine alkaloids (sanguinarine, sanguinarium chloride, sanguinarine nitrate, ethoxysanguinarine, chelerythrine, and dihydrosanguinarine) potently inhibited the recombinant TMEM16A current. The IC50 and Emax values for TMEM16A inhibition of six tested benzophenanthridine alkaloids were 5.6-12.3 μM and 77-91%, respectively. These benzophenanthridine alkaloids also significantly inhibited the endogenous TMEM16A currents and proliferation, migration, and induced apoptosis in LA795 lung adenocarcinoma cells. These data demonstrate that benzophenanthridine alkaloids are novel TMEM16A inhibitors and are potentially useful in specific cancer therapies. These findings also provide new insight for the development of TMEM16A inhibitors.
Insights
Benzophenanthridine alkaloids potently inhibit TMEM16A channels, crucial in cancer. These compounds also reduced lung cancer cell proliferation and migration, showing potential for novel cancer therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Transmembrane member 16A (TMEM16A) channels are implicated in tumorigenesis.
- Targeting TMEM16A with inhibitors is a potential cancer treatment strategy.
Purpose of the Study:
- To identify novel TMEM16A inhibitors.
- To evaluate the anti-cancer potential of benzophenanthridine alkaloids.
Main Methods:
- Drug screening of benzophenanthridine alkaloids against recombinant TMEM16A.
- Assay of TMEM16A inhibition, cell proliferation, migration, and apoptosis in lung adenocarcinoma cells.
Main Results:
- Six benzophenanthridine alkaloids demonstrated potent inhibition of TMEM16A currents (IC50: 5.6-12.3 μM; Emax: 77-91%).
- These alkaloids inhibited endogenous TMEM16A activity and suppressed proliferation and migration in LA795 lung cancer cells.
- Apoptosis was induced in lung adenocarcinoma cells treated with these compounds.
Conclusions:
- Benzophenanthridine alkaloids are novel inhibitors of TMEM16A.
- These alkaloids show therapeutic potential for cancer treatment, particularly lung adenocarcinoma.
- Findings offer new insights for developing TMEM16A-targeted cancer therapies.
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