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KMID : 1094720220270050833
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Biotechnology and Bioprocess Engineering
2022 Volume.27 No. 5 p.833 ~ p.845
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Anti-cancer Effect of Hyoscyamus muticus Extract via Its Activation of Fas/FasL-ASK1-p38 Pathway
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Amer Ali Abd El-Hafeez
Hala Mohamed M. Marzouk
Mohamed A. A. Abdelhamid
Hazim O. Khalifa
Tamer H. A. Hasanin
Ahmed G. K. Habib
Fatma Mahmoud Abdelwahed
Fatma M. Barakat
Eslam M. Bastawy
Eman M. B. Abdelghani
Lee Hye-Won
Koichiro Ozawa
Ahmed M. Aref
Takashi Fujimura
Seo Ho-Kyung
Aalaa S. O. Abdelmoniem
Hagar Elghazawy
Pradipta Ghosh
Seiji Kawamoto
Pack Seung-Pil
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Abstract
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Hyoscyamus muticus L. is a traditional medicine used as antispasmodic and sedative. Herein, we aimed to determine the phytochemical constituents and for the first time its anti-cancer activities. The phytochemical constituents of the different extracts were evaluated by calorimetric methods. The anti-cancer activities of the extracts were tested against leukemia, breast, renal, and prostate cancers cell lines. 4, 6-Diamidino-2-phenylindole (DAPI) staining, flow cytometric analysis, knockdown of ASK1, and reactive oxygen species (ROS) production were evaluated to clarify the mechanism of action. Phytochemical screening confirmed the presence of wide range of phytoconstituents. Hyoscyamus muticus methanolic extracts (HMME) showed the highest anti-cancer activities against leukemia, breast, renal, and prostate cancers as compared to ethanol and aqueous extracts. Specifically, HMME exerted cytotoxic effect against the MDA-MB-231 and MDA-MB-468 triple-negative breast cancer (TNBC) cell lines with IC50 values of 8.75 and 7.25 μg/mL, respectively. Mechanistically, DAPI staining and flow cytometric analysis revealed that HMME induces apoptosis via the death receptor, FAS, but not the mitochondrial pathway. Moreover, ASK1 and p38 were rapidly activated in response to HMME, and knockdown of ASK1 by a small interference of RNA specific to Ask1 attenuated p38 and caspase-3 activation and suppressed apoptosis, implying that HMME-induced apoptosis relies on the ASK1-p38-caspase-3 pathway. Furthermore, we confirmed that cellular ROS generation was a critical mediator in HMME-induced apoptosis because the ROS-scavenger N-acetyl cysteine significantly decreased the phosphorylation of ASK1 and HMME-induced apoptosis. Our results confirmed HMME cytotoxic effects in TNBCs via ROS-dependent activation of the Fas/FasL-ASK1-p38 axis.
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KEYWORD
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Hyoscyamus muticus, apoptosis, apoptosis signal-regulating kinase 1, breast cancer, reactive oxygen species
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