TY - JOUR
T1 - Anti-cancer Effect of Hyoscyamus muticus Extract via Its Activation of Fas/FasL-ASK1-p38 Pathway
AU - Abd El-Hafeez, Amer Ali
AU - Marzouk, Hala Mohamed M.
AU - Abdelhamid, Mohamed A.A.
AU - Khalifa, Hazim O.
AU - Hasanin, Tamer H.A.
AU - Habib, Ahmed G.K.
AU - Abdelwahed, Fatma Mahmoud
AU - Barakat, Fatma M.
AU - Bastawy, Eslam M.
AU - Abdelghani, Eman M.B.
AU - Hosoi, Toru
AU - Ozawa, Koichiro
AU - Aref, Ahmed M.
AU - Fujimura, Takashi
AU - Ibrahim, Ahmed R.N.
AU - Abdelmoniem, Aalaa S.O.
AU - Elghazawy, Hagar
AU - Ghosh, Pradipta
AU - Kawamoto, Seiji
AU - Pack, Seung Pil
N1 - Publisher Copyright:
© 2022, The Korean Society for Biotechnology and Bioengineering and Springer.
PY - 2022/10
Y1 - 2022/10
N2 - 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.
AB - 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.
KW - Hyoscyamus muticus
KW - apoptosis
KW - apoptosis signal-regulating kinase 1
KW - breast cancer
KW - reactive oxygen species
UR - https://www.scopus.com/pages/publications/85141510607
UR - https://www.scopus.com/pages/publications/85141510607#tab=citedBy
U2 - 10.1007/s12257-022-0085-x
DO - 10.1007/s12257-022-0085-x
M3 - Article
AN - SCOPUS:85141510607
SN - 1226-8372
VL - 27
SP - 807
EP - 819
JO - Biotechnology and Bioprocess Engineering
JF - Biotechnology and Bioprocess Engineering
IS - 5
ER -
