Anti-cancer Effect of Hyoscyamus muticus Extract via Its Activation of Fas/FasL-ASK1-p38 Pathway
Abd El-Hafeez, Amer Ali; Marzouk, Hala Mohamed M; Abdelhamid, Mohamed A. A; Khalifa, Hazim O; Hasanin, Tamer H. A; Habib, Ahmed G. K; Abdelwahed, Fatma Mahmoud; Barakat, Fatma M; Bastawy, Eslam M; Abdelghani, Eman M. B; Ozawa, Toru Hosoi, Koichiro; Aref, Ahmed M; Fujimura, Takashi; Ibrahim, Ahmed R. N; Abdelmoniem, Aalaa S. O; Elghazawy, Hagar; Ghosh, Pradipta; Kawamoto, Seiji; Pil Pack, Seung
Date issued:
2022-11
Publisher:
Korean Society for Biotechnology and Bioengineering
Series Info:
Biotechnology and Bioprocess Engineering;27: 807-819 (2022)
Type:
Article
Keywords:
Hyoscyamus muticus
,
apoptosis,
,
apoptosis signal-regulating kinase 1
,
breast cancer
,
reactive oxygen species
Abstract:
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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