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Mar Drugs
2017 Oct 16;1510:. doi: 10.3390/md15100314.
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Identification of (Z)-2,3-Diphenylacrylonitrileas Anti-Cancer Molecule in Persian Gulf Sea Cucumber Holothuria parva.
Amidi S
,
Hashemi Z
,
Motallebi A
,
Nazemi M
,
Farrokhpayam H
,
Seydi E
,
Pourahmad J
.
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Hepatocellular carcinoma (HCC), also named cancerous hepatoma, is the most common type of malignant neoplasia of the liver. In this research, we screened the Persian Gulf sea cucumber Holothuria parva (H. parva) methanolic sub-fractions for the possible existence of selective toxicity on liver mitochondria isolated from an animal model of HCC. Next, we purified the most active fraction. Thus the structure of the active molecule was identified. HCC was induced by diethylnitrosamine (DEN) and 2-acetylaminofluorene (2-AAF) protocol. Rat liver mitochondria for evaluation of the selective cytotoxic effects of sub-fractions of H. parva were isolated and then mitochondrial parameters were determined. Our results showed that C1 sub-fraction of methanolic extract of H. parva considerably increased reactive oxygen species (ROS) generation, collapse of mitochondrial membrane potential (MMP), swelling in mitochondria and cytochrome c release only on HCC liver mitochondria. Furthermore, the methanolic extract of H. parva was investigated furthermore and the active fraction was extracted. In this fraction, (Z)-2,3-diphenylacrylonitrile molecule, which is also known as α-cyanostilbene, was identified by mass analysis. This molecule increased ROS generation, collapse of MMP, swelling in mitochondria and finally cytochrome c release only on HCC liver mitochondria. The derivatives of (Z)-2,3-diphenylacrylonitrile in other natural products were also reported as an anti-cancer agent. These results suggest the eligibility of the (Z)-2,3-diphenylacrylonitrile as a complementary therapeutic agent for patients with HCC.
Figure 1. Thin layer chromatography (TLC) of fractionation methanolic extract using MeOH:CHCl3 (7:3) as mobile phase. The first ultraviolet (UV)-distinct band from top was named A, the second B, and the third C.
Figure 2. The fractionation of the active fraction (C) using MeOH:CHCl3 (7:3) as mobile phase by TLC plate method. C1 was the first UV-distinct band, and C2 was the second UV-distinct band.
Figure 4. The Mitochondrial Membrane Potential (MMP) assay. The effect of C1 sub-fraction of methanolic extract of H. parva (250, 500 and 1000 μg/mL) on MMP collapse in: the normal mitochondria (A); and the HCC mitochondria (B) obtained from liver hepatocytes at within 60 min of incubation. The cytochrome c release assay. (A) Control means vehicle treated normal mitochondria. (B) Control means vehicle treated HCC mitochondria. *** and **** indicate significant differences in comparison with corresponding control (HCC) groups for p < 0.001 and p < 0.0001, respectively. (C) The effect of C1 sub-fraction of methanolic extract of H. parva (500 μg/mL) on cytochrome c release in the normal mitochondria and the HCC mitochondria obtained from liver hepatocytes at within 60 min of incubation. Data are shown as mean ± SD (n = 3). *** indicate significant differences in comparison with corresponding control (HCC) groups for p < 0.001. ### Significant differences in the comparison with 500 μM (HCC) C1 sub-fraction (p < 0.001).
Figure 5. The mass (MS) Analysis of the C1 Sub-fraction.
Figure 7. The Mitochondrial Membrane Potential (MMP) assay. The effect of (Z)-2,3-diphenylacrylonitrile of H. parva (10, 20 and 40 μg/mL) on MMP collapse in: the normal mitochondria (A); and the HCC mitochondria (B) obtained from liver hepatocytes at within 60 min of incubation. (A) Control means vehicle treated normal mitochondria; (B) Control means vehicle treated HCC mitochondria; (C) The cytochrome c release assay. The effect of (Z)-2,3-diphenylacrylonitrile of H. parva (20 μg/mL) on cytochrome c release in the normal mitochondria and the HCC mitochondria obtained from liver hepatocytes at within 60 min of incubation; (D) MTT assay: Hepatocytes obtained from HCC group were treated with (Z)-2,3-diphenylacrylonitrile of H. parva (0, 2.5, 5, 10, 20, 40 and 100 μg/mL) and incubated for 24 h. Data are shown as mean ± SD (n = 3). *, **, *** and **** indicate significant differences in comparison with corresponding control (HCC) groups for p < 0.001 and p < 0.0001, respectively. ### Significant differences in the comparison with 20 μg/mL (HCC) (Z)-2,3-diphenylacrylonitrile (p < 0.001).
Figure 8. A mix probe between synthesized (Z)-2,3-diphenylacrylonitrile and C1 fraction in TLC. C: Possible main active ingredient of C1 fraction. S, Synthesized (Z)-2,3-diphenylacrylonitrile; *, both the possible main active ingredient of C1 fraction and synthesized (Z)-2,3-diphenylacrylonitrile.
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