Discovery of New Natural Products from Cultrued Soft Coral Sinularia sandensis and Investigation of Molecular Mechanisms of Apoptosis Induced by 7-Acetylsinumaximol B and Anti-metastasis of Dihydroaustrasulfone Alcohol on Cancer Cells

• Main Authors: Tsung-Chang Tsai, 蔡宗昌
• Other Authors: Jyh-Horng Sheu
• Format: Others
• Language: zh-TW
• Published: 2018
• Online Access: http://ndltd.ncl.edu.tw/handle/979y25

博士 === 國立中山大學 === 海洋生物科技暨資源學系 === 106 === Cultured soft coral Sinularia sandensis has led to the isolation of elenven natural compounds, including two new cembranoids, 4-carbomethoxyl-10-epigyrosanoldie E (1) and 7-acetylsinumaximol B (2); four known cembranoids, sinumaximol B (3), sinulacembranolide A (4), pukalide (5) and 10-epigyrosanolide E (6); two known furanosesquiterpene compounds, methyl (1′E, 5′E)-5-(2′,6′-dimethylocta-1′,5′,7′-trienyl) furan-3-carboxylate (7) and (1′E,5′E)-5-(2′,6′-dimethylocta-1′,5′,7′-trienyl)furan-3- carboxylic acid (8); three known steroids, 24-methylenecholestane-3β,5α,6β-triol (9), 11α-acetoxy-24-methylenecholesta-3β,5α,6β-triol (10) and 11α-acetoxy-24- methylenecholesta-1α,3β,5α,6β-tetraol (11). The structures of compounds 1–11 were elucidated by means of IR, MS and NMR techniques, and the absolute configurations of 1 and 5 were further confirmed by single-crystal X-ray diffraction analysis. 7-Acetylsinumaximol B (2) exerted a concentration-dependent anti-proliferative effect on human gastric cancer cells NCI-N87. Activation of mitochondria-related apoptosis was associated with the release of cytochrome c from mitochondria, activation of pro-apoptotic proteins (Bax and Bad) and inhibition of anti-apoptotic proteins (Bcl-2, Bcl-xL, and Mcl-1). Compound 2 triggered endoplasmic reticulum stress, leading to activation of the PERK/elF2α/ATF4/CHOP signal pathway. Compound 2 initiated autophagic apoptosis and induced the expression of autophagy-related proteins (Atg3, Atg5, Atg7, Atg12, LC3-I and LC3-II). Our results suggested that compound 2 has the potential to be developed as a useful anti-cancer drug for the treatment of human gastric cancer. Dihydroaustrasulfone alcohol (12) provided a concentration-dependent inhibitory effect on the invasion and migration of human renal cancer cells. The expressions of MMP-2、MMP-9 and uPA were decreased and TIMP-1 and TIMP-2 were increased. Compound 12 suppressed FAK/PI3K/Akt/mTOR and MAPKs (JNK/p38MAPK/ERK) signal pathway. We concluded that compound 12 has anti-invasion and anti-migration activity of human renal cancer cells 780-O and might be applied to clinical treatment for metastasis of human renal cell carcinoma.