Preya Umma Hafsa, Lee Kyung-Tae, Kim Nam-Jung, Lee Jung-Yun, Jang Dae Sik, Choi Jung-Hye
Department of Life and Nanopharamceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, South Korea.
Department of Life and Nanopharamceutical Sciences, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, South Korea; College of Pharmacy, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02447, South Korea.
Chem Biol Interact. 2017 Jun 25;272:72-79. doi: 10.1016/j.cbi.2017.05.011. Epub 2017 May 12.
Ovarian cancer is the most lethal gynecological malignancy worldwide. Thiophenes such as terthiophene have been shown to have anti-tumor effects on several cancer cell lines, including ovarian cancer cells. However, the underlying mechanisms behind the anti-proliferative effect of thiophenes are poorly understood. In this study, we investigated the molecular mechanisms underlying the anti-proliferative effect of α-terthienylmethanol, a terthiophene isolated from Eclipta prostrata (False Daisy), on human ovarian cancer cells. We found that α-terthienylmethanol is a more potent inhibitor of cell growth than is cisplatin in human ovarian cancer cells. α-Terthienylmethanol induces cell cycle arrest in ovarian cancer cells, as shown by the accumulation of cells in S phase. In addition, α-terthienylmethanol induced a change in S phase-related proteins cyclin A, cyclin-dependent kinase 2, and cyclin D2. Knockdown of cyclin A using specific siRNAs significantly compromised α-terthienylmethanol-induced S phase arrest. We further demonstrated that α-terthienylmethanol induced an increase in intracellular ROS, and the antioxidant N-acetyl-l-cysteine significantly reversed the S phase arrest induced by α-terthienylmethanol. Moreover, α-terthienylmethanol significantly increased the levels of p-H2AX, a DNA damage marker. These results suggest that α-terthienylmethanol inhibits the growth of human ovarian cancer cells by S phase cell cycle arrest via induction of ROS stress and DNA damage.
卵巢癌是全球最致命的妇科恶性肿瘤。噻吩类化合物，如三联噻吩，已被证明对包括卵巢癌细胞在内的多种癌细胞系具有抗肿瘤作用。然而，噻吩类化合物抗增殖作用背后的潜在机制仍知之甚少。在本研究中，我们调查了从鳢肠（假雏菊）中分离出的一种噻吩类化合物α-三联噻吩甲醇对人卵巢癌细胞抗增殖作用的分子机制。我们发现，在人卵巢癌细胞中，α-三联噻吩甲醇比顺铂是更有效的细胞生长抑制剂。α-三联噻吩甲醇诱导卵巢癌细胞的细胞周期停滞，表现为细胞在S期积累。此外，α-三联噻吩甲醇诱导S期相关蛋白细胞周期蛋白A、细胞周期蛋白依赖性激酶2和细胞周期蛋白D2发生变化。使用特异性小干扰RNA敲低细胞周期蛋白A显著削弱了α-三联噻吩甲醇诱导的S期停滞。我们进一步证明，α-三联噻吩甲醇诱导细胞内活性氧增加，抗氧化剂N-乙酰-L-半胱氨酸显著逆转了α-三联噻吩甲醇诱导的S期停滞。此外，α-三联噻吩甲醇显著增加了DNA损伤标志物p-H2AX的水平。这些结果表明，α-三联噻吩甲醇通过诱导活性氧应激和DNA损伤使S期细胞周期停滞，从而抑制人卵巢癌细胞的生长。
