Widiandani Tri, Meiyanto Edy
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Airlangga, Surabaya 60155, Indonesia.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Yogyakarta 55281, Indonesia.
J Adv Pharm Technol Res. 2020 Oct-Dec;11(4):163-168. doi: 10.4103/japtr.JAPTR_77_20. Epub 2020 Oct 10.
Breast cancer with HER-2 overexpression is sensitive to drugs which target the receptor or its kinase activity. Although the anti-HER-2 therapies commonly used have improved patient outcome, resistance usually occurs. In this present study, we investigated a modification of the chemical structure of allylthiourea derivatives in order to enhance the cytotoxicity effect on breast cancer cells with HER-2 overexpression. The aim of this research was to predict the absorption, distribution, metabolism, excretion, and toxicity by study and to explore the effect -benzoyl-3-allylthiourea (BATU) on MCF-7 cell line with overexpressing of HER-2 using MTT assay and western blot. The result showed that the cytotoxicity effects of BATU on MCF-7/HER-2 cell line (IC value 0.64 mM) were higher than on MCF-7 cell lines (IC value 1.47 mM). In addition, the cytotoxic effects of BATU on MCF-7 and MCF-7/HER-2 were higher than allylthiourea as a lead compound (IC value 5.22 and 3.17 mM). The results also confirmed that the BATU compound has the ability to effectively enhance its cytotoxicity against MCF-7/HER-2 through enhanced HER-2 expression and inhibition of nuclear factor kappa B (NF-kB) activation. Above all, the BATU compound is effective in increasing HER-2 expression and inactivating NF-kB transcription factors, thereby resulting in inhibition of protein expression which works a significant part in cell proliferation. Therefore, the BATU compound has the potential to be developed as a complementary drug in breast cancer therapy with HER-2 positive.
HER-2过表达的乳腺癌对靶向该受体或其激酶活性的药物敏感。尽管常用的抗HER-2疗法改善了患者预后，但耐药通常会出现。在本研究中，我们研究了烯丙基硫脲衍生物化学结构的修饰，以增强对HER-2过表达的乳腺癌细胞的细胞毒性作用。本研究的目的是通过研究预测吸收、分布、代谢、排泄和毒性，并使用MTT法和蛋白质印迹法探索对羟基苯甲酰基-3-烯丙基硫脲（BATU）对过表达HER-2的MCF-7细胞系的作用。结果表明，BATU对MCF-7/HER-2细胞系的细胞毒性作用（IC值为0.64 mM）高于对MCF-7细胞系的作用（IC值为1.47 mM）。此外，BATU对MCF-7和MCF-7/HER-2的细胞毒性作用高于作为先导化合物的烯丙基硫脲（IC值分别为5.22和3.17 mM）。结果还证实，BATU化合物能够通过增强HER-2表达和抑制核因子κB（NF-κB）激活，有效增强其对MCF-7/HER-2的细胞毒性。最重要的是，BATU化合物可有效增加HER-2表达并使NF-κB转录因子失活，从而导致对在细胞增殖中起重要作用的蛋白质表达的抑制。因此，BATU化合物有潜力被开发为HER-2阳性乳腺癌治疗的辅助药物。
