Dahabiyeh Lina A, Hudaib Farah, Hourani Wafa, Darwish Wesam, Abu-Irmaileh Bashaer, Deb Pran Kishore, Venugopala Katharigatta N, Mohanlall Viresh, Chandrashekharappa Sandeep, Abu-Dahab Rana, Semreen Mohammad H, Bustanji Yasser
Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan.
Depatment of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, the Hashemite University, Zarqa, 13133, Jordan.
Eur J Pharm Sci. 2023 Mar 1;182:106378. doi: 10.1016/j.ejps.2023.106378. Epub 2023 Jan 11.
Colorectal cancer (CRC) is the most frequent form of gastrointestinal cancer and one of the major causes of human mortality worldwide. Many of the current CRC therapies have limitations due to multidrug resistance and/or severe side effects. Quinazoline derivatives are promising lead compounds with a wide range of pharmacological actions. In this study, the effect of seven synthesized 2,3-dihydroquinazolin-4(1H)-one analogues as potential anticancer agents against two CRC cell lines (HCT116 and SW480) was investigated using cell viability proliferation, migration, adhesion and invasion assays. A liquid chromatography-mass spectrometry (LC-MS/MS) metabolomics approach was used to identify the underlying biochemical pathways disturbed in treated-HCT116 cells. Cell viability proliferation assay revealed that four compounds (C2, C3, C5, and C7) had IC < 10 µM with C5 displaying the most potent cytotoxic effect (IC 1.4 and 0.3 µM against HCT116 and SW480, respectively). Additionally, the compounds showed suppression of wound closure after 72 h, and both C2 and C5 significantly decreased the number of adherent cells and suppressed HCT116 cells invasion. Metabolomics study revealed that C5 induced significant perturbations in the level of several metabolites including spermine, polyamines, glutamine, creatine and carnitine, and altered biochemical processes essential for cell proliferation and progression such as amino acids biosynthesis and metabolism, redox homeostasis, energy related processes (e.g., fatty acid oxidation, second Warburg like effect) and one-carbon metabolism. Our findings indicate that 2,3-dihydroquinazolin-4(1H)-one analogues, particularly C5, have promising anticancer properties, and shed light on the role of metabolomics in identifying new therapeutic targets and providing better understanding of the pathways altered in treated cancer cells.
结直肠癌（CRC）是胃肠道癌症中最常见的类型，也是全球人类死亡的主要原因之一。由于多药耐药性和/或严重的副作用，目前许多CRC治疗方法都存在局限性。喹唑啉衍生物是具有广泛药理作用的有前景的先导化合物。在本研究中，使用细胞活力增殖、迁移、黏附和侵袭试验，研究了七种合成的2,3-二氢喹唑啉-4(1H)-酮类似物作为潜在抗癌剂对两种CRC细胞系（HCT116和SW480）的作用。采用液相色谱-质谱联用（LC-MS/MS）代谢组学方法来鉴定在处理过的HCT116细胞中受到干扰的潜在生化途径。细胞活力增殖试验表明，四种化合物（C2、C3、C5和C7）的IC<10μM，其中C5表现出最有效的细胞毒性作用（对HCT116和SW480的IC分别为1.4和0.3μM）。此外，这些化合物在72小时后显示出对伤口愈合的抑制作用，并且C2和C5均显著减少黏附细胞的数量并抑制HCT116细胞的侵袭。代谢组学研究表明，C5诱导了几种代谢物水平的显著扰动，包括精胺、多胺、谷氨酰胺、肌酸和肉碱，并改变了细胞增殖和进展所必需的生化过程，如氨基酸生物合成和代谢、氧化还原稳态、能量相关过程（如脂肪酸氧化、第二种类似瓦伯格效应）和一碳代谢。我们的研究结果表明，2,3-二氢喹唑啉-4(1H)-酮类似物，特别是C5，具有有前景的抗癌特性，并揭示了代谢组学在识别新的治疗靶点以及更好地理解处理过的癌细胞中改变的途径方面的作用。
