ANTICANCER ACTIVITY OF NATURAL PRODUCTS IN HUMULUS LUPULUS(HOPS) IN HUMAN COLORECTAL CANCER CELLS.

Abstract

Cancer is a major public health problem and the second-leading cause of death in the world. Colorectal cancer (CRC) is the third most diagnosed cancer in the U.S. CRC is highly associated with daily diet and eating patterns. A plant-based diet rich in phytochemicals has been known to be protective against the initiation and progression of CRC occurrence. The hop plant, a key ingredient in beer, contains a diverse form of bioactive compounds that possess biological benefits in tumorigenesis. Xanthohumol (XN), the most abundant prenylated flavonoid, has been used over the years to treat a broad range of chronic diseases such as diabetes, obesity, and cancer. Several derivatives of XN, including isoxanthohumol (IXN), 8-prenylnaringenin (8-PN), and tetrahydroxanthohumol (TXN), possess similar and greater biological benefits compared to XN. While XN's anti-cancer properties are well known, the effects of these derivatives have not been evaluated in human CRC models. Our study aimed to test the cancer-suppressive activities of these derivatives and elucidate anti-cancer mechanisms using human adenocarcinoma CRC cells. The results indicate that four hop compounds (XN, IXN, 8-PN, and TXN) significantly suppressed the proliferation of different types of human CRC cell lines. We selected TXN and XN for further studies due to their more significant and promising anti-proliferative activity compared with other forms. Flow cytometry analysis indicated that TXN and XN led to significant induction of S-phase and G2/M-phase arrest. An apoptotic assay showed a huge induction of early and late apoptosis in cells treated with TXN and XN at doses of 12 µM and 18 µM. Western blot data indicate that TXN and XN induce the cleavage of PARP and increase the expression of CHOP, IRE1α, and ATF4, indicating activation of caspase-dependent apoptosis and ER stress. In addition, a dose-dependent increase in intracellular ROS was observed in cells treated with 12 and 18 µM of TXN and XN, affecting mitochondrial dysfunction. Taken together, our current study proposes an anti-cancer mechanism by TXN and XN through their action on the induction of ROS release and mitochondrial dysfunction, ER stress, and apoptosis in human CRC cells.