Abstract
Warburgia ugandensis Sprague (W. ugandensis), widely distributed in Africa, is a traditional medicinal plant used for the treatment of various diseases including cancer. We intended to evaluate the anticolorectal cancer (CRC) activities of the crude extract from W. ugandensis (WUD) and reveal the underlying molecular mechanisms of its action. We found that WUD inhibited the proliferation of HT-29 and HCT116 cells in a time- and dose-dependent manner and induced intracellular ROS generation. The inhibitory effect of WUD on the proliferation of HT-29 and HCT116 cells could be attenuated by NAC (a ROS scavenger) in a dose-dependent manner. WUD induced G0/G1 phase arrest, down-regulated the protein expression of Cyclin D1 via ROS accumulation in HT-29 cells. In search of the molecular mechanism involved in WUD-induced Cyclin D1 down-regulation, it was found that WUD can suppress PI3K/Akt/GSK3β signaling pathway in HT-29 cells. Next, it was found that WUD also activated apoptosis, poly-ADP ribose polymerase 1 (PARP1) cleavage and down-regulated pro-caspase 3 in HT-29 and HCT116 cells. Besides, WUD decreased the growth of colon tumors in vivo in the xenograft mouse model. We demonstrated for the first time that ROS and their modulation in the corresponding intracellular signaling could play a significant role in the potential activity of WUD against CRC cells.
Highlights
Cancer is the second leading cause of death worldwide, resulting in an estimated 10.0 million deaths in 2020
These results indicated that W. ugandensis (WUD) could depress the cell viability of colorectal cancer (CRC) cells in a dose- and timedependent manner
We found that the intracellular Reactive oxygen species (ROS) production was remarkably increased in WUD-treated HT-29 cells and HCT116 cells in a concentration-dependent manner (Figures 2(a), 2(b), 2(d), and 2(e))
Summary
Cancer is the second leading cause of death worldwide, resulting in an estimated 10.0 million deaths in 2020. The most commonly diagnosed cancers are breast cancer, lung cancer, colorectal cancer (CRC), prostate cancer, and stomach cancer. CRC ranks third in morbidity (10.0% of the total cases) and second in mortality (9.4% of the total cancer deaths) [1]. It is noteworthy that the CRC incidence of younger individuals is increasing [2]. Current standard treatments for CRC mainly include surgery, chemotherapy, radiotherapy, immunotherapy, and targeted therapy. The facts above make chemotherapy the primary choice, which is limited by side effects, undesirable toxicity, and drug resistance. It is urgent to develop more effective but lowtoxicity anti-CRC drugs
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