Ginkgo Biflavones Cause p53 Wild-Type Dependent Cell Death in a Transcription-Independent Manner of p53

Abstract

Ginkgo biloba, as a medicinal plant in both traditional and western medicine, emerged as a potential therapeutic agent for the management of a variety of diseases, but ginkgo biflavones (bilobetin, isoginkgetin, and ginkgetin) application in cancer therapy and underlying mechanisms of action remained elusive. In the present study, we identified ginkgo biflavones as potential p53 activators that could enhance p53 protein expression level by inhibiting MDM2 protein expression. At the same time, they induced cell death independent of p53 transcriptional activity. Moreover, ginkgetin was a standout among ginkgo biflavones that reduced the survival of HCT-116 cells by induction of apoptosis and G2/M phase arrest. Furthermore, ginkgo biflavones induced ROS generation significantly, which resulted in ferroptosis. Finally, we provide evidence that ginkgetin strengthened the antitumor effect of fluorouracil (5-FU) in the HCT-116 colon cancer xenograft model. To sum up, ginkgo biflavones represent a new class of p53 activator that depends on the p53 wild-type status and warrants further exploration as potential anticancer agents.

Comparative Expression Analysis of TP53 Tumor Suppressor and MDM2 Oncogene in Colorectal Adenocarcinoma

“…Concerning new agents with anti-tumor activity that target TP53 expression, aurora-A -a key G2/M phase regulator kinaseseems to inhibit the TP53 signaling, negatively affecting the response to oxaliplatin-based treatment in CRC patients (35). Similarly, medicinal plants such as ginkgo biflavones could be used as wild type normal p53 enhancers and also MDM2 inhibitors in CRC patients with specific molecular substrates (36). Additionally, a plant substance derived from Ophiopogon japonicus, named cycloastragenol, demonstrates antioxidant, anti-inflammatory, and anti-cancer effects by inducing apoptosis through p53 and c-MYC regulation (37,38).…”