Abstract 1409: Synergistic antitumorigenic activity of Berberine and oligomeric proanthocyanidins through regulation of PI3-AKt signaling pathway in colorectal cancer
Authors: Okuno Keisuke , Garg Rachana , Tokunaga Masanori , Kinugasa Yusuke , Goel Ajay 
Published: June 2022

Abstract
Background: The development of chemo-resistance against conventional chemotherapeutic drugs presents a major clinical challenge in the management of patients with colorectal cancer (CRC). Accumulating body of data in recent years have shown that active principles within various naturally-occurring dietary botanicals not only offer time-tested safety and anti-cancer efficacy, but a combination of certain compounds can overcome the elusive chemotherapeutic resistance in cancer patients. In this regard, data in recent years have shown that berberine (BBR) and oligomeric proanthocyanidins (OPCs) from the grape-seed extract have significant anti-tumorigenic properties in CRC, and a more recent study reported existence of synergism between these two natural medicines in patients with type 2 diabetes. Accordingly, herein we hypothesized that BBR and OPCs might regulate synergistically multiple oncogenic pathways to exert a superior anti-cancer activity in CRC.
Methods: We performed a series of experiment in various cell lines, followed by their interrogation in patient-derived organoids (PDOs) to evaluate the synergistic anti-tumorigenic effects of BBR and OPCs in CRC cells. In addition, using genome-wide RNA sequencing analyses, we identified specific functional determinants and key targeted genes and pathways regulated by the combined therapeutic approach with these compounds.
Results: To confirm our hypothesis, we first evaluated the potential of OPCs to increase the cellular uptake of BBR in CRC cells, by measuring the fluorescent signal of BBR in multiple cell lines treated individually or their combination. The synergistic anti-tumorigenic effects of BBR and OPCs were observed in various functional assays including reduced cell viability, colony formation potential, wound healing, and invasion assays. Furthermore, the combined treatment with these compounds potentiated the cell apoptosis in an Annexin V binding assay. It was intriguing to note that we were able to successfully validate all cell culture findings in the PDO models from multiple CRC patients. Whole genome transcriptomic profiling identified oncogene MYB, including in PI3-AKT signaling pathway as one of the key pathways that was critically involved in mediating the anti-tumorigenic properties of this combined therapy.
Conclusions: We for the first time demonstrate that a combined treatment with BBR and OPCs synergistically promotes the anti-tumorigenic properties in CRC. This synergism was potentially due to enhanced apoptosis and the regulation of oncogenic MYB in the PI3-Akt signaling pathway; hence, offering an attractive potential for the use of these two compounds as adjuvant treatment options in patients with CRC.
Citation Format: Keisuke Okuno, Rachana Garg, Masanori Tokunaga, Yusuke Kinugasa, Ajay Goel. Synergistic antitumorigenic activity of Berberine and oligomeric proanthocyanidins through regulation of PI3-AKt signaling pathway in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1409.