![]() ![]() In this regard, OPCs and berberine (BBR), have recently been actively studied for their anti-tumorigenic properties in CRC and other human cancers ( 16, 27, 30– 33). While this list of compounds is quite large, including some of the research undertaken by our research team on curcumin ( 17– 24), Boswellic acids ( 19, 25, 26), andrographis extract ( 27– 29) and oligomeric proanthocyanidins (OPCs) ( 27, 30– 33). In recent years, accumulating body of data have shown that active principles within various naturally-occurring dietary botanicals offer a time-tested safety and anti-cancer efficacy ( 8– 16). In other words, the development of chemoresistance presents a major challenge in the management of CRC, and an optimal combination of various therapeutic modalities is a growing area of research to thwart this clinical challenge. Accordingly, a growing school of thought is that instead of the use of single agents, combination therapies by employing more than one simultaneous drugs that can modulate multiple pathways might enhance the overall therapeutic efficacy as it mitigates the opportunity to develop chemoresistance to a single therapy. The acquisition of chemoresistance is primarily due to compensatory overload or emergence of mutations in chemotherapy-induced targeted pathways in a clone of cancer cells ( 4, 5), which renders these patients unresponsive to subsequent drugs ( 6, 7). ![]() Although 5-fluorouracil based therapy is the standard of care chemotherapeutic intervention in patients with CRC ( 2, 3), a large majority of CRC patients tend to acquire resistance and become chemoresistant to such treatments. Systemic chemotherapy remains the backbone and one of the best therapeutic options for CRC patients with distant metastasis or recurrence. Finally, we successfully validated these findings in patient-derived CRC tumor organoids.Ĭonclusions: Collectively, we for the first time demonstrate that a combined treatment of BBR and OPCs synergistically promote the anti-tumorigenic properties in CRC possibly through the regulation of cellular apoptosis and oncogene MYB in the PI3K-Akt signaling pathway.Ĭolorectal cancer (CRC) is one of the most common malignancies worldwide, and currently ranks fourth in disease incidence and the second leading cause of cancer-related deaths, with an estimated 104,270 new cases and 52,980 deaths in 2021 ( 1). Transcriptomic profiling identified oncogene MYB in PI3K-AKT signaling pathway might be critically involved in the anti-tumorigenic properties of the combined treatment. Furthermore, the combination treatment potentiated the cellular apoptosis in an Annexin V binding assay. The synergism between BBR and OPCs were investigated in terms of their anti-tumorigenic effect on cell viability, clonogenicity, migration, and invasion. Results: We first demonstrated that OPCs facilitated enhanced cellular uptake of BBR in CRC cells by measuring the fluorescent signal of BBR in cells treated individually or their combination. ![]() In addition, by performing whole genome transcriptomic profiling we identified the key targeted genes and pathways regulated by the combined treatment. Methods: We performed a series of cell culture studies, followed by their interrogation in patient-derived organoids to evaluate the synergistic effect of BBR and OPCs against CRC. Accordingly, herein, we hypothesized that berberine (BBR) and oligomeric proanthocyanidins (OPCs) might regulate synergistically multiple oncogenic pathways to exert a superior anti-cancer activity in CRC. 4City of Hope Comprehensive Cancer Center, Duarte, CA, United Statesīackground: Naturally occurring dietary botanicals offer time-tested safety and anti-cancer efficacy, and a combination of certain compounds has shown to overcome the elusive chemotherapeutic resistance, which is of great significance for improving the mortality of patients with colorectal cancer (CRC).3Translational Bioinformatics, Center for Informatics, City of Hope, Duarte, CA, United States.2Department of Gastrointestinal Surgery, Tokyo Medical and Dental University, Tokyo, Japan.1Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research Institute of City of Hope, Biomedical Research Center, Monrovia, CA, United States.Keisuke Okuno 1,2†, Rachana Garg 1†, Yate-Ching Yuan 3, Masanori Tokunaga 2, Yusuke Kinugasa 2 and Ajay Goel 1,4* ![]()
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