BCM-95® (CURCUGREEN®), 06 Aug 2021

Shusuke Toden, Yoshinaga Okugawa, Thomas Jascur, Dominik Wodarz, Natalia L. Komarova, Constanze Buhrmann, Mehdi Shakibaei, C. Richard Boland and Ajay Goel

doi:10.1093/carcin/bgv006

Introduction: Resistance to cytotoxic chemotherapy is a major cause of mortality in colorectal cancer (CRC) patients. Chemoresistance has been linked primarily to a subset of cancer cells undergoing epithelial–mesenchymal transition (EMT). Curcumin, a botanical with antitumorigenic properties, has been shown to enhance sensitivity of cancer cells to chemotherapeutic drugs, but the molecular mechanisms underlying this phenomenon remain unclear. Effects of curcumin and 5-fluorouracil (5FU) individually, and in combination, were examined in parental and 5FU resistant (5FUR) cell lines.

Method: We performed a series of growth proliferation and apoptosis assays in 2D and 3D cell cultures. Furthermore, we identified and analysed the expression pattern of a subset of putative EMT-suppressive microRNAs (miRNAs) and their downstream target genes regulated by curcumin. Chemosensitizing effects of curcumin were validated in a xenograft mouse model. Combined treatment with curcumin and 5FU enhanced cellular apoptosis and inhibited proliferation in both parental and 5FURcells, whereas 5FU alone was ineffective in 5FUR cells. A group of EMT-suppressive miRNAs were upregulated by curcumintreatment in 5FUR cells. Curcumin suppressed EMT in 5FUR cells by downregulating BMI1, SUZ12 and EZH2 transcripts, key mediators of cancer stemness-related polycomb repressive complex subunits.

Observation: Using a xenograft and mathematical models, we further demonstrated that curcumin sensitized 5FU to suppress tumor growth. We provide novel mechanistic evidence for curcumin-mediated sensitization to 5FU-related chemoresistance through suppression of EMT in 5FUR cells via upregulation of EMT-suppressive miRNAs.

Conclusion: This study highlights the potential therapeutic usefulness of curcumin as an adjunct in patients with chemoresistant advanced CRC.