Tubeimoside-I sensitizes colorectal cancer cells to chemotherapy by inducing ROS-mediated impaired autophagolysosomes accumulation

Background: Tubeimoside-I (TBM), a plant-derived bioactive compound, shows antitumor activity in different tumors and can enhance the efficacy of chemotherapeutic agents. However, the detail mechanism underlying remains to be elucidated.

Methods: The cytotoxic potential of TBM towards CRC cells was examined by CCK8 assay, colony formation, LDH release assay, flow cytometry method and Western blots. The ROS levels, Autophagy, Apoptosis, chemosensitivity to 5-FU or DOX, etc. were determined between control and TBM-treated CRC cells.

Results: In this study, we found that TBM could inhibit proliferation and induce Apoptosis in colorectal Cancer (CRC) cells. Intriguingly, TBM treatment could either promote Autophagy initiation by ROS-induced AMPK activation, or block Autophagy flux through inhibiting lysosomal hydrolytic Enzymes, which leaded to massive impaired autophagylysosomes accumulation. Administration of Autophagy initiation inhibitor (3-MA or selective ablation of Autophagy related proteins) relieves TBM-induced CRC suppression, while combination use of Autophagy flux inhibitor chloroquine (CQ) slightly augments TBM-induced cell death, suggesting that impaired autophagylysosomes accumulation contributes to TBM-induced growth inhibition in CRC cells. Notably, as an Autophagy flux inhibitor, TBM works synergistically with 5-fluorouracil (5-FU) or doxorubicin (DOX) in CRC suppression.

Conclusion: Together, our study provides new insights regarding the anti-tumor activity of TBM against CRC, and established potential applications of TBM for CRC combination therapies in clinic.