5-fluorouracil (5-FU) and oxaliplatin (OxaPt) are the main chemotherapeutics for colorectal cancer (CRC). Chemotherapy response rates for advanced CRC remain low, primarily due to intrinsic or acquired chemoresistance. The importance of Notch and Wnt signaling for carcinogenesis of CRC as well as crosstalk of Notch and Wnt signaling with many oncogenic signaling pathways suggest that Notch and Wnt pathways could be responsible for chemoresistance. In this study, we compared changes in Notch and Wnt signaling after 5-FU and OxaPt treatment in CRC cells HCT116 and its chemoresistant sublines HCT116/FU and HCT116/OXA. The levels of Notch1 receptor intracellular domain NICD1 and non-phosphorylated β-catenin, the reporters of Notch and Wnt signaling, were upregulated in untreated chemoresistant HCT116/FU and HCT116/OXA cells. Our data suggest that Notch inhibitor RO4929097 (RO) and Wnt inhibitor XAV939 (XAV) enhance the survival potential of OxaPt-treated cells. The protein level of Notch target gene HES1 was significantly upregulated in chemoresistant HCT116/FU and HCT116/OXA cells, compared to HCT116. HES1 silencing increased viability of HCT116 and its chemoresistant sublines after 5-FU or OxaPt treatment. The results of HES1 downregulation coincide with RO and XAV effects on cell viability of OxaPt-treated cells.

The primary or acquired cancer chemoresistance is a major problem in the treatment of cancer patients. It could be overcome by non-overlapping treatment regimens such as photodynamic therapy (PDT). PDT is based on the oxidation of cellular components which occurs when a light-excited photosensitizer generates reactive oxygen species (ROS). In this study the effect of mTHPC mediated PDT (mTHPC-PDT) on 5-FU resistant colorectal cancer (CRC) cells HCT116 was investigated. The results show that mTHPC-PDT overcomes 5-FU resistance and is effective against chemoresistant colorectal carcinoma cells.

Macroautophagy (hereafter autophagy) is one of the adaptive pathways that contribute to cancer cell chemoresistance. Despite the fact that autophagy can both promote and inhibit cell death, there is mounting evidence that in the context of anticancer treatment, it predominantly functions as a cell survival mechanism. Therefore, silencing of key autophagy genes emerges as a potent strategy to reduce chemoresistance. Though the importance of autophagy in chemoresistance is established, the changes in autophagy in the case of acquired chemoresistance are poorly understood. In this study, we aimed to determine the changes of autophagy in the cellular model of acquired chemoresistance of colorectal cancer cell lines HCT116 and SW620, induced by 5‐fluorouracil (5‐FU) or oxaliplatin (OxaPt) treatment, and determine the susceptible factors for autophagy inhibition. Our results demonstrate that in the context of autophagy, 5‐FU and OxaPt have different effects on HCT116 and SW620 cell lines and their chemoresistant sublines. 5‐FU inhibits autophagic flux, while changes in the flux after OxaPt treatment are cell type‐ and dose‐dependent, inducing autophagy reduction or increase. The chemoresistant subline of HCT116 cells derived by OxaPt differs from the subline derived by 5‐FU treatment – it responds to OxaPt by upregulating ATG7 protein level and autophagic flux, in contrast to downregulation in cells derived by 5‐FU. Moreover, 5‐FU and OxaPt treatments significantly modulate protein levels of core‐autophagy proteins ATG7 and ATG12. The potential effects of 5‐FU and OxaPt on ATG protein levels should be taken into account to reduce chemoresistance by applying small interferingRNAs, targeting ATG proteins.