Abstract
Curcumin (CUR) has been reported to enhance the chemotherapeutic efficacy of oxaliplatin (OXA) in colorectal cancer (CRC) and inhibit OXA-induced side effects. However, shortcomings, including poor solubility and sensitivity to metabolic transformation, have greatly undermined its value in clinical applications. In this study, the potential of CUR-encapsulated hyaluronic acid (HA)–zein composite nanoparticles (HZ-CUR) as an oral adjuvant for OXA-based chemotherapy was assessed in representative CRC models in mice. Cell viability and colony formation assays in three human CRC cell lines showed that HZ-CUR had a stronger anti-CRC effect than free CUR when given alone and a stronger synergistic effect when combined with OXA, especially in HCT116 and HT29 cell lines. Western blotting, cellular uptake, and RNA interference assays revealed that OXA-induced upregulation of CD44 likely contributed to enhanced cellular uptake of HZ-CUR and thus the enhanced anticancer effect. The significantly improved anti-CRC effects and potential underlying mechanism of HZ-CUR alone and in combination with OXA were further validated in a subcutaneous xenograft and an in situ CRC model in mice. These findings support that HZ-CUR may be an effective oral adjuvant for OXA-based CRC chemotherapy that would not only improve its efficacy but also help reduce the associated side effects.
Highlights
OXA caused upregulation in the expression of CD44 in HCT116 and HT29 cells in a time-dependent manner, whereas CD44 expression was undetectable in HCT8 cells with or without treatment with OXA, which was in large agreement with the data of a previous study [29]. These results indicated that the OXA-induced upregulated expression of CD44 likely contributed to the increased cellular uptake of HA–zein composite nanoparticles (HZ)-CUR in HCT116 and HT29 cells
The results showed that CD44 knockdown significantly (p < 0.05) attenuated the OXA-induced increased intracellular CUR content in HCT116 and HT29 cells, suggesting that the increase was largely mediated through OXA-induced upregulation of CD44 expression and that CD44 receptor-mediated endocytosis is an important internalization mechanism of the colorectal cancer (CRC) cells for cellular uptake of the HZ-CUR
The present study has demonstrated that HZ-CUR was more effective than CUR
Summary
Curcumin (CUR) has been reported to enhance the chemotherapeutic efficacy of oxaliplatin (OXA) in colorectal cancer (CRC) and inhibit OXA-induced side effects. The significantly improved anti-CRC effects and potential underlying mechanism of HZ-CUR alone and in combination with OXA were further validated in a subcutaneous xenograft and an in situ CRC model in mice. These findings support that HZ-CUR may be an effective oral adjuvant for OXA-based CRC chemotherapy that would improve its efficacy and help reduce the associated side effects.
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