4.6 Article

Anti-Cancer Effects of Zotarolimus Combined with 5-Fluorouracil Treatment in HCT-116 Colorectal Cancer-Bearing BALB/c Nude Mice

Journal

MOLECULES
Volume 26, Issue 15, Pages -

Publisher

MDPI
DOI: 10.3390/molecules26154683

Keywords

5-fluorouracil; colorectal adenocarcinoma; inflammation; metastasis; zotarolimus

Funding

  1. Chang Bing Show Chwan Memorial Hospital (Taiwan) [BRD109043]

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The study demonstrates that Zotarolimus alone and in combination with 5-FU can inhibit the growth and metastasis of colorectal adenocarcinoma, as well as increase the sensitivity of tumor cells to chemotherapy. Additionally, the combination therapy shows a synergistic effect in retarding tumor growth and enhancing tumor inhibition. These findings suggest that Zotarolimus may serve as a potential anti-tumor agent in the treatment of human colon adenocarcinoma, with potential for further therapeutic development.
Zotarolimus is a semi-synthetic derivative of rapamycin and an inhibitor of mammalian target of rapamycin (mTOR) signaling. Currently, zotarolimus is used to prolong the survival time of organ grafts, but it is also a novel immunosuppressive agent with potent anti-proliferative activity. Here, we examine the anti-tumor effect of zotarolimus, alone and in combination with 5-fluorouracil, on HCT-116 colorectal adenocarcinoma cells implanted in BALB/c nude mice. Compared with the control mice, mice treated with zotarolimus or zotarolimus combined with 5-FU showed retarded tumor growth; increased tumor apoptosis through the enhanced expression of cleaved caspase 3 and extracellular signal-regulated kinase (ERK) phosphorylation; reduced inflammation-related factors such as IL-1 beta, TNF-alpha, and cyclooxygenase-2 (COX-2) protein; and inhibited metastasis-related factors such as CD44, epidermal growth factor receptor (EGFR), transforming growth factor beta (TGF-beta), and vascular endothelial growth factor (VEGF). Notably, mice treated with a combination of zotarolimus and 5-FU showed significantly retarded tumor growth, reduced tumor size, and increased tumor inhibition compared with mice treated with 5-FU or zotarolimus alone, indicating a strong synergistic effect. This in vivo study confirms that zotarolimus or zotarolimus combined with 5-FU can be used to retard colorectal adenocarcinoma growth and inhibit tumorigenesis. Our results suggest that zotarolimus may increase the chemo-sensitization of tumor cells. Therefore, zotarolimus alone and zotarolimus combined with 5-FU may be potential anti-tumor agents in the treatment of human colon adenocarcinoma. Future research on zotarolimus may lead to the development of new therapeutic strategies.

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