PMID- 34361836 OWN - NLM STAT- MEDLINE DCOM- 20210910 LR - 20210910 IS - 1420-3049 (Electronic) IS - 1420-3049 (Linking) VI - 26 IP - 15 DP - 2021 Aug 2 TI - Anti-Cancer Effects of Zotarolimus Combined with 5-Fluorouracil Treatment in HCT-116 Colorectal Cancer-Bearing BALB/c Nude Mice. LID - 10.3390/molecules26154683 [doi] LID - 4683 AB - 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-1beta, 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. FAU - Chang, Geng-Ruei AU - Chang GR AUID- ORCID: 0000-0003-0577-3339 AD - Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan. FAU - Kuo, Chan-Yen AU - Kuo CY AUID- ORCID: 0000-0002-5702-5730 AD - Department of Research, Taipei Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, 289 Jianguo Road, Xindian District, New Taipei 231405, Taiwan. AD - Department of Nursing, Cardinal Tien College of Healthcare and Management, 112 Minzu Road, Sindian District, New Taipei 231038, Taiwan. FAU - Tsai, Ming-Yang AU - Tsai MY AD - Animal Industry Division, Livestock Research Institute, Council of Agriculture, Executive Yuan, 112 Muchang, Xinhua Dist, Tainan 71246, Taiwan. AD - Graduate Institute of Bioresources, National Pingtung University of Science and Technology, 1 Shuefu Road, Neipu, Pingtung 91201, Taiwan. FAU - Lin, Wei-Li AU - Lin WL AD - Bachelor Degree Program in Animal Healthcare, Hungkuang University, 6 Section, 1018 Taiwan Boulevard, Shalu District, Taichung 433304, Taiwan. AD - General Education Center, Chaoyang University of Technology, 168 Jifeng Eastern Road, Taichung 413310, Taiwan. FAU - Lin, Tzu-Chun AU - Lin TC AD - Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan. FAU - Liao, Huei-Jyuan AU - Liao HJ AD - Department of Veterinary Medicine, National Chiayi University, 580 Xinmin Road, Chiayi 600023, Taiwan. FAU - Chen, Chung-Hung AU - Chen CH AD - Division of Gastroenterology, Department of Internal Medicine, Chang Bing Show Chwan Memorial Hospital, 6 Lugong Road, Lukang Township, Changhua 505029, Taiwan. FAU - Wang, Yu-Chen AU - Wang YC AD - Division of Cardiology, Asia University Hospital, 222 Fuxin Road, Wufeng District, Taichung 413505, Taiwan. AD - Department of Medical Laboratory Science and Biotechnology, Asia University, 500 Lioufeng Road, Wufeng District, Taichung 413305, Taiwan. AD - Division of Cardiovascular Medicine, China Medical University Hospital, 2 Yude Road, North District, Taichung 404332, Taiwan. AD - College of Medicine, China Medical University, 91 Hsueh-Shih Road, North District, Taichung 404333, Taiwan. LA - eng PT - Journal Article DEP - 20210802 PL - Switzerland TA - Molecules JT - Molecules (Basel, Switzerland) JID - 100964009 RN - H4GXR80IZE (zotarolimus) RN - U3P01618RT (Fluorouracil) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Antineoplastic Combined Chemotherapy Protocols/*pharmacology MH - Apoptosis MH - Cell Proliferation MH - Colorectal Neoplasms/*drug therapy/metabolism/pathology MH - Fluorouracil/administration & dosage MH - Humans MH - Male MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Sirolimus/administration & dosage/analogs & derivatives MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays PMC - PMC8347948 OTO - NOTNLM OT - 5-fluorouracil OT - colorectal adenocarcinoma OT - inflammation OT - metastasis OT - zotarolimus COIS- The authors declare no conflict of interest. EDAT- 2021/08/08 06:00 MHDA- 2021/09/11 06:00 PMCR- 2021/08/02 CRDT- 2021/08/07 01:11 PHST- 2021/07/12 00:00 [received] PHST- 2021/07/29 00:00 [revised] PHST- 2021/07/29 00:00 [accepted] PHST- 2021/08/07 01:11 [entrez] PHST- 2021/08/08 06:00 [pubmed] PHST- 2021/09/11 06:00 [medline] PHST- 2021/08/02 00:00 [pmc-release] AID - molecules26154683 [pii] AID - molecules-26-04683 [pii] AID - 10.3390/molecules26154683 [doi] PST - epublish SO - Molecules. 2021 Aug 2;26(15):4683. doi: 10.3390/molecules26154683.