Center for Healthy Ageing and Wellness, Faculty of Health Sciences, University Kebangsaan Malaysia, Kuala Lumpur 50300, Malaysia.
Hepatobiliary/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Transplantation, Chinese Academy of Medical Sciences, Nanjing 210000, Jiangsu, China.
Aging (Albany NY). 2022 Nov 14;14(21):8688-8699. doi: 10.18632/aging.204380.
A complex of Zn and carnosine, called Zinc-L-carnosine (ZnC), enjoys a wide application as part of a Zn supplement therapeutic method as well as in treating peptic ulcers. However, researches fail to confirm the biological functions possessed by ZnC as well as tumor immune microenvironment in colorectal cancer (CRC).
Cell counting kit 8(CCK8), 5-ethynyl-2'-deoxyuridine (EdU), transwell and wound healing assays were conducted to study the influence of ZnC in the proliferating, invading and migrating processes of CRC cell lines (HCT116, LOVO) . The antitumor activity ZnC as well as its effects on tumor immune microenvironment were then assessed using CRC subcutaneous tumors in the C57BL/6 mouse model.
According to CCK8, EdU, transwell and wound healing assays, ZnC inhibited CRC cell lines in terms of proliferation, invasion and migration. ZnC could inhibit miR-570 for up-regulating PD-L1 expression. experiments showed that gavage (100 mg/kg, once every day) of ZnC inhibited the tumor growth of CRC, and the combination of ZnC and anti-PD1 therapy significantly improved the efficacy exhibited by anti-PD1 in treating CRC. In addition, mass cytometry results showed that immunosuppressive cells including regulatory T cells (tregs), bone marrow-derived suppressor cells (MDSC), and M2 macrophages decreased whereas CD8+ T cells elevated after adding ZnC.
The present study reveals that ZnC slows the progression of CRC by inhibiting CRC cells in terms of proliferation, invasion and migration, meanwhile up-regulating PD-L1 expression via inhibiting miR-570. The ZnC-anti-PD1 co-treatment assists in synergically increasing anti-tumor efficacy in CRC therapy.
锌和肌肽的复合物，称为锌-L-肌肽（ZnC），作为锌补充治疗方法的一部分以及治疗消化性溃疡具有广泛的应用。然而，研究未能证实 ZnC 以及结直肠癌（CRC）肿瘤免疫微环境所具有的生物学功能。
使用细胞计数试剂盒 8（CCK8）、5-乙炔基-2'-脱氧尿苷（EdU）、Transwell 和划痕愈合实验研究 ZnC 对 CRC 细胞系（HCT116、LOVO）增殖、侵袭和迁移过程的影响。然后使用 C57BL/6 小鼠 CRC 皮下肿瘤模型评估 ZnC 的抗肿瘤活性及其对肿瘤免疫微环境的影响。
根据 CCK8、EdU、Transwell 和划痕愈合实验，ZnC 抑制 CRC 细胞系的增殖、侵袭和迁移。ZnC 可以抑制 miR-570 上调 PD-L1 的表达。实验表明，灌胃（100mg/kg，每天一次）ZnC 抑制 CRC 肿瘤生长，ZnC 与抗 PD1 治疗联合显著提高了抗 PD1 治疗 CRC 的疗效。此外，质谱流式细胞术结果表明，添加 ZnC 后，包括调节性 T 细胞（Tregs）、骨髓来源的抑制细胞（MDSC）和 M2 巨噬细胞在内的免疫抑制细胞减少，而 CD8+T 细胞增加。
本研究表明，ZnC 通过抑制 CRC 细胞的增殖、侵袭和迁移来减缓 CRC 的进展，同时通过抑制 miR-570 上调 PD-L1 表达。ZnC-抗 PD1 联合治疗有助于协同提高 CRC 治疗的抗肿瘤疗效。
