Institute of Translational Medicine, Nanchang University, Nanchang, 330031, Jiangxi, People's Republic of China.
Appl Microbiol Biotechnol. 2019 Jan;103(2):929-939. doi: 10.1007/s00253-018-9481-8. Epub 2018 Nov 17.
The strong human immunity and the associated toxicities of attenuated Salmonella severely limit the clinical use of Salmonella in tumour suppression. In the present study, we constructed an engineered VNP20009-DNase I strain and evaluated the synergistic effects of triptolide (TPL) and VNP20009-DNase I against melanoma in mice. Our results indicated that TPL could significantly inhibit the cell growth and cell migration and significantly enhanced the apoptosis rate of B16F10 cells in vitro. The in vivo results indicated that TPL markedly improved tumour colonisation of VNP20009-DNase I and led to a larger necrotic area in the melanoma. Moreover, the combination therapy significantly suppressed tumour volume and prolonged the life span of mice (P < 0.05) by upregulating the expression of Bcl-2/Bax and Caspase-3 and by downregulating the TLR4/NF-κB signalling, the expression of p-AKT/AKT and the production of proinflammatory factors. Therefore, the sound synergistic anti-tumour effects of TPL and VNP20009-DNase I indicate that the unconventional application of TPL and biological agents, approved by the China Food and Drug Administration (CFDA), can result in improved anti-cancer therapeutic outcomes.
减毒沙门氏菌具有强大的人体免疫力和相关毒性，严重限制了其在肿瘤抑制中的临床应用。在本研究中，我们构建了一种工程化的 VNP20009-DNase I 菌株，并评估了雷公藤红素（TPL）和 VNP20009-DNase I 联合治疗对小鼠黑色素瘤的协同作用。我们的结果表明，TPL 可显著抑制 B16F10 细胞的体外生长和迁移，并显著提高其凋亡率。体内结果表明，TPL 明显增强了 VNP20009-DNase I 的肿瘤定植，并导致黑色素瘤的坏死面积增大。此外，联合治疗通过上调 Bcl-2/Bax 和 Caspase-3 的表达，下调 TLR4/NF-κB 信号通路、p-AKT/AKT 的表达和促炎因子的产生，显著抑制肿瘤体积并延长小鼠的生存期（P<0.05）。因此，TPL 和 VNP20009-DNase I 的协同抗肿瘤作用表明，中国食品药品监督管理局（CFDA）批准的 TPL 和生物制剂的非常规应用可能会带来更好的抗癌治疗效果。
