Roiz Levava, Smirnoff Patricia, Lewin Iris, Shoseyov Oded, Schwartz Betty
T2 BIOTECH Ltd, Weizmann Science Park, Ness Ziona, ISRAEL.
The Robert H. Smith Institute of Plant Science and Genetics in Agriculture and School of Nutritional Sciences Institute of Biochemistry, Food Science and Nutrition, The Robert H. Smith Faculty of Agriculture, Food and Environment, The Hebrew University of Jerusalem, Rehovot, ISRAEL.
Oncoscience. 2016 Mar 4;3(2):71-84. doi: 10.18632/oncoscience.295. eCollection 2016.
The roles of cell motility and angiogenetic processes in metastatic spread and tumor aggressiveness are well established and must be simultaneously targeted to maximize antitumor drug potency. This work evaluated the antitumorigenic capacities of human recombinant RNASET2 (hrRNASET2), a homologue of the Aspergillus niger T2RNase ACTIBIND, which has been shown to display both antitumorigenic and antiangiogenic activities. hrRNASET2 disrupted intracellular actin filament and actin-rich extracellular extrusion organization in both CT29 colon cancer and A375SM melanoma cells and induced a significant dose-dependent inhibition of A375SM cell migration. hrRNASET2 also induced full arrest of angiogenin-induced tube formation and brought to a three-fold lower relative HT29 colorectal and A375SM melanoma tumor volume, when compared to Avastin-treated animals. In parallel, mean blood vessel counts were 36.9% lower in hrRNASET2-vs. Avastin-treated mice and survival rates of hrRNASET2-treated mice were 50% at 73 days post-treatment, while the median survival time for untreated animals was 22 days. Moreover, a 60-day hrRNASET2 treatment period reduced mean A375SM lung metastasis foci counts by three-fold when compared to untreated animals. Taken together, the combined antiangiogenic and antitumorigenic capacities of hrRNASET2, seemingly arising from its direct interaction with intercellular and extracellular matrices, render it an attractive anticancer therapy candidate.
细胞运动性和血管生成过程在转移扩散和肿瘤侵袭性中的作用已得到充分证实，必须同时针对这些方面以最大化抗肿瘤药物的效力。这项研究评估了人重组RNASET2（hrRNASET2）的抗肿瘤能力，它是黑曲霉T2核糖核酸酶ACTIBIND的同源物，已被证明具有抗肿瘤和抗血管生成活性。hrRNASET2破坏了CT29结肠癌细胞和A375SM黑色素瘤细胞内的肌动蛋白丝和富含肌动蛋白的细胞外挤压结构，并诱导A375SM细胞迁移受到显著的剂量依赖性抑制。与接受阿瓦斯汀治疗的动物相比，hrRNASET2还诱导血管生成素诱导的管形成完全停滞，并使HT29结肠直肠癌和A375SM黑色素瘤的相对肿瘤体积降低了三倍。同时，与接受阿瓦斯汀治疗的小鼠相比，hrRNASET2治疗的小鼠平均血管计数降低了36.9%，hrRNASET2治疗的小鼠在治疗后73天的存活率为50%，而未治疗动物的中位生存时间为22天。此外，与未治疗的动物相比，60天的hrRNASET2治疗期使A375SM肺转移灶的平均计数减少了三倍。综上所述，hrRNASET2具有联合抗血管生成和抗肿瘤能力，这似乎源于其与细胞内和细胞外基质的直接相互作用，使其成为一个有吸引力的抗癌治疗候选物。
