Growth Suppression of Cancer Spheroids With Mutated KRAS by Low-toxicity Compounds from Natural Products
Growth Suppression of Cancer Spheroids With Mutated KRAS by Low-toxicity Compounds from Natural Products
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DOI：
10.21873/anticanres.15207
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发表时间：
2021-08-01
影响因子：
2
通讯作者：
Tsunoda, Toshiyuki
中科院分区：
文献类型：
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作者：
Hashimoto, Sayuri;Nagai, Masayoshi;Tsunoda, Toshiyuki
背景/目的：在选择性抑制具有突变 (mt) KRAS 的癌症球体生长的天然产物化合物中，选择了 NP910 并探索了其衍生物。材料和方法：在用 18 种 NP910 衍生物处理的三维漂浮 (3DF) 培养物中测量表达野生型 (wt) KRAS (HKe3wtKRAS) 和 mtKRAS (HKe3-mtKRAS) 的 HKe3 球体面积。通过长期3DF（LT3DF）培养和裸鼠实验测定50%细胞生长抑制（GI50）。结果：我们选择NP882（命名为STAR3）作为HKe3-mtKRAS球体生长最有效的抑制剂，并且是NP910衍生物中毒性最小的。 LT3DF和裸鼠测定中STAR3的GI50分别为6μM和30.75mg/kg。然而，在 50% 的细胞系中观察到 STAR3 的生长抑制与 KRAS 突变无关，这表明 STAR3 的靶点与 KRAS 突变和 KRAS 相关信号并不直接相关。结论：STAR3是一种低毒性化合物，可抑制某些肿瘤细胞的生长。
Background/Aim: Among compounds from natural products selectively suppressing the growth of cancer spheroids, which have mutant (mt) KRAS, NP910 was selected and its derivatives explored. Materials and Methods: The area of HKe3 spheroids expressing wild type (wt) KRAS (HKe3wtKRAS) and mtKRAS (HKe3-mtKRAS) were measured in three-dimensional floating (3DF) cultures treated with 18 NP910 derivatives. The 50% cell growth inhibition (GI50) was determined by long-term 3DF (LT3DF) culture and nude mice assay. Results: We selected NP882 (named STAR3) as the most effective inhibitor of growth of HKe3-mtKRAS spheroids with the least toxicity among NP910 derivatives. GI50s of STAR3 in LT3DF and nude mice assay were 6 mu M and 30.75 mg/kg, respectively. However, growth suppression by STAR3 was observed in 50% of cell lines independent of KRAS mutation, suggesting that the target of STAR3 was not directly associated with KRAS mutation and KRAS-related signals. Conclusion: STAR3 is a low-toxicity compound that inhibits growth of certain tumour cells.