Spiclomazine displays a preferential anti-tumor activity in mutant KRas-driven pancreatic cancer.
Spiclomazine displays a preferential anti-tumor activity in mutant KRas-driven pancreatic cancer.
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Spclomazine 在突变型 KRas 驱动的胰腺癌中表现出优先的抗肿瘤活性
DOI：
10.18632/oncotarget.24025
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发表时间：
2018-01-23
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
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作者：
Guo X;Zhao W;Liu Z;Wang J
Ras靶向治疗代表了肿瘤学中的“圣杯”。根据我们的模型预测，Spiclomazine冷冻活化Ras的中间构象是癌症治疗的核心。我们在这里显示，Spiclomazine通过废除KRas驱动的胰腺癌中的KRas-GTP水平，导致Ras介导的信号传导的有效抑制。Ras介导的信号传导抑制导致5种KRas驱动的胰腺癌细胞系在处理48小时后的存活率显著降低，IC 50范围为19.7~74.2 μM。然而，在正常细胞系中未观察到显著变化。值得一提的是，突变型KRas驱动的癌细胞比野生型KRas癌细胞对Spiclomazine更敏感。随后的细胞热位移和RNA干扰试验表明，Spiclomazine在细胞内有效地与KRas结合，并在一定程度上稳定KRas。这验证了靶标接合对药物功效的影响。此外，Spiclomazine在癌细胞中将细胞周期阻滞在G2期，而在正常细胞中没有明显的细胞周期阻滞。这进一步证明了其对参与Ras-GTP介导的靶接合的癌细胞的选择性生物学应答。Spiclomazine通过腹膜内途径给予BALB/c小鼠68 mg kg−1持续2周，可完全抑制肾包膜异种移植模型上MIA PaCa-2肿瘤的生长。免疫组织化学分析显示c-Raf和p-ERK减少，TUNEL染色增加。这些观察结果进一步证实了体外结果。总之，Spiclomazine是突变KRas驱动的胰腺癌的选择性抑制剂。
Ras-targeted therapy represents a ‘holy grail’ in oncology. Based on our model prediction, Spiclomazine freezing the intermediate conformation of activated Ras is central to cancer therapeutics. We show here that Spiclomazine leads to an effective suppression in Ras-mediated signaling through abrogating the KRas-GTP level in the KRas-driven pancreatic cancer. The Ras-mediated signaling inhibition leads to dramatically reduced survivals of five KRas-driven pancreatic cancer cell lines with IC50 ranging 19.7~74.2 μM after 48 hours of treatment. However, no significant changes have been observed for normal cell lines. It is worth mentioning that the mutant KRas-driven cancer cells are more sensitive towards Spiclomazine than the wild-type KRas cancer cells. Subsequent cellular thermal shift and RNA interference assays show that Spiclomazine efficiently binds with and stabilizes KRas to a certain extent within the cells. This validates the effect of target engagement on drug efficacy. Furthermore, Spiclomazine arrests cell cycle at G2 phase in the cancer cells, without obvious cell-cycle arrest in the normal cells. This further demonstrates its selectively biological response to cancer cells involved in Ras-GTP-mediated target engagement. Spiclomazine completely inhibits the growth of MIA PaCa-2 tumors on renal capsule xenograft models in BALB/c mice administered 68 mg kg−1 for 2 weeks via intra-peritoneal route. Immunohistochemical analyses reveal the reduced c-Raf and p-ERK and the increase in TUNEL staining. These observations further confirm the in vitro findings. Taken together, Spiclomazine is a selective inhibitor for mutant KRas-driven pancreatic cancer.