DataSheet_7_CK-3, A Novel Methsulfonyl Pyridine Derivative, Suppresses Hepatocellular Carcinoma Proliferation and Invasion by Blocking the PI3K/AKT/mTOR and MAPK/ERK Pathways.doc

Hepatocellular carcinoma (HCC) is an aggressive tumor with a poor prognosis that highly expresses phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (ERK). The PI3K/AKT/mTOR and MAPK/ERK signaling pathways play a crucial role in HCC tumor formation, cell cycle, apoptosis and survival. However, no effective targeted therapies against these pathways is available, mainly due to the extensive and complex negative feedback loops between them. Here we used CK-3, a dual blocker of the PI3K/AKT/mTOR and MAPK/ERK pathways, against HCC cell lines to verify its anti-tumor activity in vitro. CK-3 exhibited cytotoxic activity against HCC, as demonstrated with MTT and colony formation assays. The anti-metastatic potential of CK-3 was demonstrated with wound healing and cell invasion assays. The ability of CK-3 to block both the PI3K/AKT/mTOR and MAPK/ERK pathways was also confirmed. CK-3 induced the apoptosis of Hep3B cells, while Bel7402 cells died via mitotic catastrophe (MC). Oral administration of CK-3 also inhibited the subcutaneous growth of BEL7402 cells in nude mice. Simultaneous PI3K/AKT/mTOR and MAPK/ERK pathway inhibition with CK-3 may be superior to single pathway monotherapies by inhibiting their feedback-regulation, and represents a potential treatment for HCC.

肝细胞癌（Hepatocellular carcinoma，HCC）是一种侵袭性较强、预后不佳的肿瘤，其高度表达磷脂酰肌醇3激酶（Phosphatidylinositol 3-kinase，PI3K）和丝裂原活化蛋白激酶（Mitogen-activated protein kinase，ERK）。PI3K/AKT/mTOR和MAPK/ERK信号通路在HCC肿瘤形成、细胞周期、细胞凋亡和存活中发挥着至关重要的作用。然而，针对这些通路的靶向治疗尚无有效方案，这主要归因于它们之间广泛而复杂的负反馈回路。本研究中，我们使用CK-3，一种PI3K/AKT/mTOR和MAPK/ERK通路的双重阻断剂，针对HCC细胞系进行体外实验，以验证其抗肿瘤活性。CK-3对HCC表现出细胞毒性，这一结论通过MTT和集落形成实验得到证实。CK-3的抗转移潜力通过伤口愈合和细胞侵袭实验得到展示。同时，CK-3阻断PI3K/AKT/mTOR和MAPK/ERK通路的性能也得到了验证。CK-3诱导Hep3B细胞的凋亡，而Bel7402细胞则通过有丝分裂灾难（Mitotic catastrophe，MC）死亡。CK-3的口服给药还能抑制裸鼠皮下BEL7402细胞的生长。CK-3同时抑制PI3K/AKT/mTOR和MAPK/ERK通路可能优于单通路单药治疗，因为它能抑制其反馈调节，并代表了一种HCC的潜在治疗策略。