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

Abstract

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.

Mitochondrial-Related Transcriptome Feature Correlates with Prognosis, Vascular Invasion, Tumor Microenvironment, and Treatment Response in Hepatocellular Carcinoma

“…The missense mutation in CTNNB1 encoding β -catenin had the trunk role in the tumorigenesis of HCC and regulated tumor cell proliferation and tumor angiogenesis [ 69 ], while molecularly targeted therapy for CTNNB1 had been found to have the potential in treatment of HCC [ 70 ], which was suggested as a promising therapy for HCC patients with low prognosis score in this study. In the high-risk group, altered genes TSC2 and MTOR were highly enriched and these genes played important roles in the activation of PI3K/AKT/mTOR pathways that could lead to the HCC carcinogenesis, progression, and invasion [ 71 ]; thus, mTOR and/or PI3K inhibitors had a potential value in treating patients with HCC [ 72 ], particularly for the advanced HCC patients in the present study. But inhibitions of these signaling pathways might generate a prooncogenic tumor microenvironment and impel the recurrence of HCC [ 72 ], so an integrated effective strategy in treating HCC patients was urgently needed by the combinational treatment of molecularly targeted therapy, immunotherapy, chemotherapy, and other potential therapeutic strategies.…”

Studies on Chemical Composition of Pueraria lobata and Its Anti-Tumor Mechanism

“…The results of network pharmacology showed that Sandwicensin could regulate CCND1 and CDK4 to exert anti-CRC effects; notably, the results of KEGG enrichment analysis showed that Sandwicensin treatment of CRC was also closely linked to the cell cycle, suggesting that Sandwicensin exerts its anti-tumor effects mainly by regulating multiple cell cycle-related proteins. In addition, the mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (MTOR) pathway plays a potential role in cell proliferation and differentiation [ 38 ]. It has been shown that aberrant expression of anillin (ANLN) can regulate CRC cell proliferation through PI3K/AKT and MAPK pathways [ 39 ].…”

Knockdown of FBI-1 Inhibits the Warburg Effect and Enhances the Sensitivity of Hepatocellular Carcinoma Cells to Molecular Targeted Agents via miR-3692/HIF-1α

“…The HCC cells were transfected with vectors and treated with agents ( 39 , 40 ). After 48 h treatment of the agents, the MTT experiments were performed according to previous publications.…”