Homoharringtonine inhibits the progression of hepatocellular carcinoma by suppressing the PI3K/AKT/GSK3β/Slug signaling pathway

Abstract

Homoharringtonine (HHT), was first isolated from the bark of Cephalotaxus harringtonia (Knight ex J. Forbes) K. Koch and Cephalotaxus fortunei Hook trees. The bark extract is used to treat leukemia and in recent years has also been used in traditional Chinese medicine (TCM) to treat solid tumors. However, the inhibitory mechanism of HHT in the progression of hepatocellular carcinoma (HCC) is rarely studied. We aimed to evaluate the antitumor efficacy of HHT on HCC in vitro and in vivo and elucidate the underlying molecular mechanism(s). HCC cell lines, including HCCLM3, HepG2 and Huh7, were used to evaluate the antitumor efficacy of HHT in vitro.Cytotoxicity and proliferative ability were evaluated by MTT and colony formation assays. Cell cycle progression and apoptosis in HHT-treated HCC cells were evaluated by flow cytometry. To determine the migration and invasion abilities of HCC cells, wound-healing and Transwell assays were used. Finally, Western blot analysis was used to reveal the proteins involved. We also established a xenograft nude mouse model for in vivo assessments of the preclinical efficacy of HHT, mainly using hematoxylin and eosin staining, immunohistochemistry, ultrasound imaging (USI) and magnetic resonance imaging (MRI). HHT suppressed the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of HCC cells and induced cell cycle arrest at G2 phase and apoptosis. In the HCC xenograft model, HHT showed an obvious tumor suppress ive signaling pathway at least partially suppressed the growth of HCC via the PI3K signaling pathway.

Uncovering the action mechanism of homoharringtonine against colorectal cancer by using network pharmacology and experimental evaluation

“…However, the detailed targets by which HHT activated PI3K/AKT/mTOR signaling remain for further investigation. Consistent with our findings, HHT suppressed cell proliferation, migration, invasion, EMT and facilitated apoptosis in hepatocellular carcinoma via inhibiting PI3K/AKT/GSK3β/Slug signaling [ 41 ]. PI3K/AKT inhibitor LY294002 potentiated the anti-myeloma activity of HHT both in vitro and in vivo [ 42 ].…”

Repurposing homoharringtonine for thyroid cancer treatment through TIMP1/FAK/PI3K/AKT signaling pathway

“…This was consistent with previous studies reporting that the PI3K/AKT signaling pathway participates in the inhibiting activity of HHT in colorectal cancer 40 and hepatocellular carcinoma. 42 TIMP1 interacts with other proteins to cause aberrant regulation of downstream signaling pathways, among which the PI3K/AKT pathway is one of the main TIMP1-related signaling pathways. 19 In colon cancer, TIMP1 promotes cell proliferation and metastasis by activating the FAK/PI3K/AKT pathway, and selective FAK or AKT inhibitors impair the pro-tumor effects of TIMP1.…”

Homoharringtonine induces apoptosis of mammary carcinoma cells by inhibiting the AKT/mTOR signaling pathway

“…4,5 It has also recently been used for the traditional Chinese medicine treatment of solid tumours. Moreover, HHT can suppress tumour cell growth in melanoma, 6 myeloma, 7 lymphoma, 8 liver cancer, 9 pancreatic cancer, 10 and lung cancer, 11,12 exerting a broad anti-tumour effect. Wang et al showed by miRNA sequencing that HHT inhibits growth and promotes apoptosis of human breast cancer cells through the miR-18a-3p/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signalling pathway.…”