Dual cyclin-dependent kinase 4/6 inhibition by PD-0332991 induces apoptosis and senescence in oesophageal squamous cell carcinoma cells.

Aberrant activation of the cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6)-Rb signalling pathway is common in oesophageal squamous cell carcinoma (ESCC). PD-0332991, a highly specific inhibitor of CDK4/6, has potent antitumour activity against many types of cancer. The purpose of this study was to examine the in vitro and in vivo antineoplastic effect of PD-0332991 against the growth and metastasis of ESCC cells. Cell viability and any synergy between PD-0332991 and 5-fluorouracil or cisplatin were measured by MTS assay and CalcuSyn software respectively. Cell migration and invasion were detected by wound healing and transwell assays. Apoptosis was evaluated by flow cytometry after staining annexin V-FITC/PI. Cellular senescence was assessed by measuring SA-β-gal activity. Nude mouse xenograft models of ESCC were employed to determine the in vivo activity of PD-0332991 against tumour growth and lung metastasis. PD-0332991 inhibited cellular growth and induced mitochondrial-dependent apoptosis in ESCC cells. PD-0332991 also suppressed migration, invasion and the expression of MMP-2 in ESCC cells. Furthermore, PD-0332991 treatment caused cell senescence in a FOXM1-dependent manner. In addition, there was synergy between PD-0332991 and cisplatin or 5-fluorouracil. Importantly, the xenografted tumour experiments demonstrated that PD-0332991 potently inhibits ESCC cell growth and lung metastasis. PD-0332991 can elicit a strong antitumour activity against ESCC growth and metastasis and may be a promising candidate drug for the treatment of patients with ESCC. Our results warrant a clinical trial to further evaluate the efficacy of PD-0332991 in ESCC patients, even those with metastasis.

Chen L ，Pan J 《-》

CDK4/6 inhibitor-SHR6390 exerts potent antitumor activity in esophageal squamous cell carcinoma by inhibiting phosphorylated Rb and inducing G1 cell cycle arrest.

Wang J ，Li Q ，Yuan J ，Wang J ，Chen Z ，Liu Z ，Li Z ，Lai Y ，Gao J ，Shen L ... -  《Journal of Translational Medicine》

Pristimerin targeting NF-κB pathway inhibits proliferation, migration, and invasion in esophageal squamous cell carcinoma cells.

Esophageal squamous cell carcinoma (ESCC) is one of the leading causes of cancer-related death with poor prognosis in China. Identifying novel targeted therapies in ESCC is urgently needed. The aberrant activation of NF-κB signalling pathway is critical for prognosis and recurrence of ESCC, which make it a potential target in the treatment of ESCC. Here, we found that pristimerin inhibited ESCC cell proliferation, migration, invasion, induced cell apoptosis, and eliminated cancer stem-like cells (CSCs). It also showed a synergistic effect on ESCC when combined with 5-fluorouracil (5-FU). Moreover, pristimerin potently inhibited the growth of ESCC xenograft in nude mice. The anti-ESCC effects of pristimerin were demonstrated to be associated with the inhibition of NF-κB pathway by suppressing tumour necrosis factor α (TNFα)-induced IκBα phosphorylation, p65 translocation, and NF-κB-dependent gene expression. This study provides an evidence for the development of pristimerin to be a new therapeutic agent for ESCC. Although several approaches including surgery, chemotherapy, and radiotherapy had been applied in the treatment of ESCC, more effective targeted chemotherapies are required to increase the survival rates of patients. This study suggested that inhibiting NF-κB signalling pathway could be an effective approach for the treatment of ESCC. Pristimerin, a potent NF-κB inhibitor, exerted potent anti-ESCC effects both in vitro and in vivo, which may be a promising therapeutic agent for ESCC.

Tu Y ，Tan F ，Zhou J ，Pan J ... -  《-》

Ivermectin suppresses tumour growth and metastasis through degradation of PAK1 in oesophageal squamous cell carcinoma.

Oesophageal squamous cell carcinoma (ESCC), the most common form of oesophageal malignancies in the Asia-Pacific region, remains a major clinical challenge. In this study, we found that ivermectin, an effective antiparasitic drug that has been approved for patients to orally treat onchocerciasis for over 30 years, displayed potent antitumour activity against ESCC cells in vitro and in nude mice. We demonstrated that ivermectin significantly inhibited cell viability and colony formation, and induced apoptosis through a mitochondrial-dependent manner in ESCC cells. Ivermectin also abrogated ESCC cell migration, invasion, as well as the protein levels of MMP-2 and MMP-9. Mechanistically, ivermectin strongly inhibited the expression of PAK1; by further gain- and loss-of-function experiments, we confirmed that PAK1 played a crucial role in ivermectin-mediated inhibitory effects on ESCC cells. In addition, the data indicated that ivermectin promoted PAK1 degradation through the proteasome-dependent pathway. Additionally, ivermectin synergized with chemotherapeutic drugs including cisplatin and 5-fluorouracil to induce apoptosis of ESCC cells. Interestingly, the in vivo experiments also confirmed that ivermectin effectively suppressed tumour growth and lung metastasis of ESCC. Collectively, these results indicate that ivermectin exerts a potent antitumour activity against ESCC and is a promising therapeutic candidate drug for ESCC patients, even those carrying metastasis.

Chen L ，Bi S ，Wei Q ，Zhao Z ，Wang C ，Xie S ... -  《-》

Transcriptional inhibition by CDK7/9 inhibitor SNS-032 suppresses tumor growth and metastasis in esophageal squamous cell carcinoma.

Metastasis is one of most lethal causes that confer a poor prognosis of patients with esophageal squamous cell carcinoma (ESCC), whereas there is no available target drug for metastatic ESCC currently. In this study, we aimed to determine whether the transcriptional inhibition by CDK7/9 inhibitor SNS-032 is activity against ESCC. MTT and soft agar assays were performed to examine the influence of SNS-032 on ESCC growth in vitro. Tumor xenograft in nude mice was used to assess the antitumor activity of SNS-032 in vivo. The roles of SNS-032 in ESCC metastasis were conducted by wound healing and transwell assays in vitro, and by a lung and a popliteal lymph node metastasis model in vivo. The results showed that CDK7 and CDK9 were highly expressed in ESCC cells; SNS-032 effectively inhibited cellular viability, abrogated anchorage-independent growth, and potentiated the sensitivity to cisplatin in ESCC cells in vitro and in vivo. In addition, SNS-032 induced a mitochondrial-dependent apoptosis of ESCC cells by reducing Mcl-1 transcription. SNS-032 also potently abrogated the abilities of ESCC cell migration and invasion through transcriptional downregulation of MMP-1. Importantly, SNS-032 remarkably inhibited the growth of ESCC xenograft, increased the overall survival, as well as diminished the lung and lymph node metastasis in nude mice. Taken together, our findings highlight that the CDK7/9 inhibitor SNS-032 is a promising therapeutic agent, and warrants a clinical trial for its efficacy in ESCC patients, even those with metastasis.

Zeng H ，Yang H ，Song Y ，Fang D ，Chen L ，Zhao Z ，Wang C ，Xie S ... -  《Cell Death & Disease》