Disulfiram enhances cisplatin cytotoxicity by forming a novel platinum chelate Pt(DDTC)3.

Despite the use of targeted therapy in non-small cell lung cancer (NSCLC) patients, cisplatin (DDP)-based chemotherapy is still the main option. However, DDP resistance is the major factor contributing to the failure of chemotherapy. In this study, we tried to screen DDP sensitizers from an FDA-approved drug library containing 1374 small-molecule drugs to overcome DDP resistance in NSCLC. As a result, disulfiram (DSF) was identified as a DDP sensitizer: DSF and DDP had synergistic anti-NSCLC effects, which are mainly reflected in inhibiting tumor cell proliferation, plate colony formation and 3D spheroidogenesis and inducing apoptosis in vitro, as well as the growth of NSCLC xenografts in mice. Although DSF has recently been reported to promote the antitumor effect of DDP by inhibiting ALDH activity or modulating some important factors or pathways, unexpectedly, we found that DSF reacted with DDP to form a new platinum chelate, Pt(DDTC)3+, which might be one of the important mechanisms for their synergistic effect. Moreover, Pt(DDTC)3+ has a stronger anti-NSCLC effect than DDP, and its antitumor activity is broad-spectrum. These findings reveal a novel mechanism underlying the synergistic antitumor effect of DDP and DSF, and provide a drug candidate or a lead compound for the development of a new antitumor drug.

Therapeutic Effect of Catgut Implantation at Acupoint in a Mouse Model of Hepatocellular Carcinoma by Suppressing Immune Escape.

BACKGROUND: The occurrence and development of hepatocellular carcinoma (HCC) are closely related to immune function, as is the capacity of hepatoma cells to escape. Immunosurveillance is a key mechanism. Catgut implantation at acupoint (CIAA) is a promising acupuncture improvement method that can regulate immunity and has been widely used in the clinical treatment of a variety of diseases. The aim of this study is to observe the therapeutic effect of CIAA on HCC and to investigate the potential mechanism of immune escape. MATERIALS AND METHODS: A total of 40 mice were randomly divided into three groups: the HCC model group (n = 15), the CIAA treatment group (n = 15), and the control group (n = 10). HCC was chemically induced in 30 mice by the combination of DEN, carbon tetrachloride, and ethanol for 150 days. Among them, 15 were selected for CIAA treatment to ascertain the therapeutic effect. The mRNA expression levels of AFP, IL-10, PD-1, and CTLA-4 in three groups were examined by using RT-PCR. AFP and AKT expressions were measured by using western blotting. PD1, CTLA-4, IL-10, CD4+, and CD8+ protein expression levels were evaluated by using IHC. The mortality rate, body weight, and psychological conditions of three groups were also compared. RESULTS: The mRNA and protein expression levels of AFP, PD-1, CTLA-4, and IL-10 were significantly downregulated in the CIAA-treated mice in comparison with HCC mice. IHC assay shows that CD4+ and CD8+ expression levels were notably upregulated after CIAA treatment. Western blotting assay shows that AKT pathway was deactivated in CIAA-treated mice. CIAA notably reduced the mortality rate and inhibited weight loss caused by HCC and improved the overall psychological condition of the mice. CONCLUSIONS: Taken together, our data corroborate the effective potency of CIAA in the treatment of HCC by and inhibiting immune escape and deactivating the AKT pathway.

Depressive Disorder promotes Hepatocellular Carcinoma metastasis via upregulation of ABCG2 gene expression and maintenance of self-renewal.

Depressive disorder (DD) is the leading cause of disability worldwide and is the most prevalent mood disorder. Accumulative evidence from epidemiological studies has shown that DD is a risk factor for cancer. However, the role and molecular mechanism of DD in hepatocellular carcinoma (HCC) are still unknown. In this study, 30 mice were randomly divided into two groups: the HCC group and the HCC-DD group. The DD mouse model of HCC was established by induction with reserpine every other day and with monthly doses of diethylnitrosamine (DEN). All of the molecular studies were based on primary cell culture, and the effects of DD on HCC cell proliferation and migration and cancer stem cell (CSC) self-renewal were determined by colony formation, wound healing, and sphere culture assays. We found that the CSC markers ABCG2 and CD133 were upregulated in HCC-DD primary cells compared with HCC primary cells. Moreover, HCC-DD primary cells were more aggressive in terms of metastasis and self-renewal than HCC primary cells. Further study revealed that DD promoted tumor growth and metastasis by activating the AKT signaling pathway followed by an increased ABCG2 expression. Taken together, our novel findings indicate that DD promotes proliferation, self-renewal, and metastasis by upregulating ABCG2 in the AKT pathway.

Retinal dehydrogenase 5 (RHD5) attenuates metastasis via regulating HIPPO/YAP signaling pathway in Hepatocellular Carcinoma.

Retinal dehydrogenase 5 (RDH5) is an important enzyme in the visual cycle. Several studies have reported that the RDH family may play crucial roles in tumor prognosis. However, the role of RDH5 in tumor prognosis is still unclear. We examined the mRNA level of RDH5 by using q-PCR in hepatocellular carcinoma (HCC) and adjacent non-cancerous tissues. The proliferation rate of HCC cells was detected by MTS assay, and the invasive ability was examined by transwell and scratch wound assays. The YAP protein localization and expression were visualized by immunofluorescence in two different cell lines. CpG islands in the promoter region were predicted by using the methprimer database. Clinical characteristics of a patient cohort data came from The Cancer Genome Atlas database. RDH5 was significantly downregulated in hepatocellular carcinoma tissues, and low RDH5 expression was associated with metastasis and poor patient prognosis. Functional assays revealed that the RDH5 promoter is methylated in HCC cell lines. Moreover, overexpressing RDH5 can suppress metastasis by reversing the epithelial-mesenchymal transition (EMT) process, and RDH5 also inhibits cell proliferation in HCC cell lines. Furthermore, suppressing RDH5 can activate the Hippo/YAP signaling pathway and promote the nuclear translocation of YAP. Clinical data demonstrated that RDH5 is an independent prognostic factor in HCC. In our study, we provided the first evidence that RDH5 plays a crucial role in suppressing proliferation and metastasis, and the RDH5 promoter is methylated in hepatocellular carcinoma. And as an important regulator, RDH5 can suppress the Hippo/YAP signaling pathway. Taken together, it revealed that RDH5 might be a potential therapeutic target in HCC patients.