Effects of natural 24-epibrassinolide on inducing apoptosis and restricting metabolism in hepatocarcinoma cells.

BACKGROUND: 24-epibrassinolide (EBR) is a ubiquitous steroidal phytohormone with anticancer activity. Yet the cytotoxic effects and mechanism of EBR on hepatocarcinoma (HCC) cells remain elusive. METHODS: Cell counting kit-8 (CCK-8) assay was performed to evaluate cell viability. Real-time cell analysis (RTCA) technology and colony formation assays were used to evaluate cell proliferation. The apoptosis ratio was measured by flow cytometry. Seahorse XFe96 was applied to detect the effects of EBR on cellular bioenergetics. RNA-seq analysis was performed to investigate differences in gene expression profiles. Western blot and qRT-PCR were used to detect the changes in target molecules. RESULTS: EBR induced apoptosis and caused energy restriction in HCC, both of which were related to insulin-like growth factor-binding protein 1 (IGFBP1). EBR rapidly and massively induced IGBFP1, part of which was transcribed by activating transcription factor-4 (ATF4). The accumulation of secreted and cellular IGFBP1 had different important roles, in which secreted IGFBP1 affected cell energy metabolism by inhibiting the phosphorylation of Akt, while intracellular IGFBP1 acted as a pro-survival factor to resist apoptosis. Interestingly, the extracellular signal-regulated kinase (ERK) inhibitor SCH772984 and MAP/ERK kinase (MEK) inhibitor PD98059 not only attenuated the EBR-induced IGFBP1 expression but also the basal expression of IGFBP1. Thus, the treatment of cells with these inhibitors further enhances the cytotoxicity of EBR. CONCLUSION: Taken together, these findings suggested that EBR can be considered as a potential therapeutic compound for HCC due to its pro-apoptosis, restriction of energy metabolism, and other anti-cancer properties. Meanwhile, the high expression of IGFBP1 induced by EBR in HCC contributes to our understanding of the role of IGFBP1 in drug resistance.

6-methoxydihydroavicine, the alkaloid extracted from Macleaya cordata (Willd.) R. Br. (Papaveraceae), triggers RIPK1/Caspase-dependent cell death in pancreatic cancer cells through the disruption of oxaloacetic acid metabolism and accumulation of reactive oxygen species.

BACKGROUND: Many extracts and purified alkaloids of M. cordata (Papaveraceae family) have been reported to display promising anti-tumor effects by inhibiting cancer cell growth and inducing apoptosis in many cancer types. However, no evidence currently exists for anti-pancreatic cancer activity of alkaloids extracted from M. cordata, including a novel alkaloid named 6­methoxy dihydrosphingosine (6-Methoxydihydroavicine, 6-ME) derived from M. cordata fruits. PURPOSE: The aim of this study was to investigate the anti-tumor effects of 6-ME on PC cells and the underlying mechanism. METHODS: CCK-8, RTCA, and colony-formation assays were used to analyze PC cell growth. Cell death ratios, changes in MMP and ROS levels were measured by flow cytometry within corresponding detection kits. A Seahorse XFe96 was employed to examine the effects of 6-ME on cellular bioenergetics. Western blot and q-RT-PCR were conducted to detect changes in target molecules. RESULTS: 6-ME effectively reduced the growth of PC cells and promoted PCD by activating RIPK1, caspases, and GSDME. Specifically, 6-ME treatment caused a disruption of OAA metabolism and increased ROS production, thereby affecting mitochondrial homeostasis and reducing aerobic glycolysis. These responses resulted in mitophagy and RIPK1-mediated cell death. CONCLUSION: 6-ME exhibited specific anti-tumor effects through interrupting OAA metabolic homeostasis to trigger ROS/RIPK1-dependent cell death and mitochondrial dysfunction, suggesting that 6-ME could be considered as a highly promising compound for PC intervention.

Single-layer MoS2 nanosheet grafted upconversion nanoparticles for near-infrared fluorescence imaging-guided deep tissue cancer phototherapy.

A multifunctional nanostructure is prepared by covalently grafting upconversion nanoparticles (UCNPs) with chitosan functionalized MoS2 (MoS2-CS) and folic acid (FA) and then loading phthalocyanine (ZnPc) on the surface of MoS2, which integrates photodynamic therapy (PDT) with photothermal therapy (PTT) and upconversion luminescence imaging into one system for enhanced antitumor efficiency.

pH-sensitive nanoformulated triptolide as a targeted therapeutic strategy for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) has one of the worst prognoses for survival as it is poorly responsive to both conventional chemotherapy and mechanism-directed therapy. This results from a lack of therapeutic concentration in the tumor tissue coupled with the highly toxic off-site effects exhibited by these compounds. Consequently, we believe the best packaging for holistic therapy for HCC will involve three components: a potent therapeutic, a rationally designed drug delivery vehicle to enrich the target site concentration of the drug, and a surface ligand that can enable a greater propensity to internalization by tumor cells compared to the parenchyma. We screened a library containing hundreds of compounds against a panel of HCC cells and found the natural product, triptolide, to be more effective than sorafenib, doxorubicin, and daunorubicin, which are the current standards of therapy. However, the potential clinical application of triptolide is limited due to its poor solubility and high toxicity. Consequently, we synthesized tumor pH-sensitive nanoformulated triptolide coated with folate for use in an HCC-subpopulation that overexpresses the folate receptor. Our results show triptolide itself can prevent disease progression, but at the cost of significant toxicity. Conversely, our pH-sensitive nanoformulated triptolide facilitates uptake into the tumor, and specifically tumor cells, leading to a further increase in efficacy while mitigating systemic toxicity.

The fruits of Maclura pomifera extracts inhibits glioma stem-like cell growth and invasion.

Glioma is the most common primary intracranial tumour. Recently, growing evidence showed that glioma possesses stem-like cells, which are thought to be chemo- and radio-resistant and believed to contribute to the poor clinical outcomes of these tumours. In this study, we found that stem-like glioma cells (CD133+) were significantly increased in neurosphere cells, which are highly invasive and resistant to multiple chemotherapeutic agents. From our natural products library, we screened 48 natural products and found one compound, Pomiferin, which was of particular interest. Our results showed that Pomiferin could inhibit cell viability, CD133+ cell population, sphere formation, and invasion ability of glioma neurosphere cells. We also found that multiple stemness-associated genes (BIM1, Nestin, and Nanog) were down-regulated by Pomiferin treatment of glioma neurosphere cells. Taken together, our results suggest that Pomiferin could kill the cancer stem-like cells in glioma and may serve as a potential therapeutic agent in the future.

[Study on effect of sho-saiko-to compound on growth of nasopharyngeal carcinoma cells in CNE-bearing nude mice].

OBJECTIVE: To investigate the role of sho-saiko-to compound (SSTC) on the growth of the well-differentiated squamous cell line 1 of nasopharyngeal carcinoma (CNE-1) and well-differentiated CNE-2 in tumor-bearing nude mouse, and try to supply scientific data for its clinical development. METHOD: SSTC were prepared by concentration gradients, and the effect of SSTC on the growth and proliferation of the CNE-1 and CNE-2 were investigated by MT assay and soft-agar colony formation test. After setting up the subcutaneous tumor-bearing nude mouse model at the right lower back (0.2 mL CNE-2 cell suspension, 5 x 10(5)/mL), we randomly divided forty mice into 5 groups and gave high, middle and low concentration groups of SSTC (0.5, 0.25, 0.125 g X mL(-1) by intragastric administration. Positive and negative groups were set up for comparison. After constant administration for 15 days, the volume and weight of the tumor were measured for inhibition rate, so as to investigate the role of SSTC on the CNE-2 bearing tumor. RESULT: In vitro, compared with negative control, SSTC at different gradient concentrations were cultured with the CNE-1 and CNE-2 for 24 h, 48 h and 72 h. It showed that the growth and proliferation of both cell lines were inhibited to some extent. The inhibition rate was increased as the concentration and culture time increasing. Both MTT assay and soft-agar colony formation test showed that the 50% inhibiting concentration (IC50) was about 2.5 g X L(-1). In vivo, compared with negative control, the SSTC could slow down the tumor growth in the SSTC treated groups. The tumor growth of the negative control group (0.76 +/- 0.28) g, (962.88 +/- 245.96) mm3 and the low concentration group of SSTC (0.88 +/- 0.40) g, (1239.66 +/- 421.93) mm3 were obviously faster than those of the high, middle concentration group of SSTC (0.22 +/- 0.14) g, (239.31 +/- 137.07) mm3; (0.20 +/- 0.16) g, (263.42 +/- 166.57) mm3 and CTX positive control group (0.20 +/- 0.10) g, (246.72 +/- 194.6) mm3 (P<0.05). CONCLUSION: SSTC could efficiently inhibit the growth and proliferation of CNE-1 and CNE-2 in vitro, and slow down the tumor growth of the CNE-2 bearing nude mice. It may be a new compound of Chinese medicine for nasopharyngeal carcinoma therapy.