Astaxanthin Supplementation Assists Sorafenib in Slowing Skeletal Muscle Atrophy in H22 Tumor-Bearing Mice via Reversing Abnormal Glucose Metabolism.

SCOPE: Cachexia, which is often marked by skeletal muscular atrophy, is one of the leading causes of death in cancer patients. Astaxanthin, a carotenoid obtained from marine organisms that can aid in the prevention and treatment of a variety of disorders. In this study, to assess whether astaxanthin ameliorates weight loss and skeletal muscle atrophy in sorafenib-treated hepatocellular carcinoma mice is aimed. METHODS AND RESULTS: H22 mice are treated with 30 mg kg-1  day-1 of sorafenib and 60 mg kg-1  day-1 of astaxanthin by gavage lasted for 18 days. Sorafenib does not delay skeletal muscle atrophy and weight loss, although it does not reduce tumor burden. Astaxanthin dramatically delays weight loss and skeletal muscle atrophy in sorafenib-treating mice, without affecting the food intake. Astaxanthin inhibits the tumor glycolysis, slows down gluconeogenesis, and improves insulin resistance in tumor-bearing mice. Astaxanthin increases glucose competition in skeletal muscle by targeting the PI3K/Akt/GLUT4 signaling pathway, and enhances glucose utilization efficiency in skeletal muscle, thereby slowing skeletal muscle atrophy. CONCLUSION: The findings show the significant potential of astaxanthin as nutritional supplements for cancer patients, as well as the notion that nutritional interventions should be implemented at the initiation of cancer treatment, as instead of waiting until cachexia sets in.

Crithmum maritimum Improves Sorafenib Sensitivity by Decreasing Lactic Acid Fermentation and Inducing a Pro-Hepatocyte Marker Profile in Hepatocellular Carcinoma.

Edible plants are gaining importance as an integrative therapy for many chronic diseases, including cancer. We first reported that the edible wild plant Crithmum maritimum L. inhibits the growth of hepatocellular carcinoma (HCC) cells by exerting a multitarget action on cellular metabolism and bioenergetic profile. Here, we show that Crithmum maritimum ethyl acetate extract significantly increases the responsiveness of HCC cells to the chemotherapeutic drug sorafenib by reducing lactic acid fermentation and inducing a pro-hepatocyte biomarker profile. Our findings strengthen the role of Crithmum maritimum L. as a valuable nutraceutical tool to support pharmacological therapeutic interventions in HCC.

A Functional Screening Identifies a New Organic Selenium Compound Targeting Cancer Stem Cells: Role of c-Myc Transcription Activity Inhibition in Liver Cancer.

Cancer stem cells (CSCs) are reported to play essential roles in chemoresistance and metastasis. Pathways regulating CSC self-renewal and proliferation, such as Hedgehog, Notch, Wnt/ß-catenin, TGF-ß, and Myc, may be potential therapeutic targets. Here, a functional screening from the focused library with 365 compounds is performed by a step-by-step strategy. Among these candidate molecules, phenyl-2-pyrimidinyl ketone 4-allyl-3-amino selenourea (CU27) is chosen for further identification because it proves to be the most effective compound over others on CSC inhibition. Through ingenuity pathway analysis, it is shown CU27 may inhibit CSC through a well-known stemness-related transcription factor c-Myc. Gene set enrichment analysis, dual-luciferase reporter assays, expression levels of typical c-Myc targets, molecular docking, surface plasmon resonance, immunoprecipitation, and chromatin immunoprecipitation are conducted. These results together suggest CU27 binds c-Myc bHLH/LZ domains, inhibits c-Myc-Max complex formation, and prevents its occupancy on target gene promoters. In mouse models, CU27 significantly sensitizes sorafenib-resistant tumor to sorafenib, reduces the primary tumor size, and inhibits CSC generation, showing a dramatic anti-metastasis potential. Taken together, CU27 exerts inhibitory effects on CSC and CSC-associated traits in hepatocellular carcinoma (HCC) via c-Myc transcription activity inhibition. CU27 may be a promising therapeutic to treat sorafenib-resistant HCC.

Cytochrome P450 3A5 polymorphism affects the metabolism of sorafenib and its toxicity for hepatocellular carcinoma cells in vitro.

OBJECTIVE: Cytochrome P450 3A5 (CYP3A5) is a highly polymorphic gene and the encoded protein variants differ in catalytic activity, leading to inter-individual variation in metabolic ability. The aim of the current study was to investigate the effects of seven allelic variants on the ability of CYP3A5 to metabolize sorafenib in vitro and further explore the impacts of CYP3A5 polymorphism on the proliferation and apoptosis of hepatocellular carcinoma cell line (HepG2) induced by sorafenib. METHODS: Wild-type and variant CYP3A5 enzymes were expressed in Spodoptera frugiperda insect cells using a baculovirus dual-expression system, and protein expression was checked by western blot. The enzymes were incubated with sorafenib at 37°C for 30 min, and formation of the major metabolite sorafenib N-oxide was assayed using ultra-performance liquid chromatography and tandem mass spectrometry. Intrinsic clearance values (Vmax/Km) were calculated for each enzyme. Additionally, recombinant HepG2 cells transfecting with CYP3A5 variants were used to investigate the effects of sorafenib on the proliferation of HepG2 cells. RESULTS: Intrinsic clearance of the six variants CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 was 26.41-71.04% of the wild-type (CYP3A5*1) value. In contrast, the clearance value of the variant CYP3A5*6 was significantly higher (174.74%). Additionally, the decreased ATP levels and cell viability and the increased cell apoptosis in HepG2 cells transfected with CYP3A5*2, CYP3A5*3A, CYP3A5*3C, CYP3A5*4, CYP3A5*5, and CYP3A5*7 were observed, whereas, the increased ATP levels and cell viability and the reduced cell apoptosis in HepG2 cells transfected with CYP3A5*6 were also investigated when compared to CYP3A5*1. CONCLUSION: Our results suggest that CYP3A5 polymorphism influences sorafenib metabolism and pharmacotherapeutic effect in hepatic carcinomas. These data may help explain differential response to drug therapy for hepatocellular carcinoma, and they support the need for individualized treatment.

Sorafenib-Conjugated Zinc Phthalocyanine Based Nanocapsule for Trimodal Therapy in an Orthotopic Hepatocellular Carcinoma Xenograft Mouse Model.

Sorafenib, a multitargeted kinase inhibitor, has been reported to elicit a limited therapeutic effect in hepatocellular carcinoma (HCC). Currently, phototherapy, including photodynamic therapy (PDT) and photothermal therapy (PTT), is emerging as a powerful modality for cancer therapy. However, few studies have been reported the effectiveness of the combination of sorafenib with PDT and PTT in HCC. Herein, we designed and synthesized bovine serum albumin (BSA)-coated zinc phthalocyanine (ZnPc) and sorafenib (SFB) nanoparticle (ZnPc/SFB@BSA). The obtained ZnPc/SFB@BSA was able to trigger PDT, PTT, and chemotherapy. After irradiation by a 730 nm light, ZnPc/SFB@BSA significantly suppressed HCC cell proliferation and metastasis while promoted cell apoptosis in vitro. Furthermore, intravenous injection of ZnPc/SFB@BSA led to dramatically reduced tumor growth in an orthotopic xenograft HCC model. More importantly, ZnPc/SFB@BSA presented low toxicity and adequate blood compatibility. Therefore, a combination of ZnPc with sorafenib via BSA-assembled nanoparticle can markedly suppress HCC growth, representing a promising strategy for HCC patients.

A Probiotic Spore-Based Oral Autonomous Nanoparticles Generator for Cancer Therapy.

Spores, the dormant life forms of probiotics, can germinate to metabolically active vegetative cells with the disintegration of their hydrophobic protein coat in the intestinal microenvironment, which provides the possibility for the formation of nanoparticles (NPs) in vivo. Inspired by the natural physiological process of spores, herein, an oral autonomous NPs generator is developed to overcome the spatially variable gastrointestinal tract environment and multibiological barriers. Spores modified with deoxycholic acid (DA) and loaded with chemotherapeutic drugs (doxorubicin and sorafenib, DOX/SOR) serve as an autonomous production line of NPs, which can efficaciously protect the drugs passing through the rugged environment of the stomach and furthermore can be transported to the intestinal environment and colonized rapidly. Subsequently, the DOX/SOR/Spore-DA NPs are produced by the autonomous NPs generator in the intestinal regions based on the disintegrated hydrophobic protein and the hydrophilic DA, and they can efficiently penetrate the epithelial cells via the bile acid pathway, increasing basolateral drug release. In vitro and in vivo studies confirm that this biological nanogenerator can autonomously produce substantial NPs in the intestine, providing a promising strategy for cancer therapy.

Selective targeting of tumor cells and tumor associated macrophages separately by twin-like core-shell nanoparticles for enhanced tumor-localized chemoimmunotherapy.

Tumor associated macrophage (TAM)-based immunotherapy has been presented as a promising strategy in cancer therapy. The combination of TAM-based immunotherapy with sorafenib (SF) could be conceivably quite more effective in hepatocellular carcinoma (HCC) treatment. A co-delivery system was superior in improving the co-accumulation of two drugs in tumor tissues for chemoimmunotherapy, while in the case of selective targeting of separated cells such as tumor cells and immune cells, a novel targeted co-delivery strategy was badly required. In this study, twin-like core-shell nanoparticles (TCN) were developed for synchronous biodistribution and separated cell targeting delivery of SF and TAM re-polarization agents IMD-0354 to cancer cells and TAM to enhance tumor-localized chemoimmunotherapy, respectively. First of all, SF loaded cationic lipid-based nanoparticles (SF-CLN) and mannose-modified IMD-0354 loaded cationic lipid-based nanoparticles (M-IMD-CLN) were prepared, respectively. SF on the surface of SF-CLN and mannose on the M-IMD-CLN were regarded as targeting ligands for selective targeting delivery of SF-CLN and M-IMD-CLN to cancer cells and TAM separately. Then, pH-responsive charge reversal polymer O-carboxymethyl-chitosan (CMCS) was coated on the SF-CLN and M-IMD-CLN to obtain twin-like CMCS/SF-CLN and CMCS/M-IMD-CLN, respectively. The results of cellular uptake assay on Hepa1-6 cells and RAW 264.7 cells in vitro, respectively, as well as the results of tumor tissue distribution of SF and IMD-0354 in vivo suggested that CMCS/SF-CLN and CMCS/M-IMD-CLN exhibited similar properties in vitro and synchronous biodistribution in vivo, and were efficient at separated cell targeting delivery. What's more, the results of antitumor efficiency in vivo and phenotype analysis of TAM in tumor tissues proved that CMCS/SF-CLN and CMCS/M-IMD-CLN exhibited superior synergistic antitumor efficacy and M2-type TAM polarization ability compared with SF treatment in Hepa1-6 tumor bearing mice. Consequently, TCN which was the combination of co-administration and nano-drug delivery systems has great potential to be used in tumor-localized chemoimmunotherapy in clinics.