Vemurafenib induces senescence in acute myeloid leukemia and myelodysplastic syndrome by activating the HIPPO signaling pathway: implications for potential targeted therapy.

BACKGROUND: The outcome of Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) remain dismal despite the development of treatment. Targeted therapy is gaining more and more attention in improving prognosis. METHODS: Expression of BRAF was analyzed by RT-qPCR in AML and MDS patients. Cells viability treated by drugs was measured by CCK-8 assay. Network pharmacology and RNA-sequence were used to analyze the mechanism of drugs and verified in vitro and xenograft tumor model. RESULTS: Here we showed that BRAF was overexpressed in AML and MDS patients, and correlated with poor prognosis. The BRAF inhibitor-Vemurafenib (VEM) could significantly induce senescence, proliferation inhibition and apoptosis in AML cells, which can be enhanced by Bortezomib (BOR). This inhibitory effect was also verified in CD34 + cells derived from AML patients. Mechanistically, we showed that VEM combined with BOR could turn on HIPPO signaling pathway, thereby inducing cellular senescence in AML cells and xenograft mouse. CONCLUSIONS: Taken together, our findings demonstrate a significant upregulation of BRAF expression in AML and MDS patients, which is associated with unfavorable clinical outcomes. We also discovered that the BRAF inhibitor Vemurafenib induces cellular senescence through activation of the HIPPO signaling pathway. Analysis of BRAF expression holds promise as a prognostic indicator and potential therapeutic target for individuals with AML and MDS.

Acteoside (Verbascoside): A Prospective Therapeutic Alternative against Hepatocellular Carcinoma by Inhibiting the Expression of AXL, FGFR, BRAF, TIE2 and RAF1 Targets.

AIM: Hepatocellular carcinoma (HCC) is the world's second leading cause of cancerrelated mortality and the fifth most prevalent cancer overall. Several synthetic and plant-based remedies are in practice to treat diverse liver disorders. Because of their minimal side effects and protective characteristics, plant phenolics have the potential to become alternative therapeutics, replacing currently existing HCC medications. The present study identifies the plant phenolics as having the capacity to inhibit HCC with low side effects and cost efficiency. BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related mortality, despite the proven effectiveness of screening programs for at-risk individuals, the majority of patients have disease progression or tumor characteristics that preclude curative therapies at the time of diagnosis. Acteoside (Verbascoside) is a naturally occurring phenylethanoid glycoside found throughout the plant kingdom. Acteoside is a physiologically active chemical with the number of pharmacological and protective effects against various liver illnesses. OBJECTIVES: Currently used HCC medications have a variety of side effects. Plant-based chemicals offer the possibility of treating HCC with minimal side effects. The work is targeted to find the best phytochemical (plant phenolic) lead molecule for future drug development research against Hepatocellular carcinoma. METHODS: The targets were selected based on an analysis of relevant literature, and the 3D structures of the selected receptors were obtained in. pdb format from the RCSB-Protein data bank (PDB, http://www.rscb.org/pdb). Based on a review of the literature, sixty plant secondary metabolites, or plant phenolics, were selected. The ligand structures were obtained and downloaded in.sdf format from the NCBI PubChem chemicals database (https://pubchem.ncbi.nlm.nih.gov/). Molecular docking between the receptor and ligands was accomplished using the Molegro Virtual Docker 6.0 (MVD) software. RESULTS: The target RAF1, BRAF chain 1, TIE2 chain 2 FGFR1, FGFR2, AXL, and FGFR4 showed the best binding effectiveness with acteoside compared to their respective positive control. RET chain 1 and BRAF chain 2 acteoside showed prominent binding efficacy after Curcumin, and Epigallocatechingallate, respectively, against positive control. Present findings clearly point towards the potentiality of acteoside in inhibiting various HCC targets. CONCLUSION: Acteoside may be used as a prominent lead molecule in the future treatment of hepatic cancer with its multifaceted binding efficiencies against various target proteins.

Carotenoids from Marine Microalgae as Antimelanoma Agents.

Melanoma cells are highly invasive and metastatic tumor cells and commonly express molecular alterations that contribute to multidrug resistance (e.g., BRAFV600E mutation). Conventional treatment is not effective in a long term, requiring an exhaustive search for new alternatives. Recently, carotenoids from microalgae have been investigated as adjuvant in antimelanoma therapy due to their safety and acceptable clinical tolerability. Many of them are currently used as food supplements. In this review, we have compiled several studies that show microalgal carotenoids inhibit cell proliferation, cell migration and invasion, as well as induced cell cycle arrest and apoptosis in various melanoma cell lines. MAPK and NF-ĸB pathway, MMP and apoptotic factors are frequently affected after exposure to microalgal carotenoids. Fucoxanthin, astaxanthin and zeaxanthin are the main carotenoids investigated, in both in vitro and in vivo experimental models. Preclinical data indicate these compounds exhibit direct antimelanoma effect but are also capable of restoring melanoma cells sensitivity to conventional chemotherapy (e.g., vemurafenib and dacarbazine).

A prognostic six-gene expression risk-score derived from proteomic profiling of the metastatic colorectal cancer secretome.

The necessity to accurately predict recurrence and clinical outcome in early stage colorectal cancer (CRC) is critical to identify those patients who may benefit from adjuvant chemotherapy. Here, we developed and validated a gene-based risk-score algorithm for patient stratification and personalised treatment in early stage disease based on alterations in the secretion of metastasis-related proteins. A quantitative label-free proteomic analysis of the secretome of highly and poorly metastatic CRC cell lines with different genetic backgrounds revealed 153 differentially secreted proteins (fold-change >5). These changes in the secretome were validated at the transcriptomic level. Starting from 119 up-regulated proteins, a six-gene/protein-based prognostic signature composed of IGFBP3, CD109, LTBP1, PSAP, BMP1, and NPC2 was identified after sequential discovery, training, and validation in four different cohorts. This signature was used to develop a risk-score algorithm, named SEC6, for patient stratification. SEC6 risk-score components showed higher expression in the poor prognosis CRC subtypes: consensus molecular subtype 4 (CMS4), CRIS-B, and stem-like. High expression of the signature was also associated with patients showing dMMR, CIMP+ status, and BRAF mutations. In addition, the SEC6 signature was associated with lower overall survival, progression-free interval, and disease-specific survival in stage II and III patients. SEC6-based risk stratification indicated that 5-FU treatment was beneficial for low-risk patients, whereas only aggressive treatments (FOLFOX and FOLFIRI) provided benefits to high-risk patients in stages II and III. In summary, this novel risk-score demonstrates the value of the secretome compartment as a reliable source for the retrieval of biomarkers with high prognostic and chemotherapy-predictive capacity, providing a potential new tool for tailoring decision-making in patient care.

Off-label use of cetuximab plus sorafenib and panitumumab plus regorafenib to personalize therapy for a patient with V600E BRAF-mutant metastatic colon cancer.

Sorafenib, the first agent developed to target BRAF mutant melanoma, is a multi-kinase inhibitor that was approved by the FDA for therapy of kidney and subsequently liver cancer, and is currently in clinical trials for thyroid, lung and brain cancer. Colorectal cancer with V600E BRAF mutation has shown relative resistance to standard chemotherapy regimens, as well as lack of efficacy to vemurafenib in clinical trials. New treatments are needed for BRAF-mutant colorectal cancer. We report a case of a patient with BRAF-mutant metastatic colon cancer whose disease had progressed on FOLFOX plus bevacizumab and subsequent FOLFIRI plus cetuximab. Based on preclinical data published in Nature in 2012 suggesting that successful therapeutic targeting of BRAF in colorectal cancer may require concomitant targeting of the EGFR, we offered this patient without other attractive options the combination of sorafenib plus cetuximab, in off-label use with informed consent. Sorafenib and cetuximab therapy led to a mixed radiographic response with some areas showing dramatic improvement and other areas showing stable disease over a 7-month period which is a notably long period of progression-free survival for V600E BRAF mutated colon cancer. The cetuximab plus sorafenib therapy was very well-tolerated by the patient who remained on it long enough until another therapy option, regorafenib, was approved in September 2012. The patient was offered single agent regorafenib at the time of progression. At the time of progression on single agent regorafenib, panitumumab was combined with regorafenib and this was also well-tolerated and appeared to slow disease progression. Further study of these approaches in the clinic as personalized treatment of BRAF-mutant advanced colorectal cancer is warranted.