Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The small molecule drug 5-fluorouracil (5-FU) is widely used in the treatment for gastric cancer (GC), however, it exerts poor efficacy and is associated with acquired and intrinsic resistance. Focal adhesion kinase (FAK), a non-receptor tyrosine kinase, plays a key role in adhesion, migration, and proliferation of gastric carcinoma cells, suggesting that this kinase may be a promising therapeutic target. Differentially expressed FAK in GC tissue was detected by RT-qPCR and TCGA database analysis. To investigate the biological functions of FAK, loss-of-function experiments were performed. CCK-8 assay, colony formation assay, flow cytometry, dual-luciferase reporter assays, and western blot assays were conducted to determine the underlying mechanisms of FAK in 5-FU chemosensitivity in GC. FAK is overexpressed in GC patients, and positively correlated with poor prognosis. The use of shRNA interference to target FAK decreased proliferation and increased apoptosis of GC cells in vitro. Importantly, FAK silencing enhanced the therapeutic efficacy of 5-FU, leading to reduced tumor growth in vivo. We further demonstrated that FAK silencing increased 5-FU-induced caspase-3 activity, and promoted p53 transcriptional activities. Clinical data also has shown that patients with higher levels of FAK had significantly shorter overall survival (OS) and time to first progression (FP) than those with lower levels of FAK. These findings indicate that FAK plays a critical role in 5-FU chemosensitivity in GC, and the use of FAK inhibitors as an adjunct to 5-FU might be an effective strategy for patients who undergo chemotherapy.
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PMID:Inhibition of protein FAK enhances 5-FU chemosensitivity to gastric carcinoma via p53 signaling pathways. 3196 73

Axl receptor tyrosine kinase has been implicated in cancer progression, invasion, and metastasis in various cancer types. Axl overexpression has been observed in many cancers, and selective inhibitors of Axl, including R428, may be promising therapeutic agents for several human cancers, such as breast, lung, and pancreatic cancers. Here, we examined the cell growth inhibition mediated by R428 and auranofin individually as well as in combination in the human breast cancer cell lines MCF-7 and MDAMB- 231 to identify new advanced combination treatments for human breast cancer. Our data showed that combination therapy with R428 and auranofin markedly inhibited cancer cell proliferation. Isobologram analyses of these cells indicated a clear synergism between R428 and auranofin with a combination index value of 0.73. The combination treatment promoted apoptosis as indicated by caspase 3 activation and poly (ADP-ribose) polymerase cleavage. Cancer cell migration was also significantly inhibited by this combination treatment. Moreover, we found that combination therapy significantly increased the expression level of Bax, a mitochondrial proapoptotic factor, but decreased that of the X-linked inhibitor of apoptosis protein. Furthermore, the suppression of cell viability and induction of Bax expression by the combination treatment were recovered by treatment with N-acetylcysteine. In conclusion, our data demonstrated that combined treatment with R428 and auranofin synergistically induced apoptosis in human breast cancer cells and may thus serve as a novel and valuable approach for cancer therapy.
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PMID:Synergistic Induction of Apoptosis by the Combination of an Axl Inhibitor and Auranofin in Human Breast Cancer Cells. 3253 18

Surgery combined with adjuvant or neoadjuvant chemotherapy is still the standard treatment for osteosarcoma. However, the high risk of tumor recurrence and side effects of chemotherapy usually lead to high mortality for cancer patients. Herein, the multi-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib (Sun) and photodynamic therapy (PDT) drug chlorin e6 (Ce6) were locally delivered to the postoperative tumor site via a zwitterionic hydrogel. This hydrogel exhibited excellent biocompatibility and redox responsiveness. In vitro study demonstrated that Sun/Ce6@Gel induced 143B human osteosarcoma cell apoptosis via downregulating the expression of Bcl-2 and upregulating the expression levels of Bax and caspase-3. Similarly, the in vivo study showed that Sun/Ce6@Gel provided sustained drug release under redox conditions, and then synergistically induced tumor apoptosis to prevent tumor recurrence without systemic toxicity. Therefore, local implantation of Sun/Ce6@Gel may be a promising topical therapeutic method for prevention of the recurrence of osteosarcoma after surgery.
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PMID:Local delivery of sunitinib and Ce6 via redox-responsive zwitterionic hydrogels effectively prevents osteosarcoma recurrence. 3257 60

Temozolomide (TMZ) therapy is the standard of care for patients with glioblastoma (GBM). Clinical studies have shown that elevated levels of DNA repair protein O (6)-methylguanine-DNA methyltransferase (MGMT) or deficiency/defect of DNA mismatch repair (MMR) genes is associated with TMZ resistance in some, but not all, GBM tumors. Another reason for GBM treatment failure is signal redundancy due to coactivation of several functionally linked receptor tyrosine kinases (RTKs), including anaplastic lymphoma kinase (ALK) and c-Met (hepatocyte growth factor receptor). As such, these tyrosine kinases serve as potential targets for GBM therapy. Thus, we tested two novel drugs: INC280 (Capmatinib: a highly selective c-Met receptor tyrosine kinase-RTK inhibitor) and LDK378 (Ceritinib: a highly selective anaplastic lymphoma kinase-ALK inhibitor), aiming to overcome TMZ resistance in MGMT-unmethylated GBM cells in in vitro cell culture models. Treatments were examined using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, caspase-3 assay and western blot analysis. Results obtained from our experiments demonstrated that preconditioning with INC280 and LDK378 drugs exhibit increased MMR protein expression, specifically MMR protein MLH1 (MutL Homolog 1) and MSH6 (MutS Homolog 6) and sensitized TMZ in MGMT-unmethylated GBM cells via suppression of ALK and c-Met expression. INC280 and LDK378 plus TMZ also induced apoptosis by modulating downstream signaling of PI3K/AKT/STAT3. Taken together, this data indicates that co-inhibition of ALK and c-MET can enhance growth inhibitory effects in MGMT-unmethylated cells and enhance TMZ sensitivity in-vitro, suggesting c-Met inhibitors combined with ALK-targeting provide a therapeutic benefit in MGMT-unmethylated GBM patients.
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PMID:Preconditioning with INC280 and LDK378 drugs sensitizes MGMT-unmethylated glioblastoma to temozolomide: Pre-clinical assessment. 3286 16


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