Multikinase inhibitor sorafenib exerts cytocidal efficacy against Non‐Hodgkin lymphomas associated with inhibition of MAPK14 and AKT phosphorylation

Chapuy, Bjoern; Schuelper, Nikolai; Panse, Melanie; Dohm, Andrea; Hand, Elisabeth; Schroers, Roland; Truemper, Lorenz; Wulf, Gerald

doi:10.1111/j.1365-2141.2010.08526.x

Cited by 16 publications

(9 citation statements)

References 36 publications

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“…Sorafenib (Bay43-9006; Nexavar, Bayer Healthcare Pharmaceuticals) is such an inhibitor that-among other pathwaysalso blocks MAPK14/p38 signaling. 34,35 It has been shown to exhibit high anticancer efficacy in acute myeloid leukemia and intra -and interstrand crosslinks. 26 This type of DNA damage is fundamentally different from the misincorporation of nucleoside analogs.…”

Section: Discussionmentioning

confidence: 99%

The MAPK-activated protein kinase 2 mediates gemcitabine sensitivity in pancreatic cancer cells

et al. 2014

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Pancreatic carcinoma is the major clinical entity where the nucleoside analog gemcitabine is used for first-line therapy. Overcoming cellular resistance toward gemcitabine remains a major challenge in this context. This raises the need to identify factors that determine gemcitabine sensitivity in pancreatic carcinoma cells. We previously found the MAPK-activated protein kinase 2 (MK2), part of the p38/MK2 stress response pathway, to be required for DNA replication fork stalling when osteosarcoma-derived cells were treated with gemcitabine. As a consequence, inhibition or depletion of MK2 protects these cells from gemcitabine-induced death (Köpper, et al. Proc Natl Acad Sci USA 2013; 110:16856-61). Here, we addressed whether MK2 also determines the sensitivity of pancreatic cancer cells toward gemcitabine. We found that MK2 inhibition reduced the intensity of the DNA damage response and enhanced survival of the pancreatic cancer cell lines BxPC-3, MIA PaCa-2, and Panc-1, which display a moderate to strong sensitivity to gemcitabine. In contrast, MK2 inhibition only weakly attenuated the DNA damage response intensity and did not enhance long-term survival in the gemcitabine-resistant cell line PaTu 8902. Importantly, in BxPC-3 and MIA PaCa-2 cells, inhibition of MK2 also rescued increased H2AX phosphorylation caused by inhibition of the checkpoint kinase Chk1 in the presence of gemcitabine. These results indicate that MK2 mediates gemcitabine efficacy in pancreatic cancer cells that respond to the drug, suggesting that the p38/MK2 pathway represents a determinant of the efficacy by that gemcitabine counteracts pancreatic cancer.

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Section: Discussionmentioning

confidence: 99%

The MAPK-activated protein kinase 2 mediates gemcitabine sensitivity in pancreatic cancer cells

et al. 2014

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“…Several in vitro trials have shown that sorafenib exerts cytotoxic activity towards lymphoma cell lines as well as proliferation arrest leading to complete loss of clonogenicity [159]. This effect has been mainly attributed to disruption of p38 MAPK and AKT signaling.…”

Section: Raf Inhibitionmentioning

confidence: 99%

B-cell receptor signaling in the pathogenesis of lymphoid malignancies

Bojarczuk

Bobrowicz

Dwojak

et al. 2015

Blood Cells, Molecules, and Diseases

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“…analyzed the cytotoxic effect of sorafenib on lymphoma cells (44) Chronic A preclinical study that Sorafenib-induced cell death of CLL cells accompanied by a loss of Mcl-1. lymphocytic evaluated the mechanism and leukemia activity of sorafenib in chronic lymphocytic leukemia (45) than with placebo (6 weeks; P=0.087).…”

Section: Hccmentioning

confidence: 99%

Molecular targeted therapies for cancer: Sorafenib monoï¿½therapy and its combination with other therapies (Review)

Ibrahim

Walsh

et al. 2012

Oncol Rep

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Abstract. Sorafenib is an oral multikinase inhibitor that acts by inhibiting tumor growth and disrupting tumor microvasculature through antiproliferative, anti-angiogenic and proapoptotic effects. It exerts these effects via inhibition of multiple targets including Raf serine/threonine kinases, vascular endothelial growth factor receptor tyrosine kinases; VEGFR-1, VEGFR-2, VEGFR-3 and platelet-derived growth factor receptor β (PDGFR-β). Current literature shows that the deregulated signaling through these receptors is commonly seen in human tumors. In addition, sorafenib is also shown to induce apoptosis through downregulation of Mcl-1 in many cancer types. Hence, sorafenib as a single agent has shown promising activity in some cancers such as renal cell carcinoma (RCC), hepatocellular carcinoma (HCC) and thyroid cancers. Currently, the drug holds FDA approval for the treatment of advanced RCC and unresectable HCC. However, many clinical studies have indicated several limitations to the application of sorafenib as a single agent in various other cancers. Owing to these reasons and the potential of sorafenib to synergize with other anticancer therapies, its combination with other targeted agents and chemotherapy has been widely explored with promising results. In addition, it has also shown synergistic results when combined with radiation. This review summarizes the current basic and clinical studies on the effects and mechanisms of sorafenib either administered alone or in combination with other anticancer treatments. IntroductionSince the 1980s, the field of cancer treatment has experienced a major paradigm shift from broad-spectrum cytotoxic chemotherapeutics to the development of targeted therapies tailored to inhibit cancer-specific pathways (1). This change was prompted by the limitations of the treatment mainstays in those days, which were surgery, chemotherapy and radiotherapy. Surgery was limited to early non-metastatic diseases, however, research demonstrates that solid tumors are frequently metastatic at presentation (2). Radiation and chemotherapy has limited capacity to discriminate between cancerous and normal cells and hence, results in severe side effects (3). Furthermore, solid tumors are inherently resistant to both radiation and chemotherapy. Therefore, the rationale for development of molecular targeted therapies was to overcome drug resistance, to make malignant cells more susceptible to suppression and damage whilst avoiding substantial toxicity to the rest of the body tissues and also to provide a higher therapeutic index.The molecular targeted therapies include monoclonal antibodies, tyrosine kinase inhibitors, rapamycin pathway inhibitors, proteasome inhibitors and inhibitors of Raf kinase (4). Many of these drugs have shown therapeutic benefit in various cancers, however, several challenges are yet to be conquered by the developers. These include overcoming certain amount of acquired resistance in cancer cells, selecting suitable dosage schedules, determining the stage to start treatmen...

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Multikinase inhibitor sorafenib exerts cytocidal efficacy against Non‐Hodgkin lymphomas associated with inhibition of MAPK14 and AKT phosphorylation

Cited by 16 publications

References 36 publications

The MAPK-activated protein kinase 2 mediates gemcitabine sensitivity in pancreatic cancer cells

The MAPK-activated protein kinase 2 mediates gemcitabine sensitivity in pancreatic cancer cells

B-cell receptor signaling in the pathogenesis of lymphoid malignancies

Molecular targeted therapies for cancer: Sorafenib monoï¿½therapy and its combination with other therapies (Review)

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