Melanoma responds poorly to standard chemotherapy due to its intrinsic chemoresistance. Multiple genetic and molecular defects, including an activating mutation in the BRaf kinase gene, are associated with melanoma, and the resulting alterations in signal transduction pathways regulating proliferation and apoptosis are thought to contribute to its chemoresistance. Sorafenib, a multikinase inhibitor that targets BRaf kinase, is Food and Drug Administration approved for use in advanced renal cell and hepatocellular carcinomas. Although sorafenib has shown little promise as a single agent in melanoma patients, recent clinical trials suggest that, when combined with chemotherapy, it may have more benefit. We evaluated the ability of sorafenib to augment the cytotoxic effects of melphalan, a regional chemotherapeutic agent, and temozolomide, used in systemic and regional treatment of melanoma, on a panel of 24 human melanoma-derived cell lines and in an animal model of melanoma. Marked differences in response to 10 micromol/L sorafenib alone were observed in vitro across cell lines. Response to sorafenib significantly correlated with extracellular signal-regulated kinase (ERK) downregulation and loss of Mcl-1 expression (P < 0.05). Experiments with the mitogen-activated protein kinase/ERK kinase inhibitor U0126 suggest a unique role for ERK downregulation in the observed effects. Sorafenib in combination with melphalan or temozolomide led to significantly improved responses in vitro (P < 0.05). In the animal model of melanoma, sorafenib in combination with regional melphalan or regional temozolomide was more effective than either treatment alone in slowing tumor growth. These results show that sorafenib in combination with chemotherapy provides a novel approach to enhance chemotherapeutic efficacy in the regional treatment of in-transit melanoma.
"In oncology, experimental therapies in humans and in animal experiments have shown that tumor treatment may be more effective when combining standard chemotherapy with biologicals, immunomodulating agents or cell-based immunotherapies. For example, the multiple kinase inhibitor sorafenib can improve melanoma chemotherapy in animal models . Combining the contact sensitizer DNCB with dacarbazine is a strategy which improves chemotherapy in mice  and humans  by inducing a T-cell dependent immune response . "
[Show abstract][Hide abstract] ABSTRACT: Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments.
B16.F10 subcutaneous melanoma bearing C57BL/6 mice were treated with new mistletoe extracts containing both water soluble compounds and solubilized triterpenoids. Tumor growth and survival was monitored. In addition, histological examinations of the tumor material and tumor surrounding tissue were performed.
Addition of solubilized triterpenoids increased the anti-tumor effects of the mistletoe extracts, resulting in reduced tumor growth and prolonged survival of the mice. Histological examination of the treated tumors showed mainly tumor necrosis and some apoptotic cells with active caspase-3 and TUNEL staining. A significant decrease of CD31-positive tumor blood vessels was observed after treatment with solubilized triterpenoids and different mistletoe extracts.
We conclude that the addition of solubilized mistletoe triterpenoids to conventional mistletoe extracts improves the efficacy of mistletoe treatment and may represent a novel treatment option for malignant melanoma.
PLoS ONE 04/2013; 8(4):e62168. DOI:10.1371/journal.pone.0062168 · 3.23 Impact Factor
"Consistent with previous studies (Augustine et al, 2010; Huber et al, 2011), however, another antiapoptotic protein, Mcl-1, was significantly downregulated by sorafenib either alone or in combination with OGX-011. Furthermore, an almost complete inactivation of Akt and p44/42 MAPK, signal transduction pathways with a potential impact on the proliferation of cancer cells, was observed in ACHN cells after combined treatment with OGX-011 and sorafenib. "
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate whether the therapeutic activity of sorafenib could be enhanced by combining with OGX-011, an antisense oligodeoxynucleotide (ODN) targeting clusterin, in renal cell carcinoma (RCC).
We investigated the effects of combined treatment with OGX-011 and sorafenib on a human RCC ACHN model both in vitro and in vivo.
Although clusterin expression was increased by sorafenib, additional treatment of ACHN with OGX-011 significantly blocked the upregulation of clusterin induced by sorafenib. Despite the lack of a significant effect on the growth of ACHN, OGX-011 synergistically enhanced the sensitivity to sorafenib, reducing the IC(50) by >50%. Apoptotic changes were intensively detected in ACHN after combined treatment with OGX-011 and a sublethal dose of sorafenib, but not either agent alone. Furthermore, this combined treatment resulted in the marked downregulation of phosphorylated Akt and p44/42 mitogen-activated protein kinase in ACHN compared with treatment with either agent alone. In vivo systemic administration of OGX-011 plus sorafenib significantly decreased the ACHN tumour volume compared with control ODN plus sorafenib.
Combined use with OGX-011 may be useful in enhancing the cytotoxic effect of sorafenib on RCC by inducing apoptosis and inactivating major signal transduction pathways.
British Journal of Cancer 05/2012; 106(12):1945-52. DOI:10.1038/bjc.2012.209 · 4.84 Impact Factor
"Various studies have shown the potential of sorafenib in inhibiting the growth of a host of malignancies including melanoma, leukemia, hepatocellular carcinoma, esophageal carcinoma in vitro and in vivo (Wilhelm et al., 2004; Sharma et al., 2005), and is successfully utilized in the treatment of renal cell carcinoma (Escudier et al., 2009). Single agent sorafenib for melanoma treatment has been largely unsuccessful, with efficacy improved when used in conjunction with chemotherapy or adjuvant immunotherapy (Eisen et al., 2006; McDermott et al., 2008; Amaravadi et al., 2009; Augustine et al., 2010; Ott et al., 2010; Egberts et al., 2011). Small molecule inhibitors with greater specificity to mutant BRAF V600E than the wild-type protein have been developed. "
[Show abstract][Hide abstract] ABSTRACT: Genomic variation is a trend observed in various human diseases including cancer. Genetic studies have set out to understand how and why these variations result in cancer, why some populations are predisposed to the disease, and also how genetics affect drug responses. The melanoma incidence has been increasing at an alarming rate worldwide. The burden posed by melanoma has made it a necessity to understand the fundamental signaling pathways involved in this deadly disease. Signaling cascades such as MAPK and PI3K/AKT have been shown to be crucial in the regulation of processes that are commonly dysregulated during cancer development such as aberrant proliferation, loss of cell cycle control, impaired apoptosis and altered drug metabolism. Understanding how these and other oncogenic pathways are regulated has been integral in our challenge to develop potent anti-melanoma drugs. With advances in technology and especially in next generation sequencing, we have been able to explore melanoma genomes and exomes leading to the identification of previously unknown genes with functions in melanomagenesis such as GRIN2A and PREX2. The therapeutic potential of these novel candidate genes is actively being pursued with some presenting as druggable targets while others serve as indicators of therapeutic responses. In addition, the analysis of the mutational signatures of melanoma tumors continues to cement the causative role of UV exposure in melanoma pathogenesis. It has become distinctly clear that melanomas from sun exposed skin areas have distinct mutational signatures including C to T transitions indicative of UV-induced damage. It is thus necessary to continue spreading awareness on how to decrease the risk factors of developing the disease while at the same time working for a cure. Given the large amount of information gained from these sequencing studies, it is likely that in the future, treatment of melanoma will follow a highly personalized route that takes into accou
Frontiers in Genetics 01/2012; 3:330. DOI:10.3389/fgene.2012.00330
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