Resistant to strategies targeting pathway may therefore multiple pathways must be aligned for maximum therapeutic benefit. 4.0. crosstalk path agents can affect the interaction between MAPK pathways has the potential to regulate Dihydrofolate Reductase the efficacy of drugs. crosstalk or interaction of this kind has the potential to make a more effective compounds, make the other unn term and f has rdern the potential drug resistance. 4.1. AKT3 inhibitory crosstalk between MAPK and many studies report crosstalk between MAPK and PI3K signaling pathways in melanoma. Stimulating activity T RAF B epidermal growth factor can be inhibited by the expression of AKT co. Moreover RAF activity B t rises after treatment LY294002, suggesting that AKT B RAF activity t downregulated in melanoma cells.
RAF B contains lt Three AKT phosphorylation sites within the consensus of its amino-terminal domain Ne of the scheme which the activity of t Of the LY404039 protein is regulated. AKT phosphorylates Ser364 and Ser428 B RAF down regulates its catalytic activity T. This was in early melanoma by ectopic expression of active AKT3 in melanoma cells, independently of the anchor Ngiges decreasing growth by inhibiting MAPK activity V600EB RAF t helped eliminate senescence and validated F Promotion of tumor progression. Mechanistic AKT3 detected directly Ser364 and Ser428 RAF B, MAPK activity Reduced t and the transformation of melanocytes was phosphorylated. Simultaneously inhibits two proteins Fa also been found Synergistic inhibition of tumor development in siRNA by nucleofection or using nanoliposomes was introduced.
This is the inhibition of the signal paths in Akt3 PI3K and MAPK activity f t rdern senescence. Studies have also shown that the A3 adenosine receptor activation can prevent the proliferation of ERK1 / 2 by antagonizing B RAF and AKT activation via stimulation of PI3K. In a model of mouse melanoma spontaneous loss of PTEN has been shown, for the progression of the nevi V600EB RAF be required in melanomas. Thus, the cross-talk between the PI3K and MAPK used to effectively treat melanoma AKT3 inhibit apoptosis f Rdern rdern and eliminate the inhibition of RAF V600EB senescence f. Target both lead to inhibition of tumor synergize. 4.2. Targeting MEK and RAF B overcome the resistance to MEK inhibitors targeting MEK1 / 2 with siRNA or pharmacological agents, CI1040, U0126, k Can AZD6244 or PD98059 inhibit the growth, invasive potential of melanoma cells and awareness chemotherapeutic agents.
Mechanistic inhibition of MEK with U0126 or siRNA sensitizes human melanoma cells to endoplasmic reticulum stress to foreign-induced apoptosis send Caspase 4, caspase-9 and caspase-3. However chemosensitizing and growth inhibitory properties of the inhibition of MEK1 / 2 are not universally observed in all melanoma cells. MEK1 / 2 inhibitors are effective in cells. The mutant RAF B compared to wild-type protein or a mutant ras Selectivity t is probable Dependence Dependence of melanoma cells mutated B RAF. Melanoma cells against certain MEK1 / 2 inhibitors, for the protection of these cells by chemotherapeutic agents. For