Are we on the right TRAIL toward Death Receptor?

September 25, 2010, Featured in Cancer and Natural Medicines, 0 Comments

Triggering of tumour cell apoptosis is the foundation of many cancer therapies. TRAIL (TNF-related apoptosis-inducing ligand) is a death pathway that, under the right circumstances, can induce cells to commit an orderly form of suicide called apoptosis. TRAIL (also known as Apo2L) is Type II transmembrane protein belonging to the Tumor Necrosis Factor (TNF) superfamily that is expressed on the surface of Natural Killer (NK) and T cells, macrophages and dendritic cells. As with other cytokines, the protein is synthesized in a pro-form with a signal sequence that is removed in the mature secreted protein.

Death receptors of TNF (the tumour necrosis factor) superfamily have been largely characterized, as have the signals that are generated when these receptors are activated. TRAIL receptors (DR4 and DR5) are promising targets for cancer therapy. TRAIL can kill any cancer or leukemia cell regardless of their degree of malignancy. But activating TRAIL production and expression of TRAIL receptors successfully are not easy in many human cancers.

TRAIL: A Sword for Killing Tumors.

TRAIL-induced apoptosis and expression of death receptor TRAIL-R1 and TRAIL-R2 in bladder cancer cells.

TRAIL receptor signalling and modulation: Are we on the right TRAIL?

TRAIL and other TRAIL receptor agonists as novel cancer therapeutics.

Defects in TRAIL receptor signaling might determine the response to cytotoxic chemotherapy as well as determining the response to the therapeutics that are specifically targeted to TRAIL receptors. Studies show that in tumor cells that are resistant to TRAIL-induced apoptosis, TRAIL treatment can cause increased growth and metastasis. The mechanism for these effects is likely related to the other signaling pathways that are induced by TRAIL receptors along side the activation of the apoptosis machinery– i.e. in cells that cannot activate apoptosis, these other signals may increase tumor cell growth and survival. Therefore, identification of patients whose tumors have developed TRAIL resistance is critically important because not only might TRAIL resistance limit the usefulness of TRAIL Receptor-targeted drugs and chemotherapeutic agents that work indirectly through TRAIL Receptors; treatment with these agents may then actually promote tumor growth and metastasis in these patients due to TRAIL-activated nuclear factor-kappaB (NF-kB) signalling. NF-kB inhibits TRAIL-induced apoptosis. It is NOT EASY TO SAFELY KILL THE CANCER CELLS.

TRAIL promotes metastasis of human pancreatic ductal adenocarcinoma.

Tumor necrosis factor-related apoptosis-inducing ligand-mediated proliferation of tumor cells with receptor-proximal apoptosis defects.

TRAIL induced survival and proliferation in cancer cells resistant towards TRAIL-induced apoptosis mediated by NF-kappaB.

Nuclear factor-kappaB maintains TRAIL resistance in human pancreatic cancer cells.

Natural compounds, occurring in vegetables, fruits, herbs, spices, propolis, tea, beer, and wine play an important role in cancer treatment. These naturally occurring compounds such as sulphoraphane or the flavonoids curcumin, quercetin, resveratrol, baicalein and wogonin can restore tumor cell sensitivity to TRAIL-induced cell death with no apparent toxicity towards normal cells. Both extrinsic and intrinsic pathways can be modulated by natural compounds, the activation of which largely depends on the cell type, the particular compound, and the conditions of treatment.

Molecular crosstalk between TRAIL and natural antioxidants in the treatment of cancer.

Combining naturally occurring polyphenols with TNF-related apoptosis-inducing ligand: a promising approach to kill resistant cancer cells?

The role of dietary polyphenols in tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis for cancer chemoprevention.

Sulforaphane enhances TRAIL and sensitizes TRAIL-resistant cells. Study shows that sulforaphane-induced apoptosis correlated with the generation of intracellular reactive oxygen species (ROS), collapse of mitochondrial membrane potential, activation of caspase-3 and caspase-9, and up-regulation of TRAIL receptors (DR4 and DR5). Sulforaphane induced the expression of Bax, Bak, Bim, and Noxa and inhibited the expression of Bcl-2, Bcl-X(L), and Mcl-1. The quenching of ROS generation with antioxidant N-acetyl-L-cysteine conferred significant protection against sulforaphane-induced ROS generation, mitochondrial membrane potential disruption, caspase-3 activation, and apoptosis

Sulforaphane enhances the therapeutic potential of TRAIL in prostate cancer orthotopic model through regulation of apoptosis, metastasis, and angiogenesis.

Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics.

Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB-induced antiapoptotic signalling.

Wogonin is a flavonoid derived from the root of Baikal skullcap (Scutellaria baicalensis Georgi), a medicinal plant traditionally used in Oriental medicine. Wogonin also sensitizes TRAIL-induced apoptosis.

Reactive oxygen species up-regulate p53 and Puma; a possible mechanism for apoptosis during combined treatment with TRAIL and wogonin.

Wogonin sensitizes resistant malignant cells to TNFalpha- and TRAIL-induced apoptosis.

Also, Curcumin, Quercetin, Diallyl trisulfide (garlic constituent), Resveratrol, Propolis and its components significantly sensitize to TRAIL-induced death in cancer cells.

Curcumin sensitizes TRAIL-resistant xenografts: molecular mechanisms of apoptosis, metastasis and angiogenesis.

Quercetin enhances TRAIL-induced apoptosis in prostate cancer cells via increased protein stability of death receptor 5.

Quercetin sensitizes human hepatoma cells to TRAIL-induced apoptosis via Sp1-mediated DR5 up-regulation and proteasome-mediated c-FLIPS down-regulation.

Quercetin enhances TRAIL-mediated apoptosis in colon cancer cells by inducing the accumulation of death receptors in lipid rafts.

Diallyl trisulfide increases the effectiveness of TRAIL and inhibits prostate cancer growth in an orthotopic model: molecular mechanisms.

Resveratrol sensitizes melanomas to TRAIL through modulation of antiapoptotic gene expression.

Ethanolic extract of propolis (EEP) enhances the apoptosis- inducing potential of TRAIL in cancer cells.

Ethanolic Extract of Propolis Augments TRAIL-Induced Apoptotic Death in Prostate Cancer Cells.

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