TRAIL, Fasl and a blocking anti‐DR5 antibody augment paclitaxel‐induced apoptosis in human non‐small‐cell lung cancer

Abstract

Key words: lung cancer; paclitaxel; TRAIL; DR5; FasL; apoptosisLung cancer is among the most commonly occurring malignancies worldwide and accounts for 1,193,000 deaths in 1999. 1 In the United States, lung cancer is the leading cause of cancer death in men, and it is the second most frequent cancer in women after breast cancer. NSCLC accounts for about 75 to 80% of lung cancer cases and carries an overall 5-year survival of about 10 -15% despite recent advancements in multimodality therapies (chemoand radio-therapies). 2 Most of the widely used chemotherapeutic agents induce apoptosis in susceptible cancer cells. 3-5 However, after a first round of multimodality therapy in NSCLC cancer, the cells responsible for NSCLC reoccurrence are drug-resistant cancer cell clones. PA is an antineoplastic plant alkaloid derived from Taxus baccata, which is widely administered in the treatment of advanced and metastatic lung, esophagus, breast and ovarian carcinomas. PA induces a single agent response rate approaching 25% in the treatment of NSCLC 6 and increases survival up to 40 weeks. 7-9 PA induces cytotoxicity by stabilizing microtubules and inhibiting their disassembly, thereby arresting the cells in the G 2 -M phase of the cell cycle. 10 In addition, downstream intracellular events include DNA cleavage 11 and activation of several caspases. 12 Thus, PA kills tumor cells by inducing both cellular necrosis and apoptosis.Apoptosis is a distinct form of programmed cell death, which normally occurs in part to annihilate overgrowth of extra-numerous cells. Apoptosis is associated with chromatin condensation (karyorrhexis) and margination to the nuclear membrane, cytoskeletal alterations, membrane blebbing and formation of apoptotic bodies. 13 In addition, mitochondrial function is irreversibly impaired early in apoptosis. 14,15 One of the best-characterized pathways for initiation of apoptosis involves the binding of extracellular death signal proteins (TNF␣, Fas ligand, TRAIL and Apo-3) to their cognate cell surface receptors. 16,17 Fas receptor (CD95) is a TNF family member containing a death effector domain (DED). Fas ligand (FasL and CD95L) induces cross-linking and trimerization of Fas, causing apoptotic cell death in both lymphoid and non-lymphoid cells. 18 Downstream signaling from the Fas receptor is initiated by recruitment of proteins to form a death-inducing signaling complex (DISC). 19 The binding of FasL to Fas results in recruitment of FADD (Fas-Associating protein with Death Domain) that is then responsible for cleavage of the first of a series of cysteine-dependent aspartate-directed proteases called caspases. The first caspase to be activated is FLICE (FADD-like Interleukin-1 beta converting enzyme) or caspase-8, which results in a caspase cascade that culminates in cell death by apoptosis. 12,18,20 Caspase-3 activation is critical for successfully trigging apoptosis. 12 Fas is constitutively expressed on a variety of tumor cells 21-24 including human lung carcinoma cells. [25][26][27] Anticancer drugs used...

Caspase Regulation in Non–Small Cell Lung Cancer and its Potential for Therapeutic Exploitation

“…In combination with chemotherapy, TRAIL is synergistic (89), and this effect does not correlate with either CASP8 nor FLIP expression level (90). Simultaneous expression of TRAIL and p53 increases apoptosis sensitivity in NSCLC cell lines (91).…”

Effect of NF-κB, survivin, Bcl-2 and Caspase3 on apoptosis of gastric cancer cells induced by tumor necrosis factor related apoptosis inducing ligand

“…TRAIL, also known as APO-2L [1,2] , is highly homologous to FasL. TRAIL is capable of inducing apoptosis of many kinds of cancer cells but nontoxic to normal cells [3][4][5][6][7][8][9][10][11][12][13] . It has been found that cells of different cancers and even different types of cells of a cancer exhibit significantly different sensitivity to TRAIL [14][15][16][17] .…”

Enhanced apoptosis of glioma cell lines is achieved by co-delivering FasL-GFP and TRAIL with a complex Ad5 vector

“…[21][22][23][24] Recently, studies have shown that both FasL and TRAIL can induce apoptosis in a number of tumor cell lines of various origins. [25][26][27][28][29] These proteins may have an advantage as therapeutics for brain tumors (BTs), since both they and their receptors are membrane proteins. Death ligand-induced apoptosis is mediated through cellcell contact, allowing the cell expressing the ligand to induce apoptosis in a number of surrounding receptorexpressing cells -a bystander effect not directly achieved with intracellular apoptosis-inducing proteins like p53 and Bax, and which does not require transport of prodrugs across the blood-brain barrier, as is the case for TK and cytosine deaminase.…”