Abstract
BackgroundTumor Necrosis Factor-α Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. Although TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. In the current work, we screened a small library of fifty-five FDA and foreign-approved anti-neoplastic drugs in order to identify candidates that sensitized resistant prostate and pancreatic cancer cells to TRAIL-induced apoptosis.MethodsFDA-approved drugs were screened for their ability to sensitize TRAIL resistant prostate cancer cells to TRAIL using an MTT assay for cell viability. Analysis of variance was used to identify drugs that exhibited synergy with TRAIL. Drugs demonstrating the highest synergy were selected as leads and tested in different prostate and pancreatic cancer cell lines, and one immortalized human pancreatic epithelial cell line. Sequential and simultaneous dosing modalities were investigated and the annexin V/propidium iodide assay, in concert with fluorescence microscopy, was employed to visualize cells undergoing apoptosis.ResultsFourteen drugs were identified as having synergy with TRAIL, including those whose TRAIL sensitization activities were previously unknown in either prostate or pancreatic cancer cells or both. Five leads were tested in additional cancer cell lines of which, doxorubicin, mitoxantrone, and mithramycin demonstrated synergy in all lines. In particular, mitoxantrone and mithramycin demonstrated significant synergy with TRAIL and led to reduction of cancer cell viability at concentrations lower than 1 μM. At these low concentrations, mitoxantrone demonstrated selectivity toward malignant cells over normal pancreatic epithelial cells.ConclusionsThe identification of a number of FDA-approved drugs as TRAIL sensitizers can expand chemotherapeutic options for combination treatments in prostate and pancreatic cancer diseases.
Highlights
Tumor Necrosis Factor-a Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells
In the current study, we screened a small library of fiftyfive FDA- and foreign-approved antineoplastic drugs from the Johns Hopkins Clinical Compound Library (JHCCL) in order to identify chemotherapeutics that sensitize prostate and pancreatic cancer cells to TRAILinduced apoptosis
PC3-TR (TR: TRAIL resistant) human prostate cancer cells were used in the primary screening, since it was hypothesized that lead candidates discovered for this resistant cell line might be relevant to clinical phenotypes that develop resistance to TRAIL
Summary
Tumor Necrosis Factor-a Related Apoptosis Inducing Ligand (TRAIL) and agonistic antibodies to death receptor 4 and 5 are promising candidates for cancer therapy due to their ability to induce apoptosis selectively in a variety of human cancer cells, while demonstrating little cytotoxicity in normal cells. TRAIL and agonistic antibodies to DR4 and DR5 are considered safe and promising candidates in cancer therapy, many malignant cells are resistant to DR-mediated, TRAIL-induced apoptosis. TRAIL has attracted significant attention in recent years due to its ability to selectively induce apoptosis in transformed (malignant) cells while demonstrating little is hypothesized that these receptors play a role in maintaining the homeostasis of TRAIL activity in vivo [2,8]. Recombinant TRAIL induces apoptosis in a variety of human cancer cell lines including those of breast, colon, lung, prostate, liver, leukemia, lymphoma, and neuroblastoma [4,6,8,9]. As a consequence of the selectivity towards malignant cells, certain TRAIL formulations (e.g. non-histidine tagged TRAIL) are considered safe for potential therapeutic applications [15]
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