Combination of adenoviruses expressing melanoma differentiation-associated gene-7 and chemotherapeutic agents produces enhanced cytotoxicity on esophageal carcinoma

Abstract

We examined the combinatory antitumor effects of adenoviruses expressing human mda-7/IL-24 gene (Ad-mda-7) and chemotherapeutic agents on nine kinds of human esophageal carcinoma cells. All the carcinoma cells expressed the melanoma differentiation-associated gene-7/interleukin-24 (MDA-7/IL-24) receptor complexes, IL-20R2 and either IL-20R1 or IL-22R1, and were susceptible to Ad-mda-7, whereas fibroblasts were positive only for IL-20R2 gene and resistant to Ad-mda-7-mediated cytotoxicity. Sensitivity of these esophageal carcinoma cells to Ad-mda-7 was however lower than that to Ad expressing the wild-type p53 gene. We thereby investigated a possible combination of Ad-mda-7 and anticancer agents and found that Ad-mda-7 with 5-fluorouracil (5-FU), cisplatin, mitomycin C or etoposide produced greater cytotoxic effects than those by Ad-mda-7 or the agent alone. Half-maximal inhibitory concentration values of the agents in respective cells were decreased by the combination with Ad-mda-7. Cell cycle analyses showed that Ad-mda-7 and 5-FU increased G2/M-phase and S-phase populations, respectively, and the combination augmented sub-G1 populations. Ad-mda-7-treated cells showed cleavages of caspase-8, -9 and -3 and poly (ADP-ribose) polymerase, but the cleavage levels were not different from those of the combination-treated cells. Ad-mda-7 treatments upregulated Akt phosphorylation but suppressed IκB-α levels, whereas 5-FU treatments induced phosphorylation of p53 and extracellular signal-regulated protein kinases 1 and 2. Molecular changes caused by the combination were similar to those by Ad-mda-7 treatments, but the Ad-mda-7-mediated upregulation of Akt phosphorylation decreased with the combination. These data collectively suggest that Ad-mda-7 induced apoptosis despite Akt activation and that the combinatory antitumor effects with 5-FU were produced partly by downregulating the Ad-mda-7-induced Akt activation.

Targeted silencing of SOX2 by an artificial transcription factor showed antitumor effect in lung and esophageal squamous cell carcinoma

“…Delivery of therapeutic viral vectors into the target organ and tumor is required for the treatment of lung cancer or esophageal cancer [ 41 – 43 ]. One of the drawbacks of this approach is the lack of means to effectively deliver the therapeutic virus to target different kinds of cells that reside within an intricate lung and esophageal structure.…”

Secreted recombinant human IL-24 protein inhibits the proliferation of esophageal squamous cell carcinoma Eca-109 cells in vitro and in vivo

“…Secreted rhIL-24 by normal cells inhibits invasion and sensitizes specific cancer cells containing functional IL-20R to radiation (19). With regard to ESCC, Ma et al (20) reported that Ad-IL-24 enhanced agent-mediated cytotoxicity in certain cell lines (TE-1, TE-2, TE-10, TE-11, YES-2, YES-4, YES-5, YES-6 and T.Tn cells), and the combination with 5-fluorouracil, cisplatin, mitomycin and etoposide produced greater antitumor effects than monotherapy. Our previous study showed that the human IL-24 peptide created by computer-guided design contributed to suppression of proliferation in ESCC Eca-109 cells (21).…”

Identification of IL20RB as a Novel Prognostic and Therapeutic Biomarker in Clear Cell Renal Cell Carcinoma

“…Although IL20RB was initially found to be involved in many nonmalignant diseases, such as psoriasis [ 16 ], rheumatoid arthritis [ 17 ], vitiligo [ 18 ], ulcerative colitis [ 19 ], glaucoma [ 20 ], asthma [ 21 ], endometriosis [ 22 ], and chronic rhinosinusitis [ 23 ] as well as infectious diseases [ 24 ], novel discoveries indicate IL20RB could also play an important role in malignant diseases. Recently, increasing evidence supports IL20RB also plays a vital role in human cancers such as colorectal adenocarcinoma [ 25 ], breast cancer [ 26 ], and esophageal carcinoma [ 27 ], while its role in ccRCC still remains unclear.…”