Sialic acid-binding lectin (leczyme) induces apoptosis to malignant mesothelioma and exerts synergistic antitumor effects with TRAIL

Abstract

Malignant mesothelioma is a highly aggressive tumor with poor prognosis. An effective drug for treatment of malignant mesothelioma is greatly needed. Sialic acid-binding lectin (SBL) isolated from oocytes of Rana catesbeiana is a multifunctional protein which has lectin activity, ribonuclease activity and antitumor activity, so it could be developed as a new type of anticancer drug. The validity of SBL for treatment of malignant mesothelioma was assessed using three malignant mesotheliomas and a non-malignant mesothlial cell line. Effectiveness of combinatorial treatment of SBL and tumor necrosis factor-related apoptosis inducing ligand (TRAIL) was also elucidated and characterized. SBL induced tumor-selective cytotoxicity that was attributed to induction of apoptosis. Combinatorial treatment of SBL and TRAIL showed synergistic apoptosis-inducing effect. Additional experiments revealed that Bid was the mediating molecule for the synergistic effect in SBL and TRAIL. These results suggested that SBL could be a promising candidate for the therapeutics for malignant mesothelioma. Furthermore, the combinatorial treatment of SBL and TRAIL could be an effective regimen against malignant mesothelioma.

Antitumor Potential of Marine and Freshwater Lectins

“…Indeed, the antitumor activity of SBLc decreases with the increase of differentiation of both hepatoma [121] and leukemia cells [118]. SBLc does not affect any of the several non-transformed cell lines tested that are all characterized by a high degree of differentiation: fibroblasts [109,120,121,133,139], epidermal melanocytes [109], keratinocytes [109], and mesothelial cells [110].…”

“…In other words, as Aristotle would suggest, in medio stat virtus. When inside the cell, SBLc activates the intrinsic apoptotic pathway on more than 30 tumor cell lines representing leukemia [107][108][109]118,120,131,132], Burkitt's lymphoma [108,109], cervical [133], hepatocellular [120,121,133], and estrogen-positive and -negative breast carcinomas [113,114,116,117,120], glioblastoma [119], and malignant mesothelioma [110,113] (Table 3).…”

“…Just as in a jigsaw puzzle, many studies have tried to elucidate the proper molecular mechanism of action of SBLc. The pieces of the puzzles are a tumor-specific mechanism of action, the activation of the intrinsic apoptotic pathway with the involvement of heat shock protein 70 (HSP70) and the phosphorylation of p38 MAPK [108,110,116,120,134,135]. The role of the lectin part of SBLc is to select cancer cells through the binding of specific sialic acid carbohydrates residues; then, specific receptors allow it to penetrate the cells, where the RNAse activity promotes the cleavage of RNA.…”

“…If cisplatin sharply increases p21 expression, SBLc antagonizes it, resulting in a lack of synergy [112]. In the case of SBLc plus TNF-related apoptosis-inducing ligand, a synergistic effect on H28 cells has been recorded, probably caused by an enhancement in the cleavage of the proapoptotic protein Bid that reinforces caspase activation [110]. SBLc also synergizes the antitumor cytotoxicity of interferon-γ (IFN-γ) in a cell-type-dependent way on different cell lines.…”

Conformational study reveals amino acid residues essential for hemagglutinating and anti-proliferative activities of <italic>Clematis montana</italic> lectin

“…Notably, several plant lectins have been shown to induce apoptotic cancer cell death [27,28], but the mechanism is still not clear. In our previous study, we reported the extraordinary antitumor activity of CML and determined its N-terminal amino acid sequence as DNVKYSGQVKNTGSA [7].…”